Patent Publication Number: US-2003235831-A1

Title: Nucleic acids, proteins, and antibodies

Description:
STATEMENT UNDER 37 C.F.R. § 1.77(b)(4)  
     [0001] This application refers to a “Sequence Listing” listed below, which is provided as an electronic document on two identical compact discs (CD-R), labeled “Copy 1” and “Copy 2.” These compact discs each contain the file “PC003C1_seqList.txt” (2,329,258 bytes, created on Sep. 13, 2002), which is hereby incorporated in its entirety herein.  
     [0002] The Sequence Listing may be viewed on an IBM-PC machine running the MS-Windows operating system. 
    
    
     
       FIELD OF THE INVENTION  
       [0003] The present invention relates to novel excretory system related polynucleotides, the polypeptides encoded by these polynucleotides herein collectively referred to as “excretory system antigens,” and antibodies that immunospecifically bind these polypeptides, and the use of such excretory system polynucleotides, antigens, and antibodies for detecting, treating, preventing and/or prognosing disorders of the excretory system, including, but not limited to, the presence of cancer of excretory system tissues and cancer metastases. More specifically, isolated excretory system nucleic acid molecules are provided encoding novel excretory system polypeptides. Novel excretory system polypeptides and antibodies that bind to these polypeptides are provided. Also provided are vectors, host cells, and recombinant and synthetic methods for producing human excretory system polynucleotides, polypeptides, and/or antibodies. The invention further relates to diagnostic and therapeutic methods useful for diagnosing, treating, preventing and/or prognosing disorders related to the excretory system, including cancer of excretory system tissues, and therapeutic methods for treating such disorders. The invention further relates to screening methods for identifying agonists and antagonists of polynucleotides and polypeptides of the invention. The invention further relates to methods and/or compositions for inhibiting or promoting the production and/or function of the polypeptides of the invention.  
       BACKGROUND OF THE INVENTION  
       [0004] The Human Excretory System is comprised of specialized organs and body tissues responsible for the removal of metabolic wastes and the retention of the proper amounts of water, salts, and nutrients. Components of this system include liver, lungs, skin, and the urinary system. All of these organs work synergistically to keep the body&#39;s water, salts, and nutrients level properly balanced.  
       [0005] The urinary system is a subgroup of organs, consisting of the kidneys, ureters, bladder, and uretha, specialized in removing waste materials and water from the blood. This waste is generated from the normal breakdown of food and other energy sources and is translated into urine as it passes through the kidneys. The kidneys perform a complex chemical exchange with the blood, where waste products are filtered out into the urinary system while essential water and conserved molecules (e.g. sodium, phosphorous, and potassium) are reabsorbed into the blood.  
       [0006] Kidneys also release three important hormones into the body. Erythropoietin, or EPO, stimulates the production of red blood cells in bone marrow. Renin is important for regulating blood pressure. The kidneys also release the active form of vitamin D, which is essential for the maintenance of calcium in the bones and for normal chemical balance in the body.  
       [0007] Once waste, in the form of urine, is released from the kidneys, it travels down two thin tubes called ureters to the bladder. The bladder is a hollow, balloon-shaped organ responsible for storing urine until the nerves in the bladder cause the need for urination.  
       [0008] Excretory diseases most commonly affect the kidneys and the bladder. Disorders range in severity from easily treatable to life threatening. Generally, the two most common causes of kidney disease are diabetes (diabetic nephropathy) and hypertension. Diabetes is a disease resulting from an excess of sugar in the bloodstream. Damage done to the nephrons of the kidney by this sugar excess is called diabetic nephropathy. High blood pressure can damage the small blood vessels in the kidney impairing the waste removal function of these vessels.  
       [0009] Damage from trauma or poisons may also lead to kidney disease. For instance, interstitial nephritis may occur with an allergic reaction to a drug or as a side effect of medications and involves inflammation of the spaces between the renal tubes and glomeruli. Interstitial nephritis causes reduction in kidney function including decreased urine output and other signs of renal failure.  
       [0010] Kidney disease is not an exclusive result of external factors. Hereditary factors may also contribute to kidney disease. For example, polycystic kidney disease (PKD), is a genetic disorder where many cysts grow on the kidney, reducing its mass and function, and eventually resulting in kidney failure. Congenital nephrotic syndrome is an inherited disorder, primarily affecting families of Finnish origin, characterized by protein in the urine and swelling of the body. The disorder develops shortly after birth, results in infection, malnutrition, and kidney failure, and is usually fatal with the first year.  
       [0011] Goodpasture&#39;s syndrome is a form of rapidly progressive glomerulonephritis and pulmonary bleeding characterized by deposits of antibodies in the basement membranes of both the kidney glomerulus and the lung alveoli. It is an autoimmune disorder that may be triggered by a viral infection or inhalation of hydrocarbon solvents such as gasoline. Smoking has been found to increase the risk of developing this order. There can also be an inherited predisposition to Goodpasture&#39;s syndrome.  
       [0012] Kidney disease may also result from the malfunction of the body&#39;s basic functions. Nephrocalcinosis is a disorder where an excess of calcium and oxalate or phosphate is deposited in the renal tubules and interstitium resulting in reduced kidney function. Fragments of the calcium oxalate or calcium phosphate may break free from the kidney and form stones.  
       [0013] IgM mesangial proliferative glomerulonephritis is caused by the inflammation of the glomerulus, the enlargement of certain glomerular cells, and the IgM antibody deposits in the mesangium layer of the glomerular capillary. The disorder is characterized by edema and bloody or dark urine. The trigger for this condition is unknown but it may be the result of some type of immune response. Although IgM mesangial proliferative glomerulonephritis is rare, it can affect both adults and children and may progress to renal failure.  
       [0014] Membranoproliferative glomerulonephritis I and II are disorders caused by an abnormal immune response resulting in deposits of antibodies in the kidneys. Mesangial cells are increased in number and parts of the glomerular membrane changes in structure. These changes make the glomerulus permeable to protein and blood cells which may result in edema, hypertension, azotemia, or ultimately, chronic renal failure.  
       [0015] Unfortunately, there are no cures for kidney disease. Currently, treatment has revolved around reduction of symptoms, prevention of complications, and slowed progression of the disorder towards kidney failure, mostly through diet and medications. However, once kidney failure ensues, only dialysis or transplantation is remotely effective in prolonging life.  
       [0016] Several types of cancer can develop in the kidney. For example, the most common adult form of kidney cancer is hypernephroma, or renal cell cancer. This cancer affects the filtering of blood and production of urine by developing in the lining of the renal tubules. A less common form, called transitional cell cancer, develops in the lining of the bladder, ureter, or renal pelvis. Wilm&#39;s tumor, the most common intraabdominal tumor in children and the most common type of kidney tumor, develops in children usually under the age of five. The cause of this tumor is unknown, but it probably develops in the fetal tissue.  
       [0017] Although surgery to remove the kidney, or nephrectomy, is the most common treatment for kidney cancer, several other therapies are available as alternatives. External radiotherapy is sometimes used to kill the cancer cells and relieve pain when the cancer has spread to the bone. Chemotherapy has been used infrequently to treat kidney cancer due to its limited effectiveness. Hormone therapy may also be used with patients with advanced kidney cancer to relieve pain. Immunotherapy has recently become a more popular alternative to surgery. Currently, interleukin-2 and interferon are types of immunotherapy used to treat advanced kidney cancer.  
       [0018] Bladder disorders, in which muscles in the bladder weaken, can result from aging, illness, or injury. Many of these disorders result in the same symptoms, for example, problems with urination, which complicates the accuracy of clearly diagnosing these diseases. Failure to effectively treat bladder disorders may result in further damage to the urinary system, especially the kidneys, as toxin may become backed up in the kidneys.  
       [0019] The most common bladder disorders are urinary incontinence and urinary retention. Urinary incontinence affects women more often than men and results in the loss of bladder control. Treatments range from exercise to surgery. Urinary retention can have many causes and results in the inability to urinate. Common causes can include obstruction in the urinary system, stress, bladder muscle failure, or nerve damage, and treatment regimens usually depend on the cause.  
       [0020] Other bladder disorders result in painful urination such as urinary tract infections, interstitial cystitis (IC), or prostatitis. Urinary tract infections (UTI) can be caused by bacterial infection. Several species that are known to cause urinary tract infections are  Escherichia coli, Staphylococcus saprophyticus,  Klebsiella,  Proteus mirabillis, Ureaplasma urealythicum,  and Entercocci. Treatment consists of a course of antibiotics or flushing out the bacteria by consuming plenty of fluids. Urinary tract infections are more common in women than men. In interstitial cystitis, also known as painful bladder syndrome and frequency-urgency-dysuria syndrome, the bladder wall becomes inflamed and irritated, resulting in stiffening of the bladder, decreased bladder capacity, pinpoint bleeding, and, in rare cases, ulcers in the bladder lining. No cause or reliable treatment for IC has been found.  
       [0021] Prostatitis is the inflammation of the prostate gland that results in urinary frequency or urgency, painful urination, and lower back/genital area pain. Some cases have been shown to be caused by bacterial infection and are treatable by antibiotics. However, in most instances, prostatitis is not associated with any known infectious agent and is unaffected by antibiotic treatment.  
       [0022] The bladder can also be susceptible to cancer. About 90 percent of bladder cancers begin in the bladder lining and are called transitional cell carcinomas. If the cancer is confined to the lining of the bladder, e.g., superficial bladder cancer, it can be readily treated. However, the cancer can recur, and most often, it recurs as another superficial cancer.  
       [0023] Treatment of bladder cancer depends on the stage of the disease and if, or how deeply, the cancer has invaded the bladder wall. Surgery is the most common treatment of bladder cancer, the extent depending on the stage of the disease. Surgery to remove part or all of the bladder is called cystectomy. Superficial bladder cancer may be treated at the time of diagnosis by a transurethral resection (TUR) to remove the cancer or bum away the cancer cells with an electric current, e.g. fulguration.  
       [0024] Alternative therapies are available to treat bladder cancer. Either external or internal radiotherapy may be used to kill the cancer cells. Chemotherapy can also be used alone or in combination with surgery and/or radiation therapy or after TUR with fulguration to treat superficial bladder cancer. Chemotherapy can be administered intravesically through a catheter directly through the urethra or can be administered systemically through intravenous injection.  
       [0025] In addition, superficial bladder cancer can be treated with immunotherapy. Currently, BCG (bacille calmette-Guerin) vaccine, an anticancer drug, is placed in the bladder for several hours to stimulate the body&#39;s natural immune system. Like chemotherapy, immunotherapy can be used alone to treat superficial bladder cancer or after TUR with fulguration to help prevent the cancer from recurring. Other forms of immunotherapy are also being studied for other stages of bladder cancer.  
       [0026] Cancer of the bladder can also become malignant (e.g., invasive bladder cancer), growing through the bladder wall and spread to nearby organs. Most commonly, the cancer cells spread to the lymph nodes surrounding the bladder and require more aggressive treatments. For invasive bladder cancer, a radical cystectomy is the most recommended treatment where the entire bladder, nearby lymph nodes, and any surrounding organs containing cancerous cells are removed.  
       [0027] Diseases affecting the ureters ultimately result in damage to the kidneys. Chronic (e.g., slow, progressive) and acute (e.g., sudden) unilateral obstructive uropathy occurs when one of ureter becomes blocked, resulting in the backup of urine into the kidney. These disorders do not cause kidney failure if there are two functioning kidneys; however, they may result in permanent damage to the kidney with distention of the renal pelvis and calysces or may cause hypertension. Reflux nephropathy also causes internal kidney structure damage from the backup of urine by the malfunction of the valve-like mechanisms between the ureters and bladder. The backup of urine may expose the kidneys to pyelonephritis and may lead to chronic renal failure and end-stage renal disease if not properly treated. Treatments for these diseases may involve antibiotics (e.g., for simple reflux) or may require ureteral reimplantation or reconstructive repair.  
       [0028] Carcinoma of the ureter usually manifests as either transitional cell cancer or squamous cell carcinoma. This cancer is closely associated with and treated as kidney cancer. Cancer of the urethra is a rare, mostly malignant type of cancer that occurs more often in women than men. Prognosis and treatment depend on the anatomical location and the depth of invasion. Superficial tumors, located in the anterior urethra are generally curable; however, deeply invasive lesions or lesions in the posterior urethra are rarely curable by any known combinations of therapy.  
       [0029] The discovery of novel human excretory system associated polynucleotides and the polypeptides encoded by them satisfies a need in the art by providing new compositions which are useful in the diagnosis, and treatment, prevention and/or prognosis of diseases or disorders of the urinary system, including, but not limited to, renal disorders (e.g., kidney failure, nephritis, blood vessel disorders of kidney, metabolic and congenital kidney disorders, urinary disorders of the kidney, autoimmune disorders, sclerosis and necrosis, and electrolyte imbalance, and kidney cancer), bladder disorders (e.g, urinary tract infection, bladder obstruction, urination disorders, and bladder cancer), urether disorders (e.g., obstruction of the ureter and ureter cancer), urethra disorders (e.g., obstruction of the urethra and urethra cancers) and/or those disorders as discribed under “Urinary System Disorders” below.  
       SUMMARY OF THE INVENTION  
       [0030] The present invention relates to novel excretory system related polynucleotides, the polypeptides encoded by these polynucleotides herein collectively referred to as “excretory system antigens,” and antibodies that immunospecifically bind these polypeptides, and the use of such excretory system polynucleotides, antigens, and antibodies for detecting, treating, preventing and/or prognosing disorders of the excretory system, including, but not limited to, the presence of cancer of excretory system tissues and cancer metastases. More specifically, isolated excretory system nucleic acid molecules are provided encoding novel excretory system polypeptides. Novel excretory system polypeptides and antibodies that bind to these polypeptides are provided. Also provided are vectors, host cells, and recombinant and synthetic methods for producing human excretory system polynucleotides, polypeptides, and/or antibodies. The invention further relates to diagnostic and therapeutic methods useful for diagnosing, treating, preventing and/or prognosing disorders related to the excretory system, including cancer of excretory system tissues, and therapeutic methods for treating such disorders. The invention further relates to screening methods for identifying agonists and antagonists of polynucleotides and polypeptides of the invention. The invention further relates to methods and/or compositions for inhibiting or promoting the production and/or function of the polypeptides of the invention.  
       DETAILED DESCRIPTION  
       [0031] Tables  
       [0032] Table 1A summarizes some of the polynucleotides encompassed by the invention (including cDNA clones related to the sequences (Clone ID NO: Z), contig sequences (contig identifier (Contig ID:) and contig nucleotide sequence identifier (SEQ ID NO: X)) and further summarizes certain characteristics of these polynucleotides and the polypeptides encoded thereby. The first column provides a unique clone identifier, “Clone ID NO: Z”, for a cDNA plasmid related to each excretory system associated contig sequence disclosed in Table 1A. The second column provides a unique contig identifier, “Contig ID:” for each of the contig sequences disclosed in Table 1A. The third column provides the sequence identifier, “SEQ ID NO: X”, for each of the contig polynucleotide sequences disclosed in Table 1A. The fourth column, “ORF (From-To)”, provides the location (i.e., nucleotide position numbers) within the polynucleotide sequence of SEQ ID NO: X that delineate the preferred open reading frame (ORF) shown in the sequence listing and referenced in Table 1A as SEQ ID NO: Y (column 5). Column 6 lists residues comprising predicted epitopes contained in the polypeptides encoded by each of the preferred ORFs (SEQ ID NO: Y). Identification of potential immunogenic regions was performed according to the method of Jameson and Wolf (CABIOS, 4:181-186 (1988)); specifically, the Genetics Computer Group (GCG) implementation of this algorithm, embodied in the program PEPTIDESTRUCTURE (Wisconsin Package v10.0, Genetics Computer Group (GCG), Madison, Wis.). This method returns a measure of the probability that a given residue is found on the surface of the protein. Regions where the antigenic index score is greater than 0.9 over at least 6 amino acids are indicated in Table 1A as “Predicted Epitopes.” In particular embodiments, excretory system associated polypeptides of the invention comprise, or alternatively consist of, one, two, three, four, five or more of the predicted epitopes described in Table 1A. It will be appreciated that depending on the analytical criteria used to predict antigenic determinants, the exact address of the determinant may vary slightly. Column 7, “Tissue Distribution” shows the expression profile of tissue, cells, and/or cell line libraries, which express the polynucleotides of the invention. The number in column 7 (preceding the colon), represents the tissue/cell source identifier code corresponding to the code and description provided in Table 4. Expression of these polynucleotides was not observed in the other tissues and/or cell libraries tested. For those identifier codes in which the first two letters are not “AR”, the second number in column 7 (following the colon) represents the number of times a sequence corresponding to the reference polynucleotide sequence (e.g., SEQ ID NO: X) was identified in the tissue/cell source. Those tissue/cell source identifier codes in which the first two letters are “AR” designate information generated using DNA array technology. Utilizing this technology, cDNAs were amplified by PCR and then transferred, in duplicate, onto the array. Gene expression was assayed through hybridization of first strand cDNA probes to the DNA array. cDNA probes were generated from total RNA extracted from a variety of different tissues and cell lines. Probe synthesis was performed in the presence of  33 P dCTP, using oligo(dT) to prime reverse transcription. After hybridization, high stringency washing conditions were employed to remove non-specific hybrids from the array. The remaining signal, emanating from each gene target, was measured using a Phosphorimager. Gene expression was reported as Phosphor Stimulating Luminescence (PSL) which reflects the level of phosphor signal generated from the probe hybridized to each of the gene targets represented on the array. A local background signal subtraction was performed before the total signal generated from each array was used to normalize gene expression between the different hybridizations. The value presented after “[array code]:” represents the mean of the duplicate values, following background subtraction and probe normalization. One of skill in the art could routinely use this information to identify normal and/or diseased tissue(s) which show a predominant expression pattern of the corresponding polynucleotide of the invention or to identify polynucleotides which show predominant and/or specific tissue and/or cell expression. Column 8, “Cytologic Band,” provides the chromosomal location of polynucleotides corresponding to SEQ ID NO: X. Chromosomal location was determined by finding exact matches to EST and cDNA sequences contained in the NCBI (National Center for Biotechnology Information) UniGene database. Given a presumptive chromosomal location, disease locus association was determined by comparison with the Morbid Map, derived from Online Mendelian Inheritance in Man (Online Mendelian Inheritance in Man, OMIM™. McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University (Baltimore, Md.) and National Center for Biotechnology Information, National Library of Medicine (Bethesda, Md.) 2000. World Wide Web URL: http://www.ncbi.nlm.nih.gov/omim/). If the putative chromosomal location of the Query overlapped with the chromosomal location of a Morbid Map entry, an OMIM identification number is provided in Table 1A, column 9 labeled “OMIM Disease Reference(s)”. A key to the OMIM reference identification numbers is provided in Table 5.  
       [0033] Table 1B summarizes additional polynucleotides encompassed by the invention (including cDNA clones related to the sequences (Clone ID NO: Z), contig sequences (contig identifier (Contig ID:) contig nucleotide sequence identifiers (SEQ ID NO: X)), and genomic sequences (SEQ ID NO: B). The first column provides a unique clone identifier, “Clone ID NO: Z”, for a cDNA clone related to each contig sequence. The second column provides the sequence identifier, “SEQ ID NO: X”, for each contig sequence. The third column provides a unique contig identifier, “Contig ID:” for each contig sequence. The fourth column, provides a BAC identifier “BAC ID NO: A” for the BAC clone referenced in the corresponding row of the table. The fifth column provides the nucleotide sequence identifier, “SEQ ID NO: B” for a fragment of the BAC clone identified in column four of the corresponding row of the table. The sixth column, “Exon From-To”, provides the location (i.e., nucleotide position numbers) within the polynucleotide sequence of SEQ ID NO: B which delineate certain polynucleotides of the invention that are also exemplary members of polynucleotide sequences that encode polypeptides of the invention (e.g., polypeptides containing amino acid sequences encoded by the polynucleotide sequences delineated in column six, and fragments and variants thereof).  
       [0034] Table 2 summarizes homology and features of some of the polypeptides of the invention. The first column provides a unique clone identifier, “Clone ID NO: Z”, corresponding to a cDNA disclosed in Table 1A. The second column provides the unique contig identifier, “Contig ID:” corresponding to contigs in Table 1A and allowing for correlation with the information in Table 1A. The third column provides the sequence identifier, “SEQ ID NO: X”, for the contig polynucleotide sequences. The fourth column provides the analysis method by which the homology/identity disclosed in the row was determined. Comparisons were made between polypeptides encoded by the polynucleotides of the invention and either a non-redundant protein database (herein referred to as “NR”), or a database of protein families (herein referred to as “PFAM”) as further described below. The fifth column provides a description of PFAM/NR hits having significant matches to a polypeptide of the invention. Column six provides the accession number of the PFAM/NR hit disclosed in the fifth column. Column seven, “Score/Percent Identity”, provides a quality score or the percent identity, of the hit disclosed in column five. Columns 8 and 9, “NT From” and “NT To” respectively, delineate the polynucleotides in “SEQ ID NO: X” that encode a polypeptide having a significant match to the PFAM/NR database as disclosed in the fifth column. In specific embodiments, polypeptides of the invention comprise, or alternatively consist of, an amino acid sequence encoded by the polynucleotides in SEQ ID NO: X as delineated in columns 8 and 9, or fragments or variants thereof.  
       [0035] Table 3 provides polynucleotide sequences that may be disclaimed according to certain embodiments of the invention. The first column provides a unique clone identifier, “Clone ID NO: Z”, for a cDNA clone related to excretory system associated contig sequences disclosed in Table 1A. The second column provides the sequence identifier, “SEQ ID NO: X”, for contig polynucleotide sequences disclosed in Table 1A. The third column provides the unique contig identifier, “Contig ID”, for contigs disclosed in Table 1A. The fourth column provides a unique integer ‘a’ where ‘a’ is any integer between 1 and the final nucleotide minus 15 of SEQ ID NO: X, represented as “Range of a”, and the fifth column provides a unique integer ‘b’ where ‘b’ is any integer between 15 and the final nucleotide of SEQ ID NO: X, represented as “Range of b”, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO: X, and where b is greater than or equal to a +14. For each of the polynucleotides shown as SEQ ID NO: X, the uniquely defined integers can be substituted into the general formula of a−b, and used to describe polynucleotides which may be preferably excluded from the invention. In certain embodiments, preferably excluded from the polynucleotides of the invention (including polynucleotide fragments and variants as described herein and diagnostic and/or therapeutic uses based on these polynucleotides) are at least one, two, three, four, five, ten, or more of the polynucleotide sequence(s) having the accession number(s) disclosed in the sixth column of this Table (including for example, published sequence in connection with a particular BAC clone). In further embodiments, preferably excluded from the invention are the specific polynucleotide sequence(s) contained in the clones corresponding to at least one, two, three, four, five, ten, or more of the available material having the accession numbers identified in the sixth column of this Table (including for example, the actual sequence contained in an identified BAC clone).  
       [0036] Table 4 provides the key to the tissue/cell source identifier code disclosed in Table 1A, column 7. Column 1 provides a key to the tissue/cell source identifier code disclosed in Table 1A, Column 7. Columns 2-5 provide a description of the tissue or cell source. Codes corresponding to diseased tissues are indicated in column 6 with the word “disease”. The use of the word “disease” in column 6 is non-limiting. The tissue or cell source may be specific (e.g. a neoplasm), or may be disease-associated (e.g., a tissue sample from a normal portion of a diseased organ). Furthermore, tissues and/or cells lacking the “disease” designation may still be derived from sources directly or indirectly involved in a disease state or disorder, and therefore may have a further utility in that disease state or disorder. In numerous cases where the tissue/cell source is a library, column 7 identifies the vector used to generate the library.  
       [0037] Table 5 provides a key to the OMIM™ reference identification numbers disclosed in Table 1A, column 9. OMIM reference identification numbers (Column 1) were derived from Online Mendelian Inheritance in Man (Online Mendelian Inheritance in Man, OMIM™. McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University (Baltimore, Md.) and National Center for Biotechnology Information, National Library of Medicine, (Bethesda, Md.) 2000. World Wide Web URL: http://www.ncbi.nlm.nih.gov/omim/). Column 2 provides diseases associated with the cytologic band disclosed in Table 1A, column 8, as determined from the Morbid Map database.  
       [0038] Table 6 summarizes ATCC Deposits, Deposit dates, and ATCC designation numbers of deposits made with the ATCC in connection with the present application.  
       [0039] Table 7 shows the cDNA libraries sequenced, tissue source description, vector information and ATCC designation numbers relating to these cDNA libraries.  
       [0040] Table 8 provides a physical characterization of clones encompassed by the invention. The first column provides the unique clone identifier, “Clone ID NO: Z”, for certain cDNA clones of the invention, as described in Table 1A. The second column provides the size of the cDNA insert contained in the corresponding cDNA clone.  
       [0041] Definitions  
       [0042] The following definitions are provided to facilitate understanding of certain terms used throughout this specification.  
       [0043] In the present invention, “isolated” refers to material removed from its original environment (e.g., the natural environment if it is naturally occurring), and thus is altered “by the hand of man” from its natural state. For example, an isolated polynucleotide could be part of a vector or a composition of matter, or could be contained within a cell, and still be “isolated” because that vector, composition of matter, or particular cell is not the original environment of the polynucleotide. The term “isolated” does not refer to genomic or cDNA libraries, whole cell total or mRNA preparations, genomic DNA preparations (including those separated by electrophoresis and transferred onto blots), sheared whole cell genomic DNA preparations or other compositions where the art demonstrates no distinguishing features of the polynucleotide sequences of the present invention.  
       [0044] As used herein, a “polynucleotide” refers to a molecule having a nucleic acid sequence encoding SEQ ID NO: Y or a fragment or variant thereof, a nucleic acid sequence contained in SEQ ID NO: X (as described in column 3 of Table 1A) or the complement thereof, a cDNA sequence contained in Clone ID NO: Z (as described in column 1 of Table 1A and contained within a library deposited with the ATCC); a nucleotide sequence encoding the polypeptide encoded by a nucleotide sequence in SEQ ID NO: B as defined in column 6 of Table 1B or a fragment or variant thereof, or a nucleotide coding sequence in SEQ ID NO: B as defined in column 6 of Table 1B or the complement thereof. For example, the polynucleotide can contain the nucleotide sequence of the full length cDNA sequence, including the 5′ and 3′ untranslated sequences, the coding region, as well as fragments, epitopes, domains, and variants of the nucleic acid sequence. Moreover, as used herein, a “polypeptide” refers to a molecule having an amino acid sequence encoded by a polynucleotide of the invention as broadly defined (obviously excluding poly-Phenylalanine or poly-Lysine peptide sequences which result from translation of a polyA tail of a sequence corresponding to a cDNA).  
       [0045] As used herein, an “excretory system antigen” refers collectively to any polynucleotide disclosed herein (e.g., a nucleic acid sequence contained in SEQ ID NO: X or the complement therof, or cDNA sequence contained in Clone ID NO: Z, or a nucleotide sequence encoding the polypeptide encoded by a nucleotide sequence in SEQ ID NO: B as defined in column 6 of Table 1B, or a nucleotide coding sequence in SEQ ID NO: B as defined in column 6 of Table 1B or the complement thereof and fragments or variants thereof as described herein) or any polypeptide disclosed herein (e.g., an amino acid sequence contained in SEQ ID NO: Y, an amino acid sequence encoded by SEQ ID NO: X, or the complement thereof, an amino acid sequence encoded by the cDNA sequence contained in Clone ID NO: Z, an amino acid sequence encoded by SEQ ID NO: B, or the complement thereof, and fragments or variants thereof as described herein). These excretory system antigens have been determined to be predominantly expressed in excretory system tissues, including normal or diseased tissues (as shown in Table 1A column 7 and Table 4).  
       [0046] In the present invention, “SEQ ID NO: X” was often generated by overlapping sequences contained in multiple clones (contig analysis). A representative clone containing all or most of the sequence for SEQ ID NO: X is deposited at Human Genome Sciences, Inc. (HGS) in a catalogued and archived library. As shown, for example, in column 1 of Table 1A, each clone is identified by a cDNA Clone ID (identifier generally referred to herein as Clone ID NO: Z). Each Clone ID is unique to an individual clone and the Clone ID is all the information needed to retrieve a given clone from the HGS library. Furthermore, certain clones disclosed in this application have been deposited with the ATCC on Oct. 5, 2000, having the ATCC designation numbers PTA 2574 and PTA 2575; and on Jan. 5, 2001, having the depositor reference numbers TS-1, TS-2, AC-1, and AC-2. In addition to the individual cDNA clone deposits, most of the cDNA libraries from which the clones were derived were deposited at the American Type Culture Collection (hereinafter “ATCC”). Table 7 provides a list of the deposited cDNA libraries. One can use the Clone ID NO: Z to determine the library source by reference to Tables 6 and 7. Table 7 lists the deposited cDNA libraries by name and links each library to an ATCC Deposit. Library names contain four characters, for example, “HTWE.” The name of a cDNA clone (Clone ID NO: Z) isolated from that library begins with the same four characters, for example “HTWEP07”. As mentioned below, Table 1A correlates the Clone ID NO: Z names with SEQ ID NO: X. Thus, starting with an SEQ ID NO: X, one can use Tables 1A, 6 and 7 to determine the corresponding Clone ID NO: Z, which library it came from and which ATCC deposit the library is contained in. Furthermore, it is possible to retrieve a given cDNA clone from the source library by techniques known in the art and described elsewhere herein. The ATCC is located at 10801 University Boulevard, Manassas, Va. 20110-2209, USA. The ATCC deposits were made pursuant to the terms of the Budapest Treaty on the international recognition of the deposit of microorganisms for the purposes of patent procedure.  
       [0047] In specific embodiments, the polynucleotides of the invention are at least 15, at least 30, at least 50, at least 100, at least 125, at least 500, or at least 1000 continuous nucleotides but are less than or equal to 300 kb, 200 kb, 100 kb, 50 kb, 15 kb, 10 kb, 7.5 kb, 5 kb, 2.5 kb, 2.0 kb, or 1 kb, in length. In a further embodiment, polynucleotides of the invention comprise a portion of the coding sequences, as disclosed herein, but do not comprise all or a portion of any intron. In another embodiment, the polynucleotides comprising coding sequences do not contain coding sequences of a genomic flanking gene (i.e., 5′ or 3′ to the gene of interest in the genome). In other embodiments, the polynucleotides of the invention do not contain the coding sequence of more than 1000, 500, 250, 100, 50, 25, 20, 15, 10, 5, 4, 3, 2, or 1 genomic flanking gene(s).  
       [0048] A “polynucleotide” of the present invention also includes those polynucleotides capable of hybridizing, under stringent hybridization conditions, to sequences contained in SEQ ID NO: X, or the complement thereof (e.g., the complement of any one, two, three, four, or more of the polynucleotide fragments described herein), the polynucleotide sequence delineated in columns 8 and 9 of Table 2 or the complement thereof, and/or cDNA sequences contained in Clone ID NO: Z (e.g., the complement of any one, two, three, four, or more of the polynucleotide fragments, or the cDNA clone within the pool of cDNA clones deposited with the ATCC, described herein) and/or the polynucleotide sequence delineated in column 6 of Table 1B or the complement thereof “Stringent hybridization conditions” refers to an overnight incubation at 42 degree C. in a solution comprising 50% formamide, 5×SSC (750 mM NaCl, 75 mM trisodium citrate), 50 mM sodium phosphate (pH 7.6), 5× Denhardt&#39;s solution, 10% dextran sulfate, and 20 μg/ml denatured, sheared salmon sperm DNA, followed by washing the filters in 0.1×SSC at about 65 degree C.  
       [0049] Also contemplated are nucleic acid molecules that hybridize to the polynucleotides of the present invention at lower stringency hybridization conditions. Changes in the stringency of hybridization and signal detection are primarily accomplished through the manipulation of formamide concentration (lower percentages of formamide result in lowered stringency), salt conditions, or temperature. For example, lower stringency conditions include an overnight incubation at 37 degree C. in a solution comprising 6×SSPE (20×SSPE=3M NaCl; 0.2M NaH 2 PO 4 ; 0.02M EDTA, pH 7.4), 0.5% SDS, 30% formamide, 100 ug/ml salmon sperm blocking DNA; followed by washes at 50 degree C. with 1×SSPE, 0.1% SDS. In addition, to achieve even lower stringency, washes performed following stringent hybridization can be done at higher salt concentrations (e.g. 5×SSC).  
       [0050] Note that variations in the above conditions may be accomplished through the inclusion and/or substitution of alternate blocking reagents used to suppress background in hybridization experiments. Typical blocking reagents include Denhardt&#39;s reagent, BLOTTO, heparin, denatured salmon sperm DNA, and commercially available proprietary formulations. The inclusion of specific blocking reagents may require modification of the hybridization conditions described above, due to problems with compatibility.  
       [0051] Of course, a polynucleotide which hybridizes only to polyA+ sequences (such as any 3′ terminal polyA+ tract of a cDNA shown in the sequence listing), or to a complementary stretch of T (or U) residues, would not be included in the definition of “polynucleotide,” since such a polynucleotide would hybridize to any nucleic acid molecule containing a poly (A) stretch or the complement thereof (e.g., practically any double-stranded cDNA clone generated using oligo dT as a primer).  
       [0052] The polynucleotide of the present invention can be composed of any polyribonucleotide or polydeoxribonucleotide, which may be unmodified RNA or DNA or modified RNA or DNA. For example, polynucleotides can be composed of single- and double-stranded DNA, DNA that is a mixture of single- and double-stranded regions, single- and double-stranded RNA, and RNA that is mixture of single- and double-stranded regions, hybrid molecules comprising DNA and RNA that may be single-stranded or, more typically, double-stranded or a mixture of single- and double-stranded regions. In addition, the polynucleotide can be composed of triple-stranded regions comprising RNA or DNA or both RNA and DNA. A polynucleotide may also contain one or more modified bases or DNA or RNA backbones modified for stability or for other reasons. “Modified” bases include, for example, tritylated bases and unusual bases such as inosine. A variety of modifications can be made to DNA and RNA; thus, “polynucleotide” embraces chemically, enzymatically, or metabolically modified forms.  
       [0053] The polypeptide of the present invention can be composed of amino acids joined to each other by peptide bonds or modified peptide bonds, i.e., peptide isosteres, and may contain amino acids other than the 20 gene-encoded amino acids. The polypeptides may be modified by either natural processes, such as posttranslational processing, or by chemical modification techniques which are well known in the art. Such modifications are well described in basic texts and in more detailed monographs, as well as in a voluminous research literature. Modifications can occur anywhere in a-polypeptide, including the peptide backbone, the amino acid side-chains and the amino or carboxyl termini. It will be appreciated that the same type of modification may be present in the same or varying degrees at several sites in a given polypeptide. Also, a given polypeptide may contain many types of modifications. Polypeptides may be branched, for example, as a result of ubiquitination, and they may be cyclic, with or without branching. Cyclic, branched, and branched cyclic polypeptides may result from posttranslation natural processes or may be made by synthetic methods. Modifications include acetylation, acylation, ADP-ribosylation, amidation, covalent attachment of flavin, covalent attachment of a heme moiety, covalent attachment of a nucleotide or nucleotide derivative, covalent attachment of a lipid or lipid derivative, covalent attachment of phosphotidylinositol, cross-linking, cyclization, disulfide bond formation, demethylation, formation of covalent cross-links, formation of cysteine, formation of pyroglutamate, formylation, gamma-carboxylation, glycosylation, GPI anchor formation, hydroxylation, iodination, methylation, myristoylation, oxidation, pegylation, proteolytic processing, phosphorylation, prenylation, racemization, selenoylation, sulfation, transfer-RNA mediated addition of amino acids to proteins such as arginylation, and ubiquitination. (See, for instance, PROTEINS—STRUCTURE AND MOLECULAR PROPERTIES, 2nd Ed., T. E. Creighton, W. H. Freeman and Company, New York (1993); POSTTRANSLATIONAL COVALENT MODIFICATION OF PROTEINS, B. C. Johnson, Ed., Academic Press, New York, pgs. 1-12 (1983); Seifter et al., Meth. Enzymol. 182:626-646 (1990); Rattan et al., Ann. N.Y. Acad. Sci. 663:48-62 (1992).)  
       [0054] “SEQ ID NO: X” refers to a polynucleotide sequence described, for example, in Tables 1A or 2, while “SEQ ID NO: Y” refers to a polypeptide sequence described in column 5 of Table 1A. SEQ ID NO: X is identified by an integer specified in column 3 of Table 1A. The polypeptide sequence SEQ ID NO: Y is a translated open reading frame (ORF) encoded by polynucleotide SEQ ID NO: X. “Clone ID NO: Z” refers to a cDNA clone described in column 1 of Table 1A.  
       [0055] “A polypeptide having biological activity” refers to a polypeptide exhibiting activity similar to, but not necessarily identical to, an activity of a polypeptide of the present invention, including mature forms, as measured in a particular biological assay, with or without dose dependency. In the case where dose dependency does exist, it need not be identical to that of the polypeptide, but rather substantially similar to the dose-dependence in a given activity as compared to the polypeptide of the present invention (i.e., the candidate polypeptide will exhibit greater activity or not more than about 25-fold less and, preferably, not more than about tenfold less activity, and most preferably, not more than about three-fold less activity relative to the polypeptide of the present invention).  
       [0056] Table 1A summarizes some of the excretory system associated polynucleotides encompassed by the invention (including contig sequences (SEQ ID NO: X) and clones (Clone ID NO: Z) and further summarizes certain characteristics of these polynucleotides and the polypeptides encoded thereby.  
       [0057] Polynucleotides and Polypeptides  
                                               TABLE 1A                                       AA       Tissue Distribution                               SEQ       Library code: count       OMIM       Clone ID   Contig   SEQ   ORF   ID       (see Table IV for   Cytologic   Disease       NO: Z   ID:   ID NO: X   (From-To)   NO: Y   Predicted Epitopes   Library Codes)   Band   Reference(s):                                                                    H7MBA84   625386   11   111-1    331   Ile-1 to Trp-16.   S0288: 2               H7MBC38   705707   12   98-3    332       S0288: 2       H7MBD34   928552   13   72-1    333       S0288: 2       HBAFB96   573392   14    55-219   334       H0411: 2       HBAGJ74   945133   15    8-256   335   Phe-1 to Leu-7,   AR089: 3, AR061: 2                           Gly-16 to Gln-23.   H0411: 2           947471   326   264-181   646       HBAGK69   881903   16    59-499   336   Ser-20 to Ser-31,   H0411: 2, L0163: 1                           Asp-36 to Gly-41,   and L0485: 1.                           Leu-45 to Arg-56.       HBAGU08   959191   17   119-289   337   Gly-29 to Arg-37.   H0411: 2       HBAMC12   968816   18    2-325   338   Gln-9 to Ser-14,   H0410: 2                           Ser-85 to Lys-98.       HBAMC47   854049   19   367-522   339       H0410: 3       HBAMC68   849402   20   197-298   340   Ser-7 to Glu-16.   H0410: 2       HBAMC92   572947   21   225-377   341   Glu-5 to Met-13,   H0410: 2                           Ile-22 to Asn-33.       HCKAA13   534965   22   211-360   342       H0119: 2       HCKAA41   694397   23    2-211   343   Thr-18 to Cys-24.   H0431: 1 and H0119:                               1.       HFKCJ86   504445   24   154-44    344       AR051: 20, AR054:                               16, AR050: 10                               H0012: 2       HFKEA55   530256   25    1-168   345   Gln-17 to Leu-24.   H0012: 2       HFKEA65   932094   26   350-481   346       H0620: 6 and H0012:                               3.       HFKEH40   523591   27    1-267   347   Pro-6 to Leu-14.   H0012: 3       HFKEJ40   909830   28    53-322   348   Thr-21 to Ala-28,   H0012: 2                           Asp-46 to Glu-56,                           Lys-69 to Thr-76.       HFKEJ77   529919   29    95-247   349       H0012: 1 and H0620:                               1.       HFKEM26   573949   30    85-183   350   Asn-7 to Lys-12,   H0012: 2                           Leu-22 to Trp-27.       HFKEM70   963178   31    1-327   351       H0012: 2 and H0620:                               1.       HFKEN74   974309   32    2-355   352   Pro-20 to Pro-27,   H0012: 3 and H0620:                           Ser-74 to Ser-81.   1.       HFKER27   926744   33   196-303   353   His-12 to Gly-17.   H0012: 1 and H0620:                               1.       HFKER69   918290   34   234-503   354   Glu-13 to Ala-28.   AR051: 25, AR050:                               20, AR054: 17                               H0620: 5 and H0012:                               2.       HFKEU09   855045   35    3-302   355   His-1 to Gly-7,   H0012: 2 and H0620:                           Ser-28 to Thr-33.   1.       HFKEW23   854952   36    98-415   356   Ser-56 to Trp-61.   H0620: 2, H0012: 1                               and L0775: 1.       HFKFB18   935988   37   156-365   357   Gly-1 to Pro-7.   H0012: 2 and H0620:                               2.       HFKFB23   675175   38   116-424   358   Ser-9 to Lys-18.   H0012: 2 and L0742:                               1.       HFKFB42   522037   39    82-318   359   Pro-21 to Thr-29.   H0012: 3       HFKFE05   932306   40    92-322   360   Glu-1 to Ser-8.   H0012: 1 and H0620:                               1.       HFKFE23   881475   41   165-545   361   Glu-12 to Ala-18,   H0620: 4 and H0012:                           Gln-46 to Glu-56.   3.       HFKFE59   854991   42    32-328   362   Glu-65 to Glu-72.   H0620: 2 and H0012:                               1.       HFKFI14   670322   43   198-398   363       AR051: 1, AR054: 1                               H0012: 3, H0620: 3,                               L0662: 1 and L0666: 1.           966320   327   144-407   647   Lys-26 to Val-37,                           Arg-40 to Val-47.       HFKFI22   930982   44    76-330   364   Arg-23 to Arg-28,   H0012: 1 and H0620:                           Pro-75 to Lys-81.   1.       HFKFI44   929786   45    1-261   365   Ala-3 to Pro-10,   H0012: 2, H0620: 1                           Pro-39 to Pro-45.   and L0595: 1.       HFKFJ12   582587   46    1-219   366       H0012: 3 and H0620:                               3.       HFKFJ14   787260   47    2-193   367   Ser-13 to Glu-23.   H0012: 2       HFKFJ25   963144   48    2-226   368   Lys-1 to Asn-11,   H0620: 3, H0012: 1,                           Ser-19 to Val-24.   L0435: 1, L0806: 1 and                               L0438: 1.       HFKFN66   511046   49   474-253   369       H0012: 2 and L0748:                               2.       HFKFO75   573840   50    3-263   370       H0012: 2       HFKFQ24   530222   51    1-186   371       H0012: 2       HFKGA94   855099   52    68-322   372   Ser-10 to Pro-17,   H0012: 2                           Gly-49 to Gln-57.       HFKGC14   573785   53    66-257   373   Lys-18 to Trp-29,   H0620: 6 and H0012:                           Arg-48 to Arg-54.   2.       HFKGD10   968172   54   270-392   374   Lys-17 to Trp-22.   H0012: 1, H0620: 1                               and L0366: 1.       HFKGD48   954952   55   196-396   375   Pro-2 to Asp-11.   H0012: 1 and H0620:                               1.       HFKHB46   965767   56   127-420   376   Ser-19 to Lys-34,   H0620: 4 and H0012:                           Ala-45 to Leu-53.   1.       HFKHB67   965847   57   322-636   377   Leu-34 to Pro-43.   H0620: 4, L0542: 2                               and L0769: 1.       HFKHB84   854902   58    34-216   378       H0620: 2 and H0012:                               1.       HFKHD35   854887   59   384-563   379       H0620: 6, H0012: 1                               and L0809: 1.       HFKHD38   854861   60   286-504   380   Leu-3 to Arg-11.   H0620: 2, L0779: 1                               and L0777: 1.       HFKHE67   881093   61    1-285   381   Leu-3 to Asn-14,   H0620: 2                           Ser-31 to Ala-44,                           Leu-60 to Glu-65,                           Thr-70 to Gln-76.       HFKHF54   855118   62   361-134   382   Asn-11 to Ile-16,   H0620: 3                           Arg-19 to Leu-24.       HFKHG06   965906   63    3-353   383   Pro-11 to Pro-16,   H0620: 2   12q12-q13   107777,                           Glu-61 to Ser-67,           123940,                           Thr-71 to Thr-82,           139350,                           Lys-96 to Ser-105,           139350,                           Thr-107 to Gly-115.           148040,                                       148041,                                       148043,                                       148070,                                       231550,                                       600194,                                       600231,                                       600536,                                       600808,                                       600956,                                       601284,                                       601769,                                       601769,                                       601928,                                       602116,                                       602153       HFKHH68   961433   64   249-545   384   Gln-44 to Trp-49.   H0620: 5, H0012: 2                               and L0774: 1.       HFKHR74   953800   65    69-263   385   Leu-23 to Leu-33.   H0620: 2, H0012: 1                               and L0438: 1.       HFKHZ39   928269   66    71-346   386   Asp-6 to Arg-13,   H0620: 3 and L0777:                           Ser-19 to His-24.   2.       HFKID43   854988   67    2-280   387   Pro-44 to Trp-50,   H0620: 4                           Tyr-62 to Leu-82.       HFKID48   879771   68    2-310   388   Ala-37 to His-61.   H0620: 2       HFKIF01   914971   69   229-378   389   Thr-24 to Thr-30.   H0620: 2       HFKIF60   914948   70    1-426   390   Gln-23 to Ser-28,   H0620: 5 and H0012:                           Ser-71 to Tyr-79.   3.       HFKIH06   934051   71    16-348   391   Gly-8 to Leu-16,   H0620: 3, L0565: 1                           Pro-61 to Ala-70,   and L0745: 1.                           Ser-73 to Asn-82,                           Lys-100 to Phe-105.       HFKII05   930948   72    11-283   392   Pro-1 to Pro-7,   H0620: 5                           Ala-52 to Glu-61.       HFKII11   965846   73    2-130   393       H0620: 2       HFKIP07   924825   74    1-351   394   Gly-14 to Asn-26,   H0620: 2 and H0012: 1.                           Gln-31 to Trp-38,                           Ser-43 to Gly-49,                           Ala-60 to Arg-65,                           Arg-73 to Thr-82.       HFKIP11   965072   75    1-447   395   Pro-13 to Pro-18,   AR061: 12, AR089: 3                           Arg-66 to Met-71,   L0774: 4, H0620: 3,                           Gly-88 to Asp-93,   L0749: 2, L0753: 2 and                           Ser-126 to Arg-132.   L0803: 1.       HFKIR40   883093   76    37-330   396   Asp-1 to Ser-8,   H0620: 2 and L0747: 1.                           Asp-83 to Lys-88.       HFKIS93   854862   77    3-221   397   Ser-7 to Lys-12.   H0620: 2       HFKIV55   922739   78    56-178   398   Gly-15 to Cys-22.   H0620: 2       HFKIW31   918243   79    1-426   399   Gly-4 to Ala-10,   AR061: 4, AR089: 3   12q13   107777,                           His-13 to Arg-23.   H0620: 2       123940,                                       139350,                                       139350,                                       148040,                                       148041,                                       148043,                                       148070,                                       231550,                                       600194,                                       600231,                                       600536,                                       600808,                                       600956,                                       601284,                                       601769,                                       601769,                                       601928,                                       602116,                                       602153       HFKIX76   854993   80    1-171   400   Gly-7 to Gln-12,   H0620: 2                           Arg-33 to Arg-42.       HFKJE03   959898   81    3-242   401   Pro-15 to His-21.   H0620: 2 and H0012: 1.       HFKJK90   926511   82   451-612   402   Pro-13 to Glu-25.   H0620: 5       HFKJL17   854829   83    1-243   403   Gly-30 to Gly-35.   H0620: 3       HFKJL36   930422   84   136-267   404   Ser-1 to Gln-9,   H0620: 2                           Leu-13 to Glu-26.       HFKJP08   918312   85   317-105   405       H0620: 4       HFKJW29   932310   86   113-265   406   Trp-3 to Glu-19,   H0620: 2 and H0012: 1.                           Glu-24 to Ala-29.       HFKKG09   854888   87    3-209   407       H0620: 4       HFKKM02   918260   88    5-97   408   Pro-15 to His-31.   H0620: 2       HFKKM61   855082   89   294-533   409       H0620: 2 and H0012:                               1.       HFKKQ02   918270   90   102-338   410   Pro-17 to Glu-22,   H0620: 2 and H0012:                           Val-42 to Gly-47.   1.       HFKKR11   965858   91   133-390   411   Glu-1 to Met-7,   H0012: 1 and H0620:                           Lys-12 to Arg-20.   1.       HFKKS48   854927   92    28-201   412   Asp-41 to Gly-46.   H0620: 3 and H0012:                               1.       HFKKU68   854913   93   151-429   413   Thr-1 to Leu-9,   H0620: 2, L0517: 2,                           Lys-29 to Gln-35,   L0471: 1 and H0012: 1.                           Pro-55 to Ser-71,                           Asn-87 to Gly-93.       HFKLD11   965830   94    15-626   414   His-8 to Gly-18,   H0620: 3                           Arg-29 to Ser-36,                           Arg-57 to Asp-66,                           Pro-77 to His-85,                           Leu-87 to Arg-93,                           Val-106 to Ser-114,                           Lys-147 to Ala-153.       HFKLD58   918235   95   196-360   415       H0620: 2       HFKLJ15   918247   96   174-1    416   Gly-12 to Arg-21.   H0620: 2       HFKLL08   958065   97   127-282   417       H0620: 5 and L0594:                               1.       HFKLR52   879749   98   225-509   418   Gln-10 to Ala-18,   H0620: 2   19p13.3   108725,                           Pro-20 to Ser-29,           120700,                           Lys-39 to Thr-47,           133171,                           Asp-73 to Gly-78.           136836,                                       145981,                                       147141,                                       164953,                                       188070,                                       600957,                                       601238,                                       601846,                                       602216,                                       602477       HFKLX38   880220   99    3-308   419       AR089: 1, AR061: 1                               H0620: 2       HFKLY01   914907   100    17-223   420   Gly-20 to Gly-27,   H0012: 2, H0620: 1,                           Arg-45 to Arg-59.   L0748: 1 and L0749: 1.       HFKMI01   914876   101    2-403   421   His-70 to Gly-86,   H0620: 2                           Arg-89 to Pro-95.       HKDAE56   733549   102    2-331   422   Thr-1 to Ser-7,   H0356: 2                           Ala-10 to Gly-16.       HKDAF34   703405   103   256-453   423   Trp-36 to Asp-41.   H0356: 2       HKDAF84   781937   104    53-313   424       H0356: 2       HKDBC65   572866   105    2-46   425       H0356: 2       HKDBI41   537508   106    82-219   426       H0356: 3       HKDBL02   920498   107    1-189   427       H0356: 2       HKIBB08   960371   108    4-183   428   Asn-14 to Pro-23,   S0023: 2                           Leu-33 to Gln-38.       HKIBB81   525592   109   213-371   429   Glu-18 to Ser-30.   S0023: 2       HKIMC34   573424   110   28-99   430       H0399: 2       HKIXA02   920413   111    2-259   431   Gly-9 to Arg-14,   H0441: 2                           Met-21 to Ala-48,                           Pro-50 to Ser-59.       HKIXA37   735445   112    1-273   432   Gly-1 to His-6,   H0441: 2                           Pro-14 to Pro-31,                           Pro-38 to Cys-46.       HKIXB03   924636   113    21-371   433   Arg-1 to Val-10.   AR061: 5, AR089: 4                               H0441: 2       HKIXB53   727457   114   147-374   434       H0441: 2       HKIXB79   770139   115    3-350   435   His-1 to Pro-6,   H0441: 2                           Arg-69 to Trp-79,                           Lys-88 to Lys-106.       HKIXD42   683533   116    2-115   436   Thr-1 to Asn-7.   H0441: 2       HKIXG58   464241   117    3-200   437   Ser-9 to Lys-14.   AR061: 2, AR089: 2                               H0441: 3, L0794: 2,                               L0805: 2, L0764: 1 and                               L0521: 1.       HKIXH32   920217   118   227-343   438       H0441: 3       HKIXI82   779905   119    19-444   439   Leu-2 to Leu-17,   H0441: 5                           Asp-19 to Gly-25,                           Leu-44 to Trp-52,                           Pro-77 to Pro-84.       HKIXM09   920219   120   13-96   440   Ser-18 to Ser-24.   H0441: 15       HKIXM81   961026   121    1-120   441   Gly-1 to Ser-16,   H0441: 3 and L0753:                           Lys-24 to Ser-31.   1.       HKIXP16   881511   122    60-650   442       H0441: 2       HKIXQ25   681855   123    2-295   443       H0441: 3, L0758: 3,                               L0666: 2, L0774: 1 and                               L0779: 1.       HKIXX58   666516   124    1-147   444       H0441: 2, L0643: 1                               and L0597: 1.       HKIXY04   736085   125    1-333   445   Glu-1 to Gly-6,   L0742: 3, H0441: 2                           Gly-13 to Arg-21,   and L0753: 1.                           Gly-23 to Gln-31,                           Gln-37 to Asp-43,                           Pro-60 to Gly-67,                           Phe-101 to Lys-107.       HKIYF45   970756   126    2-286   446   Thr-59 to Thr-65.   H0441: 2       HKIYJ26   927503   127    2-169   447   Gly-13 to Arg-28.   H0441: 4       HKIYJ63   703320   128    85-174   448   Arg-15 to Asn-21.   H0441: 2       HKIYK78   699311   129    2-88   449   Leu-23 to Thr-29.   H0441: 4 and L0532:                               1.       HKIYQ89   625636   130    29-238   450   Cys-7 to Asp-12,   H0441: 2                           Arg-24 to Gln-32.       HKMAA07   954358   131   105-230   451   Lys-8 to Ser-19.   S0015: 2       HKMAD31   825566   132    78-332   452   Thr-9 to Tyr-15.   S0015: 2       HKMAD43   842064   133    2-217   453   Glu-1 to Gly-26.   S0015: 2       HKMBA17   534523   134    14-142   454       S0024: 3       HKMBD44   715761   135    31-114   455       S0024: 2       HKMLD48   575873   136    30-293   456   Ala-14 to Ser-21,   H0431: 2 and L0794:                           Arg-29 to Leu-37,   1.                           Thr-44 to Gln-53,                           Glu-56 to Leu-62,                           Asn-69 to Cys-75.       HKMLJ39   705467   137   193-369   457       H0431: 2       HKMLM38   951020   138   171-347   458   Arg-13 to Ala-23.   H0431: 2       HKMLN96   881479   139   139-357   459       H0431: 2       HKMLS46   575879   140    74-241   460   Pro-44 to Gln-49.   H0431: 2       HKMMB01   851712   141    4-63   461       H0431: 3       HKMMF21   969002   142   110-859   462   Ser-1 to Asp-7.   H0431: 2       HKMMG47   720379   143    2-313   463   Ala-1 to Lys-10,   H0431: 1 and H0012:                           Ser-52 to Ser-57,   1.                           Pro-74 to Gly-80,                           Leu-94 to Ser-101.       HKMMJ67   575750   144    1-108   464       H0431: 2       HKQAF25   529197   145   126-452   465   Pro-18 to Pro-24.   H0334: 2       HRAAC11   966861   146    2-163   466   Lys-24 to Met-54.   H0555: 2       HRAAS14   658067   147    81-308   467   Gln-7 to Gly-19.   H0555: 2       HRABC50   720370   148    1-159   468   Lys-26 to Ile-31.   H0441: 1 and H0555:                               1.       HRABQ95   961330   149   232-438   469       H0555: 2       HRABT03   923842   150   304-489   470       H0555: 2       HRABY74   666239   151    33-374   471       AR089: 8, AR061: 3                               H0555: 2       HRACE09   625425   152    51-128   472   Gln-18 to Ala-26.   H0555: 2       HRACF86   867212   153    20-283   473   Ser-10 to Phe-17.   H0555: 2       HRACK33   701937   154    95-247   474       H0555: 2       HRACL64   674012   155    3-284   475   Gly-21 to Glu-33,   H0555: 2                           Lys-83 to Arg-92.       HRACM94   785191   156    74-172   476       H0555: 2       HRACW03   923428   157   120-284   477   Ser-1 to Cys-7,   H0555: 2                           Asn-15 to Pro-20,                           Leu-28 to Glu-33.       HRACW27   682578   158    38-208   478   Ser-39 to Phe-45.   H0555: 2       HRACW36   708201   159    95-298   479   Gly-1 to Arg-10.   H0555: 2       HRACW69   708769   160    40-216   480   Ala-3 to Arg-10.   H0555: 3       HRACY16   659733   161   185-325   481   Asn-21 to His-34.   H0555: 2       HRADF21   670398   162    43-240   482   Pro-45 to Trp-52.   H0620: 1, H0555: 1.                               and L0599: 1.       HRADJ92   756539   163   268-462   483   Pro-1 to Gln-13.   H0555: 3       HRADN24   877323   164   231-476   484       H0555: 2       HRADP10   963784   165    8-253   485   Glu-1 to Arg-9,   H0555: 2 and L0794:                           Val-35 to His-47.   1.       HRADP39   732757   166    34-210   486       H0555: 2       HRAEC03   923401   167   247-474   487       H0555: 2       HRKAB10   968272   168   127-255   488       H0361: 3       HRKAB42   575562   169    63-275   489   Ala-3 to Ala-15.   H0361: 7       HRKAE11   967519   170   205-393   490       H0361: 3       HRKAF31   698347   171   265-372   491       L0748: 2, H0361: 1,                               L0662: 1 and L0766: 1.       HRKAE24   677443   172   278-433   492   Ser-13 to Asp-21,   L0599: 2 and H0361:                           Asp-27 to Lys-43.   1.       HRKAC62   742429   173    3-200   493       H0361: 1 and L0745:                               1.       HRKAB80   930473   174    2-355   494   Pro-9 to Glu-16.   L0005: 1 and H0361:                               1.       HRKAA82   880783   175   252-461   495       H0361: 1, L0518: 1                               and L0779: 1.       HRAEF05   931998   176   556-732   496       H0555: 1, L0748: 1                               and L0599: 1.       HRAED30   867176   177    79-411   497   Glu-73 to Pro-94.   L0438: 3 and H0555:                               1.       HRAEB43   714842   178    81-236   498       H0555: 1 and L0748:                               1.       HRAEB29   690179   179   129-275   499       L0745: 2 and H0555:                               1.       HRADZ48   883281   180    2-541   500       AR054: 12, AR050:                               7, AR061: 2, AR051:                               2, AR089: 1                               H0555: 1           956920   328   339-127   648   Lys-20 to Gly-26.       HRADZ34   703680   181    3-185   501       H0555: 1 and L0748:                               1.       HRADZ26   681117   182    3-461   502   Gln-65 to Tyr-71,   L0731: 4, H0555: 1                           Gly-79 to Tyr-85.   and L0777: 1.       HRADR43   714857   183    63-167   503   Tyr-8 to Arg-13.   H0555: 1 and L0744:   9q11-q22   229600,                               1.       264300,                                       600542,                                       602014,                                       602088       HRADR21   830039   184    41-139   504       L0766: 1 and H0555:                               1.       HRADO13   656380   185    1-189   505       H0555: 1 and L0744:                               1.       HRADM45   717358   186    2-472   506   Lys-1 to Leu-6,   AR089: 14, AR061: 6                           Asp-25 to Pro-30.   H0555: 1 and L0777:                               1.       HRADK79   774597   187   108-329   507   Arg-16 to Lys-21.   H0555: 1, L0748: 1                               and L0754: 1.       HRADE49   722595   188   289-411   508   Asn-1 to Met-8.   H0555: 1 and L0748:                               1.       HRADC18   665268   189   306-449   509       L0439: 5, L0438: 2                               and H0555: 1.       HRADA93   792001   190    1-309   510   Pro-14 to Gly-20,   H0555: 1 and L0745:                           Asp-34 to Gly-40,   1.                           Arg-44 to Glu-55,                           Gly-71 to Phe-77.       HRADA17   867198   191    1-213   511       L0763: 1, L0764: 1,                               L0766: 1, H0555: 1 and                               L0752: 1.       HRACX37   711466   192   200-436   512   Leu-6 to Thr-14.   L0748: 2, H0555: 1   2p13   203800,                               and L0755: 1.       602404       HRACV73   764141   193    48-125   513   Pro-16 to Ser-21.   H0555: 1 and L0597:                               1.       HRACV26   793997   194   645-391   514   Ile-29 to Thr-36,   AR054: 10, AR051:                           Thr-64 to Cys-71.   10, AR050: 2                               H0555: 1       HRACT91   789974   195   700-837   515       L0751: 2, H0555: 1,                               L0439: 1 and L0600: 1.       HRACR57   745443   196   181-537   516   Ala-13 to Glu-24,   H0555: 1                           Trp-29 to Arg-35.       HRACR49   722524   197    96-218   517       H0555: 1       HRACM83   780394   198   165-386   518   Trp-1 to Lys-8.   L0756: 2 and H0555:                               1.       HRACH20   669556   199   424-648   519   Ser-3 to Ile-32.   L0439: 3 and H0555:                               1.       HRACF04   615036   200   148-297   520   His-43 to Asn-50.   H0555: 1 and L0756:                               1.       HRACD65   918345   201    72-386   521   Asp-75 to Glu-94.   H0555: 1 and L0748:                               1.       HRACC06   867214   202   225-356   522   Arg-27 to Glu-33.   L0519: 1 and H0555:                               1.       HRACA82   778964   203    99-299   523       H0555: 1 and L0777:                               1.       HRACA19   668528   204   366-602   524       H0555: 1 and L0599:                               1.       HRABZ94   793278   205    2-226   525   Glu-3 to Gly-13,   H0555: 1, L0439: 1                           Ser-55 to Gln-61.   and L0749: 1.       HRABZ67   751496   206    1-183   526   Ser-17 to Gly-24,   L0748: 2, H0555: 1,                           Pro-32 to Lys-47.   L0754: 1 and L0756: 1.       HRABR30   691157   207   242-475   527   Pro-9 to Asn-14.   H0555: 1 and L0599:                               1.       HRABO60   871380   208   141-311   528       L0369: 1 and H0555:                               1.       HRABO08   959104   209   172-390   529   Leu-18 to Glu-23.   L0651: 1 and H0555:                               1.       HRABM45   875735   210   128-502   530   Gln-1 to Leu-21,   L0600: 3, L0789: 2,                           Ser-23 to Gln-36,   H0555: 1, L0754: 1,                           Ser-38 to Cys-45,   L0746: 1 and L0596: 1.                           Trp-64 to Ser-82,                           Pro-87 to Ser-92,                           Trp-101 to Thr-110.       HRABD15   867228   211    3-155   531       L0803: 2 and H0555:                               1.       HRABC08   959124   212   251-433   532   Thr-42 to Ala-54.   L0740: 2, L0598: 1,                               L0373: 1 and H0555: 1.       HRABA59   867239   213   166-342   533   Ser-44 to Trp-52.   L0761: 1 and H0555:                               1.       HRABA25   847318   214   310-182   534       L0766: 2, L0754: 2,                               L0521: 1, L0768: 1,                               H0555: 1, L0747: 1,                               L0777: 1, L0731: 1 and                               L0591: 1.       HRAAW62   742631   215    1-207   535   Pro-23 to Ala-28,   H0555: 1 and L0731:                           Asn-63 to Arg-69.   1.       HRAAO95   582177   216   408-593   536       H0555: 1 and L0747:                               1.       HRAAM31   945071   217    2-355   537       AR089: 19, AR061: 9                               H0555: 1       HRAAJ29   867255   218    2-553   538       L0666: 4 and H0555:                               1.       HRAAI91   790090   219   331-540   539       L0748: 2 and H0555:                               1.       HRAAH86   785398   220   173-445   540       L0749: 2 and H0555:                               1.       HRAAD24   676567   221    18-491   541   Glu-48 to Val-55,   L0603: 2, H0555: 1,                           Glu-78 to Leu-84,   L0751: 1 and L0592: 1.                           Thr-96 to Asp-105,                           Pro-137 to Trp-145.       HRAAD13   657088   222   166-351   542   Pro-43 to Val-49.   H0555: 1 and L0748:                               1.       HKTAB66   525582   223    50-259   543   Phe-21 to Tyr-26.   AR054: 118, AR050:                               100, AR051: 87                               H0239: 1       HKTAA13   971677   224   226-363   544       H0239: 1 and L0766:                               1.       HKPMB95   795060   225    46-165   545   Asp-24 to Lys-30.   L0756: 2 and H0453:                               1.       HKPBA75   767550   226    8-187   546       S0025: 1       HKPBA63   525587   227    3-260   547   Ala-13 to Gly-19.   S0025: 1       HKPBA51   518897   228   22-69   548       S0025: 1       HKMSA84   783091   229    1-201   549       H0461: 1 and L0748:                               1.       HKMSA12   970839   230   495-340   550   Tyr-41 to Thr-48.   H0461: 1, L0766: 1                               and L0777: 1.       HKMNC21   575816   231    1-195   551   Gly-7 to Lys-18,   H0431: 1                           Thr-46 to His-57.       HKMMY63   745145   232    3-173   552   Ser-22 to Gln-35,   H0431: 1 and L0743:                           Arg-50 to Val-56.   1.       HKMMX31   731638   233   145-294   553   Lys-9 to Cys-18,   H0431: 1, L0747: 1,                           Ala-35 to Trp-41,   L0750: 1 and L0605: 1.                           Ser-43 to Glu-50.       HKMMU45   871759   234   214-447   554       L0748: 2, H0431: 1,                               L0769: 1, L0750: 1 and                               L0777: 1.       HKMMR58   736099   235   117-308   555   Leu-13 to Glu-25.   H0431: 1 and L0599:                               1.       HKMMJ41   920910   236   130-426   556   Pro-49 to Gly-55,   L0748: 3 and H0431:                           Ser-73 to Arg-79.   1.       HKMMB27   575799   237    59-304   557   Glu-1 to Ser-18.   H0431: 1       HKMMB10   964728   238   221-388   558       H0431: 1       HKMLY45   575805   239   155-304   559   Gln-23 to Pro-32.   H0431: 1       HKMLO33   859903   240   218-343   560   Glu-11 to Val-16.   L0527: 3, L0536: 2,                               H0431: 1 and L0662: 1.       HKMLM54   825104   241   105-404   561   Val-18 to Asp-23,   H0431: 1 and L0731:                           Leu-47 to Ser-53,   1.                           Pro-58 to Ser-66.       HKMLK76   840137   242   265-480   562   Pro-6 to Ala-16.   H0431: 1 and L0748:                               1.       HKMLF28   705533   243   223-354   563   Lys-10 to Lys-21,   H0431: 1 and L0740:                           Pro-33 to Trp-44.   1.       HKMLD21   671010   244   190-261   564       H0431: 1 and L0756:                               1.       HKMLC74   765669   245    77-211   565       H0431: 1 and L0594:                               1.       HKMLC56   733473   246    29-181   566   Gln-20 to Leu-25.   H0431: 1 and L0756:                               1.       HKMBD80   522402   247    2-58   567   Val-14 to Tyr-19.   S0024: 1       HKMBD57   522406   248   174-347   568       S0024: 1       HKMBC21   670144   249   102-293   569   Glu-14 to Ala-19.   S0024: 1 and L0749:                               1.       HKMBA94   793011   250    1-111   570   Cys-29 to Ile-34.   S0024: 1 and L0744:                               1.       HKIYT69   843327   251    27-284   571   Gly-15 to Ala-28,   H0441: 1   3p                           Phe-32 to Ala-38,                           His-47 to Thr-61,                           Lys-66 to Ala-85.       HKIYS82   779904   252   273-452   572   Met-17 to Asn-22.   L0755: 2 and H0441:                               1.       HKIYN76   770080   253    95-172   573   Asn-11 to Gly-23.   H0441: 1 and L0777:                               1.       HKIYM14   658464   254   184-456   574   Gly-64 to Thr-70,   H0441: 1, L0770: 1                           Ile-85 to Lys-91.   and L0439: 1.       HKIYL69   757602   255    1-273   575       L0439: 2 and H0441:                               1.       HKIYF03   924241   256   346-534   576       L0439: 5, L0438: 3,                               L0749: 2, L0717: 1,                               H0441: 1 and L0520: 1.       HKIYC59   868263   257    36-209   577   Cys-20 to Thr-25,   L0439: 3, H0441: 1,                           Tyr-41 to Arg-46.   L0438: 1 and L0747: 1.       HKIYC29   725699   258    95-463   578   Ser-5 to Trp-12,   H0441: 1 and L0747:                           Thr-42 to Ser-50,   1.                           Val-57 to Asp-67,                           Pro-97 to Gln-112.       HKIXT41   881507   259   111-293   579   Pro-50 to His-56.   H0441: 1 and L0439:                               1.       HKIXQ80   775405   260    2-232   580   Thr-12 to Leu-18,   H0441: 1                           Thr-35 to Trp-40.       HKIXQ47   720373   261    51-278   581   Ser-52 to Cys-59.   L0777: 2, H0441: 1,                               L0794: 1, L0803: 1,                               L0776: 1 and L0529: 1.       HKIXB15   660458   262    74-148   582   Val-14 to Lys-25.   H0441: 1 and L0598:                               1.       HKISB59   739423   263   163-399   583   Phe-8 to Arg-15,   L0439: 4, H0408: 1                           Lys-27 to Ala-37,   and L0594: 1.                           Arg-50 to Gly-63.       HKISA86   785613   264   186-398   584   Lys-5 to Gly-12.   L0439: 2 and H0408:                               1.       HKIMG64   857190   265   136-294   585   Gly-24 to Ser-32.   H0399: 1 and L0532:                               1.       HKIMG03   924745   266   250-552   586   Thr-1 to Ala-6,   H0399: 1 and L0759:                           His-14 to Phe-26,   1.                           Gln-33 to Ser-40.       HKIBB62   742526   267    3-146   587   Gly-33 to Arg-43.   L0754: 2 and S0023:                               1.       HKDBF75   881308   268    14-367   588       L0803: 7, L0774: 4                               and H0356: 1.       HFKLK34   907556   269    3-269   589   Gly-30 to Pro-35,   H0620: 1 and L0749:                           Leu-50 to Gly-60.   1.       HFKLC10   963164   270   156-425   590   Gly-1 to Pro-14,   H0620: 1, L0794: 1                           Pro-28 to Asp-40,   and L0803: 1.                           Arg-46 to Glu-53,                           His-57 to Cys-72.       HFKJP91   836476   271    1-537   591   His-11 to Trp-18.   H0620: 1, L0475: 1                               and L0594: 1.       HFKGB24   677402   272    2-214   592   Val-29 to Cys-37,   H0012: 1 and L0731:                           Ser-42 to Arg-47.   1.       HFKFI85   589991   273   280-513   593   Ile-2 to Trp-7,   H0012: 1                           Thr-14 to Asp-41.           855078   329   199-447   649       HFKFI46   586801   274    2-418   594   Ala-9 to Trp-25,   H0012: 1                           Gly-32 to Arg-40,                           Ala-43 to Thr-52,                           Pro-57 to Pro-62,                           Ala-64 to Gly-70,                           Pro-72 to Arg-89,                           Glu-96 to Glu-103.       HFKEM62   917769   275    3-302   595   Thr-13 to Gly-24,   H0012: 1 and L0759:                           Ala-35 to Asp-58,   1.                           Tyr-66 to Lys-77,                           Thr-81 to Ile-91.       HFKDH49   826803   276   184-2    596   Thr-5 to Arg-10,   H0012: 1                           Lys-36 to Pro-46.           912742   330   547-296   650       HFKDF03   960977   277   234-437   597   Pro-12 to Lys-18,   H0012: 1 and L0783:                           Arg-25 to Lys-31,   1.                           Met-37 to Glu-45.       HFKDE75   766436   278   356-183   598       L0599: 2 and H0012:                               1.       HFKCO51   725968   279   432-64    599   Met-9 to His-16.   H0012: 1 and L0591:                               1.       HFKCO02   917279   280   433-203   600       H0012: 1       HFKCJ69   753680   281   147-1    601       H0012: 1 and L0740:                               1.       HFKCJ52   725974   282   303-1    602   Asn-1 to Trp-9,   H0012: 1, L0748: 1                           Gln-62 to Glu-67,   and L0754: 1.                           Ala-71 to Asp-80,                           Ser-86 to Arg-94.       HFKCG41   712718   283   480-349   603       H0012: 1 and L0751:                               1.       HFKCC73   742991   284   164-331   604   Leu-2 to Lys-12,   L0439: 2 and H0012:                           Pro-21 to Arg-34,   1.                           Pro-38 to Val-45,                           Ser-47 to Lys-56.       HFKBC11   967999   285   827-666   605       H0011: 1 and L0750:                               1.       HFKBC08   960526   286   612-382   606       L0774: 3 and H0011:                               1.       HCKAA51   534949   287    2-85   607       H0119: 1       HBAMD83   573369   288    1-156   608   Pro-1 to Leu-19.   H0410: 1       HBAMD81   778176   289   112-369   609   Arg-67 to Ser-86.   H0410: 1       HBAMD79   573373   290    2-94   610       H0410: 1       HBAMD74   573372   291   120-368   611       H0410: 1       HBAMD69   573371   292    95-352   612   Tyr-17 to Ser-22,   H0410: 1                           Ser-46 to Glu-52.       HBAMD66   750532   293   180-374   613   Tyr-28 to Gly-36,   H0410: 1                           Thr-51 to Leu-57.       HBAMD57   573370   294    2-178   614   Asn-48 to Phe-54.   H0410: 1       HBAMD50   864379   295   130-318   615   Glu-55 to Lys-61.   H0410: 1       HBAMD41   573374   296   243-368   616       H0410: 1       HBAMD36   573367   297   223-318   617   His-2 to Thr-10.   H0410: 1       HBAMD35   571354   298   205-333   618   Glu-1 to Pro-14,   H0410: 1                           Phe-32 to Leu-37.       HBAMD33   573365   299    50-166   619   Pro-22 to Arg-30.   H0410: 1       HBAMD32   573362   300    17-175   620   Gly-1 to Asp-13,   H0410: 1                           Ser-15 to Lys-23.       HBAMD31   698280   301   155-256   621   Trp-10 to Ser-21.   H0410: 1       HBAMD14   573378   302    48-170   622   Lys-12 to Arg-21,   H0410: 1                           Asp-29 to Asn-35.       HBAMC66   575218   303    1-243   623   Cys-26 to Gly-35,   H0410: 1                           Tyr-45 to Val-54,                           Tyr-56 to Asn-63.       HBAMC65   750405   304    74-328   624       H0410: 1       HBAMC63   572936   305   199-324   625   His-7 to Tyr-18.   H0410: 1       HBAMC62   572927   306    51-242   626       H0410: 1       HBAMC52   572935   307    29-211   627       H0410: 1       HBAMC51   572929   308    1-144   628   Trp-9 to Gly-16.   H0410: 1       HBAMC42   572938   309    2-79   629       H0410: 1       HBAMC35   571360   310   166-360   630       H0410: 1       HBAMC34   572926   311   175-297   631       H0410: 1       HBAMC23   572946   312   146-241   632   Phe-19 to Tyr-32.   H0410: 1       HBAMC05   932234   313    57-203   633   Pro-10 to Pro-15.   H0410: 1       HBAGW31   960146   314   373-702   634   Lys-2 to Asn-12,   L0601: 5, L0748: 3,                           Asp-43 to Arg-51,   H0411: 1 and L0755: 1.                           Pro-82 to Ser-98.       HBAGR76   864389   315   115-321   635   Arg-7 to Val-16,   H0411: 1 and L0749:                           Pro-36 to Asn-46.   1.       HBAGH38   487933   316   122-238   636       H0411: 1 and L0439:   15q15   177070,                               1.       177070,                                       182500,                                       218000,                                       227220,                                       243500,                                       600839,                                       601800       HBAFV71   932783   317    2-436   637   Ser-8 to Glu-13,   H0411: 1 and L0758:                           Arg-28 to Leu-34,   1.                           Phe-75 to Ser-80.       HBAFU01   916248   318   294-473   638       H0411: 1 and L0759:                               1.       HBAFP29   690521   319   161-337   639       H0411: 1 and L0746:                               1.       HBAFI04   615078   320   178-41    640       H0411: 1 and L0743:                               1.       HBAFF55   753801   321    96-467   641   Pro-2 to Leu-11,   H0411: 1 and L0747:                           Ala-13 to His-32,   1.                           Cys-55 to Asn-69.       HBAFF09   926667   322    1-642   642   Phe-45 to Tyr-50,   AR054: 11, AR051:                           Gln-56 to Asp-63,   2, AR050: 1                           Gln-87 to Gly-93,   H0411: 1                           Cys-106 to Arg-116,                           Arg-128 to Ile-133,                           Pro-151 to Lys-158,                           Glu-179 to Gly-188.       HBAFC04   615472   323    12-266   643   Thr-5 to Trp-29,   H0411: 1 and L0777:                           Ser-49 to Gln-62,   1.                           Gly-75 to Pro-80.       HAKAD91   509854   324   186-320   644   Pro-20 to Tyr-25.   H0053: 1       HAKAD72   509855   325   380-240   645   Pro-6 to Phe-25,   H0053: 1                           Gln-36 to Ser-47.                  
 
       [0058] The first column in Table 1A provides a unique “Clone ID NO: Z” for a cDNA clone related to each contig sequence disclosed in Table 1A. This clone ID references the cDNA clone which contains at least the 5′ most sequence of the assembled contig, and at least a portion of SEQ ID NO: X was determined by directly sequencing the referenced clone. The reference clone may have more sequence than described in the sequence listing or the clone may have less. In the vast majority of cases, however, the clone is believed to encode a full-length polypeptide. In the case where a clone is not full-length, a full-length cDNA can be obtained by methods known in the art and/or as described elsewhere herein.  
       [0059] The second column in Table 1A provides a unique “Contig ID” identification for each contig sequence. The third column provides the “SEQ ID NO: X” identifier for each of the excretory system associated contig polynucleotide sequences disclosed in Table 1A. The fourth column, “ORF (From-To)”, provides the location (i.e., nucleotide position numbers) within the polynucleotide sequence “SEQ ID NO: X” that delineate the preferred open reading frame (ORF) shown in the sequence listing and referenced in Table 1A, column 5, as SEQ ID NO: Y. Where the nucleotide position number “To” is lower than the nucleotide position number “From”, the preferred ORF is the reverse complement of the referenced polynucleotide sequence.  
       [0060] The fifth column in Table 1A provides the corresponding SEQ ID NO: Y for the polypeptide sequence encoded by the preferred ORF delineated in column 4. In one embodiment, the invention provides an amino acid sequence comprising, or alternatively consisting of, a polypeptide encoded by the portion of SEQ ID NO: X delineated by “ORF (From-To)”. Also provided are polynucleotides encoding such amino acid sequences and the complementary strand thereto.  
       [0061] Column 6 in Table 1A lists residues comprising epitopes contained in the polypeptides encoded by the preferred ORF (SEQ ID NO: Y), as predicted using the algorithm of Jameson and Wolf, (1988) Comp. Appl. Biosci. 4:181-186. The Jameson-Wolf antigenic analysis was performed using the computer program PROTEAN (Version 3.11 for the Power MacIntosh, DNASTAR, Inc., 1228 South Park Street Madison, Wis.). In specific embodiments, polypeptides of the invention comprise, or alternatively consist of, at least one, two, three, four, five or more of the predicted epitopes as described in Table 1A. It will be appreciated that depending on the analytical criteria used to predict antigenic determinants, the exact address of the determinant may vary slightly.  
       [0062] Column 7 in Table 1A provides an expression profile and library code: count for each of the contig sequences (SEQ ID NO: X) disclosed in Table 1A, which can routinely be combined with the information provided in Table 4 and used to determine the normal or diseased tissues, cells, and/or cell line libraries which predominantly express the polynucleotides of the invention. The first number in column 7 (preceding the colon), represents the tissue/cell source identifier code corresponding to the code and description provided in Table 4. For those identifier codes in which the first two letters are not “AR”, the second number in column 7 (following the colon) represents the number of times a sequence corresponding to the reference polynucleotide sequence was identified in the tissue/cell source. Those tissue/cell source identifier codes in which the first two letters are “AR” designate information generated using DNA array technology. Utilizing this technology, cDNAs were amplified by PCR and then transferred, in duplicate, onto the array. Gene expression was assayed through hybridization of first strand cDNA probes to the DNA array. cDNA probes were generated from total RNA extracted from a variety of different tissues and cell lines. Probe synthesis was performed in the presence of  33 P dCTP, using oligo(dT) to prime reverse transcription. After hybridization, high stringency washing conditions were employed to remove non-specific hybrids from the array. The remaining signal, emanating from each gene target, was measured using a Phosphorimager. Gene expression was reported as Phosphor Stimulating Luminescence (PSL) which reflects the level of phosphor signal generated from the probe hybridized to each of the gene targets represented on the array. A local background signal subtraction was performed before the total signal generated from each array was used to normalize gene expression between the different hybridizations. The value presented after “[array code]:” represents the mean of the duplicate values, following background subtraction and probe normalization. One of skill in the art could routinely use this information to identify normal and/or diseased tissue(s) which show a predominant expression pattern of the corresponding polynucleotide of the invention or to identify polynucleotides which show predominant and/or specific tissue and/or cell expression. The sequences disclosed herein have been determined to be predominantly expressed in excretory system tissues, including normal and diseased excretory system tissues (See Table 1A, column 7 and Table 4).  
       [0063] Column 8 in Table 1A provides a chromosomal map location for certain polynucleotides of the invention. Chromosomal location was determined by finding exact matches to EST and cDNA sequences contained in the NCBI (National Center for Biotechnology Information) UniGene database. Each sequence in the UniGene database is assigned to a “cluster”; all of the ESTs, cDNAs, and STSs in a cluster are believed to be derived from a single gene. Chromosomal mapping data is often available for one or more sequence(s) in a UniGene cluster; this data (if consistent) is then applied to the cluster as a whole. Thus, it is possible to infer the chromosomal location of a new polynucleotide sequence by determining its identity with a mapped UniGene cluster.  
       [0064] A modified version of the computer program BLASTN (Altshul et al., J. Mol. Biol. 215:403-410 (1990), and Gish et al., Nat. Genet. 3:266-272 (1993)) was used to search the UniGene database for EST or cDNA sequences that contain exact or near-exact matches to a polynucleotide sequence of the invention (the ‘Query’). A sequence from the UniGene database (the ‘Subject’) was said to be an exact match if it contained a segment of 50 nucleotides in length such that 48 of those nucleotides were in the same order as found in the Query sequence. If all of the matches that met this criteria were in the same UniGene cluster, and mapping data was available for this cluster, it is indicated in Table 1A under the heading “Cytologic Band”. Where a cluster had been further localized to a distinct cytologic band, that band is disclosed; where no banding information was available, but the gene had been localized to a single chromosome, the chromosome is disclosed.  
       [0065] Once a presumptive chromosomal location was determined for a polynucleotide of the invention, an associated disease locus was identified by comparison with a database of diseases, which have been experimentally associated with genetic loci. The database used was the Morbid Map, derived from OMIM™ (supra). If the putative chromosomal location of a polynucleotide of the invention (Query sequence) was associated with a disease in the Morbid Map database, an OMIM reference identification number was noted in column 9, Table 1A, labeled “OMIM Disease Reference(s)”. Table 5 is a key to the OMIM reference identification numbers (column 1), and provides a description of the associated disease in Column 2.  
                                   TABLE 1B                           SEQ                       Clone ID   ID   CONTIG   BAC ID:   SEQ ID   EXON       NO: Z   NO: X   ID:   A   NO: B   From-To                                                        H7MBC38   12   705707   AL035088   651    1-86       H7MBC38   12   705707   AL035088   652    1-189       HBAGK69   16   881903   AL160251   653    1-830       HBAGK69   16   881903   AC007721   654    1-805                           1510-1798                           4114-4607       HBAGK69   16   881903   AC007721   655    1-100       HBAGK69   16   881903   AC007721   656     1-1263       HBAMC12   18   968816   AC009554   657    1-375       HBAMC12   18   968816   AC009554   658    1-469       HBAMC47   19   854049   AL139799   659    1-507       HBAMC92   21   572947   AC023353   660    1-440       HBAMC92   21   572947   AC064832   661    1-447       HCKAA13   22   534965   AC040919   662    1-652       HCKAA13   22   534965   AP001845   663    1-652       HCKAA13   22   534965   AP001374   664    1-652       HCKAA13   22   534965   AC040919   665    1-191                           201-308                            454-1086                           3154-3282                           3440-3857                           4633-4941       HCKAA13   22   534965   AP001845   666    1-271       HCKAA13   22   534965   AP001374   667    1-308       HCKAA41   23   694397   AC018663   668    1-402       HCKAA41   23   694397   AC018663   669    1-248       HCKAA41   23   694397   AC018663   670     1-1609       HFKEA55   25   530256   AP000859   671    1-108                           205-628                           1117-1259                           1538-1745                           2172-2690                           2786-3154                           3246-3403                           4031-4131                           4234-6030                           6184-7366       HFKEA55   25   530256   AC018780   672    1-108                           205-627                           1088-1230                           1509-1716                           2143-2661                           2757-3125                           3217-3374                           4002-4102                           4205-6001                           6155-7337       HFKEA55   25   530256   AP001785   673    1-99                           368-765                            963-1141                           1966-2078                           2175-2597                           3058-3200                           3479-3686                           4113-4631                           4727-5095                           5187-5344                           5973-6073                           6176-7972                           8126-9308       HFKEA55   25   530256   AP000859   674    1-428       HFKEA55   25   530256   AC018780   675    1-428       HFKEA55   25   530256   AP001785   676    1-224       HFKEA55   25   530256   AP001785   677    1-428       HFKEA65   26   932094   AC027598   678    1-638       HFKEA65   26   932094   AC002366   679    1-649       HFKEA65   26   932094   AC002366   680     1-1471                           2332-2618                           2700-3922       HFKEH40   27   523591   AC021138   681    1-426       HFKEH40   27   523591   AC008737   682    1-431       HFKEH40   27   523591   AC021138   683    1-162                           420-504                           1469-1565                           2108-2321                           2421-4280       HFKEH40   27   523591   AC008737   684    1-556                            568-1178       HFKEH40   27   523591   AC008737   685    1-32                           757-942                           3844-4463                           5615-5787                           5904-6600                           6947-7075                           7265-7475                           7586-8105                           8828-8996                           10237-10411                           10669-10753                           11720-11816                           12360-12573                           12673-14535       HFKEJ77   29   529919   AC073640   686    1-238       HFKEJ77   29   529919   AC020928   687    1-667       HFKEJ77   29   529919   AC073266   688    1-667       HFKEJ77   29   529919   AC073640   689    1-654       HFKEJ77   29   529919   AC020928   690    1-650       HFKEJ77   29   529919   AC073266   691    1-676       HFKEJ77   29   529919   AC073266   692    1-650       HFKEM26   30   573949   AC004982   693    1-420                           1344-1738                           2682-2852                           5545-5607                           5615-5894                           6449-6611                           8468-8843                           12028-12179                           12613-13049                           13304-13617                           13895-14373                           14981-15243                           16721-17118                           17305-21277                           22988-23119                           23726-26190       HFKEM26   30   573949   AC004982   694    1-101       HFKEM70   31   963178   AL136528   695    1-892                           1133-2737                           3760-4178                           4229-4310                           4391-4668                           5176-5753                           6229-6333                           7984-8053       HFKEN74   32   974309   AC008878   696    1-927       HFKEN74   32   974309   AC008878   697    1-471       HFKER27   33   926744   AL157386   698    1-416       HFKER27   33   926744   AL157386   699    1-129       HFKER69   34   918290   AC013396   700    1-502       HFKER69   34   918290   AC013396   701    1-277                           502-616                           3690-3819                           5390-5441       HFKEU09   35   855045   AC019214   702    1-100                           482-945                           2126-2202                           2478-2600                           3182-3343                           5248-5664                           6502-6587                           6940-7103                           7254-7391                           7680-7733                           7971-8806                           8812-9045                            9281-11575                           11591-11897                           12403-12621                           12700-12744       HFKEU09   35   855045   AC015551   703    1-100                           482-945                           2100-2176                           2452-2574                           3116-3277                           5189-5605                           6442-6527                           6880-7043                           7194-7331                           7620-7673                           7911-8745                           8751-8984                            9220-11514                           11530-11836                           12342-12560                           12639-12683       HFKEU09   35   855045   AC019214   704    1-167                           257-354                           575-718                            990-1289                           1379-1530                           1982-2132                           2584-2814                           2928-3098                           3416-3717                           4047-4314                           4517-4667                           4990-5016                           5147-5299                           5360-6252       HFKEU09   35   855045   AC015551   705    1-167                           257-354                           575-672                            992-1291                           1381-1532                           1984-2134                           2586-2816                           2930-3100                           3431-3714                           4045-4312                           4515-4665                           4986-5012                           5143-5294                           5355-6248       HFKEW23   36   854952   AL353801   706    1-727       HFKEW23   36   854952   AL353801   707    1-837       HFKFB42   39   522037   AL109839   708     1-1091                           1327-1458                           2095-2434                           5393-5501                           6605-7036                           9708-9880                           10516-10580                           10796-11504                           12943-13099                           13380-13848                           14050-14420                           16213-17031                           18080-18301       HFKFE05   40   932306   AL049775   709    1-383       HFKFE05   40   932306   AL049775   710    1-370       HFKFE59   42   854991   AC007601   711    1-593       HFKFE59   42   854991   AC037438   712    1-593       HFKFE59   42   854991   AC007601   713    1-220       HFKFE59   42   854991   AC037438   714    1-220       HFKFI22   44   930982   AC013396   715    1-459       HFKFI22   44   930982   AC013396   716    1-157       HFKFI22   44   930982   AC013396   717    1-200       HFKFN66   49   511046   AL359389   718     1-1384                           1747-2350       HFKFO75   50   573840   AC073619   719    1-335       HFKFO75   50   573840   AL354745   720    1-335       HFKFO75   50   573840   AC073619   721    1-224       HFKFO75   50   573840   AL354745   722    1-176       HFKGC14   53   573785   AC019124   723    1-480       HFKGC14   53   573785   AC019124   724    1-264       HFKGD10   54   968172   AC015883   725    1-480       HFKGD10   54   968172   AC015883   726    1-522       HFKGD48   55   954952   AC010368   727    1-420       HFKGD48   55   954952   AC010368   728    1-444       HFKHB46   56   965767   AC055792   729    1-47                           1466-1551                           1881-3009       HFKHB46   56   965767   AL035405   730    1-87                           3979-4108                           4445-4939                           5138-5294                           7382-7428                           8845-8930                            9260-10388       HFKHB46   56   965767   AC055792   731     1-1559       HFKHB46   56   965767   AL035405   732     1-1559       HFKHB67   57   965847   AC021857   733    1-35                           232-952       HFKHD38   60   854861   AC040995   734    1-612       HFKHD38   60   854861   AC069030   735    1-612       HFKHD38   60   854861   AC069030   736    1-590       HFKHF54   62   855118   AC067943   737    1-879                           3052-3359       HFKHF54   62   855118   AC067943   738    1-465       HFKHF54   62   855118   AC067943   739    1-623       HFKHG06   63   965906   AC004643   740     1-1151                           1269-1388                           1489-1633                           2129-2539                           2655-2804                           3076-3506                           3614-3734                           3804-5071                           5163-5218                           5299-5402                           5493-5570                           5666-6156                           6257-6375                           6671-7129                           7353-7440                           7709-8851                           9077-9456       HFKHG06   63   965906   AC004643   741    1-246       HFKHG06   63   965906   AC004643   742    1-616                           694-833                           1064-1175                           1420-2038       HFKHZ39   66   928269   AC009123   743    1-635                           1708-1794       HFKHZ39   66   928269   AC009123   744    1-118       HFKID43   67   854988   AC022116   745    1-537       HFKID43   67   854988   AC022116   746    1-564       HFKID43   67   854988   AC022116   747    1-672       HFKID48   68   879771   AC018730   748    1-53                           1553-1660                           4422-4614                           4641-5155                           5981-6234       HFKID48   68   879771   AC018730   749    1-59                            352-2091       HFKID48   68   879771   AC018730   750    1-140       HFKIF01   69   914971   AC015541   751    1-210                           416-623                            845-1481                           1820-2565                           3128-3565                           3626-4034                           4318-4416       HFKIF01   69   914971   AC018501   752    1-210                           416-623                            845-1481                           1820-2565                           3128-3565                           3626-4034                           4318-4416       HFKIF01   69   914971   AC018816   753    1-210                           416-623                            845-1481                           1820-2565                           3128-3565                           3626-4034                           4318-4416       HFKIF01   69   914971   AC015541   754    1-382       HFKIF01   69   914971   AC018501   755    1-382       HFKIF01   69   914971   AC018816   756    1-382       HFKIH06   71   934051   AL021878   757    1-814                           1532-1652                           1791-2285                           2588-2900                           3277-3506                           4106-4504                           4651-5299                           5432-6325                           6595-6648                           7112-7229                            9857-10545                           11800-12045                           13750-13860                           14992-15089                           15126-15234                           16713-16887                           17559-17687                           21811-23565                           24540-24804                           25938-26263                           26678-26895                           27833-28312                           32924-32968                           34093-34274                           35551-35990                           36375-36727                           37669-39039                           39351-39826       HFKIH06   71   934051   AL021878   758    1-359       HFKIH06   71   934051   AL021878   759     1-1737       HFKII11   73   965846   AL139330   760    1-468       HFKII11   73   965846   AL139330   761    1-100       HFKII11   73   965846   AL139330   762    1-481       HFKIP11   75   965072   AC008743   763    1-191                           774-896                           1248-1398                           1656-1742                           1855-2023                           2089-2532                           2895-3068       HFKIP11   75   965072   AC020909   764    1-191                           774-896                           1248-1398                           1656-1742                           1855-2023                           2089-2532                           2895-3068       HFKIP11   75   965072   AC008743   765    1-329                           746-911                           1114-1425                           3498-3617       HFKIP11   75   965072   AC020909   766    1-329                           749-839       HFKIR40   76   883093   AC019071   767    1-372                           414-512                           1060-1165                           1659-1928                           2070-2230                           2342-2438                           2506-2617                           2645-2849                           3087-3559                           3767-4021                           4589-4762                           5003-5323                           5558-5807                           6092-6922       HFKIR40   76   883093   AC019071   768    1-412       HFKIS93   77   854862   AC031984   769     1-1431       HFKIS93   77   854862   AC026539   770     1-2935       HFKIS93   77   854862   AL050318   771     1-1024                           1255-1346                           1550-1761                           1936-2203                           3305-3853                           4515-4876                           4908-5677                           7375-7473                            8813-11992       HFKIS93   77   854862   AL050318   772     1-1487       HFKIS93   77   854862   AL050318   773    1-115       HFKIV55   78   922739   AC068248   774    1-475       HFKIV55   78   922739   AC073160   775    1-99                           1373-1952                           2365-2666                           4560-4982                           5137-5611                           6290-6784                           7269-7317                           8500-8559       HFKIV55   78   922739   AC068248   776    1-423       HFKIV55   78   922739   AC068248   777    1-495       HFKIV55   78   922739   AC073160   778    1-275       HFKIX76   80   854993   AC008074   779    1-88                           305-539                           737-973                           1093-1180                           1791-1973                           3574-6888       HFKIX76   80   854993   AC008074   780    1-186       HFKJE03   81   959898   AC026093   781    1-482       HFKJK90   82   926511   AC022401   782    1-612       HFKJK90   82   926511   AC022401   783    1-186       HFKJL17   83   854829   AC025085   784    1-699                           774-815                           1120-1886                           1981-4592                           4908-5627       HFKJL17   83   854829   AL162581   785    1-699                           774-815                           1120-1886                           1981-2345                           2586-2723                           2809-4595                           4911-5626                           8746-9204                            9575-10225       HFKJL17   83   854829   AL121969   786    1-699                           774-815                           1120-1886                           1981-4592                           4908-5627                           8746-9204                            9575-10225       HFKJL36   84   930422   AC046197   787    1-548       HFKJL36   84   930422   AC007465   788    1-547       HFKJP08   85   918312   AC044859   789    1-365       HFKJW29   86   932310   AP001822   790    1-385                           2074-2451       HFKJW29   86   932310   AP000761   791    1-385                           2074-2451       HFKJW29   86   932310   AC020997   792    1-351       HFKJW29   86   932310   AP000761   793    1-75                           224-447                           1437-3370       HFKJW29   86   932310   AP001822   794    1-75                           222-443                           1435-3369       HFKKG09   87   854888   AL359926   795    1-591       HFKKG09   87   854888   AL359175   796    1-591       HFKKG09   87   854888   AL359926   797    1-266       HFKKG09   87   854888   AL359175   798    1-266       HFKKM02   88   918260   AL356781   799    1-300       HFKKM02   88   918260   AL356781   800    1-177       HFKKM61   89   855082   AC010932   801    1-533       HFKKM61   89   855082   AL133510   802    1-533       HFKKS48   92   854927   AC008749   803    1-541       HFKKS48   92   854927   AC026803   804    1-497                           1331-1441                           1539-2079                           2914-3038                           4330-4471                           4831-4987                           5304-5446       HFKKS48   92   854927   AC026803   805    1-240       HFKKS48   92   854927   AC026803   806    1-289       HFKLD58   95   918235   AC062037   807    1-674                            985-1160       HFKLD58   95   918235   AC062037   808    1-444       HFKLD58   95   918235   AC062037   809     1-1242       HFKLJ15   96   918247   AL139260   810    1-503       HFKLJ15   96   918247   AL139260   811    1-283       HFKLJ15   96   918247   AL139260   812    1-128       HFKLL08   97   958065   AC073410   813    1-878       HFKLL08   97   958065   AC073410   814    1-248       HFKLX38   99   880220   AL136383   815    1-32                           1288-1454                           1561-1646                           3840-4700                           5482-6798       HFKLY01   100   914907   AC013480   816    1-154                           1410-1729                           3081-3322                           3480-4064                           4551-4675                           5305-6348                           6596-6706                           6872-7414                           7421-8472                           8530-8709                           8913-9839       HFKLY01   100   914907   AC013480   817    1-534       HKDAF84   104   781937   AC020633   818    1-30                            341-7207       HKDAF84   104   781937   AC020633   819    1-254       HKDAF84   104   781937   AC020633   820    1-583       HKDBL02   107   920498   AC023124   821    1-506       HKDBL02   107   920498   AC012361   822    1-506       HKIBB08   108   960371   AC011639   823    1-476       HKIBB08   108   960371   AC009679   824    1-641       HKIBB08   108   960371   AC016824   825    1-641       HKIBB08   108   960371   AC009679   826    1-218       HKIBB08   108   960371   AC009679   827    1-195       HKIBB08   108   960371   AC016824   828    1-151                           166-224       HKIBB08   108   960371   AC016824   829    1-195       HKIBB81   109   525592   AL118558   830    1-339       HKIBB81   109   525592   AC022281   831    1-339       HKIBB81   109   525592   AL118558   832    1-730       HKIBB81   109   525592   AL118558   833    1-90       HKIBB81   109   525592   AC022281   834    1-90       HKIBB81   109   525592   AC022281   835    1-624       HKIMC34   110   573424   AC023906   836    1-653       HKIMC34   110   573424   AC023906   837    1-396       HKIXA37   112   735445   AC015941   838     1-1559       HKIXA37   112   735445   AC021852   839     1-1745                           2030-2499       HKIXA37   112   735445   AC021852   840    1-335       HKIXD42   116   683533   AC027225   841    1-419       HKIXD42   116   683533   AF127577   842    1-418       HKIXD42   116   683533   AF127577   843    1-143                           466-768       HKIXI82   119   779905   AC011448   844    1-141                           2130-2301                           3021-3567                           3611-3875                           4085-4375                           4486-4916                           4930-5579                           5726-5837                           5916-6061                           7070-7973       HKIXI82   119   779905   AC011448   845    1-102       HKIXI82   119   779905   AC011448   846    1-544       HKIXX58   124   666516   AP000941   847    1-401       HKIXX58   124   666516   AP000714   848    1-401       HKIXX58   124   666516   AP000846   849    1-400       HKIXX58   124   666516   AP000869   850    1-186                           343-743       HKIXX58   124   666516   AP000941   851    1-292       HKIXX58   124   666516   AP000714   852    1-261       HKIXX58   124   666516   AP000846   853    1-292       HKIXX58   124   666516   AP000869   854    1-292       HKIYF45   126   970756   AC062010   855    1-446       HKIYF45   126   970756   Z82243   856    1-446       HKIYF45   126   970756   AC062010   857    1-268       HKIYF45   126   970756   AC062010   858    1-117       HKIYF45   126   970756   Z82243   859    1-268       HKIYF45   126   970756   Z82243   860    1-117       HKIYJ26   127   927503   AC018984   861    1-593                           2673-2789                           3069-3213       HKIYJ63   128   703320   AC008807   862     1-1113       HKIYJ63   128   703320   AC026439   863     1-1113       HKIYJ63   128   703320   AC008807   864    1-849       HKIYJ63   128   703320   AC008807   865    1-128       HKIYJ63   128   703320   AC026439   866    1-115       HKIYJ63   128   703320   AC026439   867    1-847       HKIYQ89   130   625636   AL158834   868    1-728                           1030-1238                           1582-1665       HKIYQ89   130   625636   AL158834   869    1-134                            506-1282       HKMAA07   131   954358   AC012124   870    1-260       HKMAA07   131   954358   AF176680   871    1-261       HKMAA07   131   954358   AC062010   872    1-226       HKMAA07   131   954358   AC015871   873    1-118       HKMAA07   131   954358   AC055735   874    1-143       HKMAA07   131   954358   AC046131   875    1-238       HKMAA07   131   954358   AC044892   876    1-168       HKMAA07   131   954358   AC036181   877    1-119       HKMAA07   131   954358   AC006451   878    1-992                           1238-2766                           2970-3258                           4727-4925                           5365-5841                           6281-6790                           6934-7264                           8088-8627                           9080-9148                           10250-10345                           11254-12473                           12516-13371       HKMAA07   131   954358   AC006451   879    1-264       HKMBA17   134   534523   AC005293   880    1-301       HKMBA17   134   534523   AC005293   881    1-421       HKMLD48   136   575873   AC012626   882    1-76                            83-286                            575-1023                           3442-3552                           3568-3747                           5131-5259                           6073-6318       HKMLD48   136   575873   AC020816   883    1-443       HKMLD48   136   575873   AC040173   884    1-76                            83-286                            575-1023                           3445-3736                           5120-5248                           6062-6307       HKMLD48   136   575873   AC012626   885    1-606       HKMLD48   136   575873   AC040173   886    1-605       HKMLS46   140   575879   AC010674   887    1-321       HKMLS46   140   575879   AC010674   888    1-133                            985-1071                           1887-2686       HKMLS46   140   575879   AC010674   889    1-149       HKMMF21   142   969002   AL139154   890    1-431                            598-1537                           2081-2194                           2838-2906                           3531-3905                           3964-4935                           6101-6251                           6329-6908                           8000-8334                           8505-8691                           8954-9485                            9569-10044                           10639-11625                           12043-12128                           12460-12700                           13146-13660       HKMMF21   142   969002   AL139154   891     1-3258                           3398-3707       HKMMF21   142   969002   AL139154   892    1-359       HKMMG47   143   720379   AL160286   893    1-29                           1089-2148       HKMMJ67   144   575750   AC013583   894    1-133       HKMMJ67   144   575750   AC015776   895    1-101       HKMMJ67   144   575750   AC008439   896    1-125       HKMMJ67   144   575750   AC021923   897    1-104       HKMMJ67   144   575750   AC020834   898    1-360       HKMMJ67   144   575750   AC021923   899    1-139                            935-1002       HKMMJ67   144   575750   AC020834   900     1-2033       HRABC50   148   720370   AC058800   901    1-722       HRABC50   148   720370   AL390294   902    1-722       HRABC50   148   720370   AL159172   903    1-722       HRABC50   148   720370   AC058800   904    1-709       HRABC50   148   720370   AL390294   905    1-709       HRABC50   148   720370   AL159172   906    1-707       HRABT03   150   923842   AC010310   907    1-547       HRABT03   150   923842   AC010308   908    1-547       HRABT03   150   923842   AC010358   909    1-547       HRABT03   150   923842   AC010473   910    1-547       HRABT03   150   923842   AC010310   911    1-112       HRABT03   150   923842   AC010308   912    1-112       HRABT03   150   923842   AC010473   913    1-112       HRACE09   152   625425   AL359176   914     1-1635       HRACE09   152   625425   AC026900   915     1-2078                           2378-2968                           3217-4094                           4180-4659                           4664-6770                           6814-7224       HRACE09   152   625425   AC060753   916     1-3585                           3715-4305                           4546-5403       HRACE09   152   625425   AL109937   917    1-142       HRACE09   152   625425   AL356004   918     1-1636       HRACE09   152   625425   AL390296   919    1-142       HRACE09   152   625425   AC027209   920     1-2282                           2412-3002                           3469-4126                           4211-6401                           6472-6802                           6854-7412                           7505-7877                           8817-9469                            9531-10355                           11182-11518                           11841-12049                           12639-12673                           13026-13612                           13639-15711                           15745-16135                           16215-16907                           17307-17773       HRACE09   152   625425   AL049742   921     1-1857                           1863-2229                           2699-5270                           5474-7109       HRACE09   152   625425   AL359176   922     1-2152       HRACE09   152   625425   AC026900   923     1-1310       HRACE09   152   625425   AC060753   924    1-292       HRACE09   152   625425   AL109937   925    1-164       HRACE09   152   625425   AL359176   926     1-1407       HRACE09   152   625425   AC026900   927    1-374       HRACE09   152   625425   AL109937   928    1-666                            680-1146       HRACE09   152   625425   AL356004   929    1-761                            796-1915                           2046-2636                           2885-3700                           3848-6031                           6105-6435                           6750-7508                           8743-9098       HRACE09   152   625425   AL390296   930    1-665                            683-1151       HRACE09   152   625425   AL390296   931    1-502       HRACE09   152   625425   AC027209   932    1-423       HRACE09   152   625425   AC027209   933     1-1301       HRACE09   152   625425   AL049742   934     1-1554                           1998-3175       HRACE09   152   625425   AL049742   935    1-762                            797-1916                           2047-2637                           2886-3701                           3849-4328                           4614-5981                           6055-6385                           6700-7458                           8693-9048       HRACL64   155   674012   AL049780   936    1-33                           2486-3028                           3593-3681                           3828-3889                           6854-6907                           7350-7545                           9474-9717                            9723-10077                           10527-11087                           11166-11594                           13231-13400                           14027-14327                           15465-15573                           16076-16238                           19959-20368                           21799-21859                           23602-24438                           24694-24797                           25509-25961                           26557-27070                           28587-28750                           28843-29088                           29996-30215                           30398-30446                           32541-35115       HRACL64   155   674012   AC007055   937    1-33                           2488-3030                           3594-3682                           3829-3890                           6855-6908                           7351-7546                           9459-9702                            9708-10062                           10512-11071                           11150-11578                           13215-13384                           14006-14311                           15449-15557                           16060-16222                           19946-20355                           21782-21842                           23585-24421                           25493-25945                           26541-27054                           28572-28735                           28828-29073                           29981-30200                           32526-35100       HRACL64   155   674012   AL049780   938    1-133       HRACL64   155   674012   AL049780   939    1-295       HRACL64   155   674012   AC007055   940    1-266       HRACL64   155   674012   AC007055   941    1-133       HRACW03   157   923428   AC073879   942    1-490       HRACW36   159   708201   AC005746   943    1-556       HRACW36   159   708201   AC005746   944    1-383       HRACW69   160   708769   AL162424   945    1-539       HRACW69   160   708769   AL162424   946    1-117       HRADP39   166   732757   AC024729   947    1-502       HRAEC03   167   923401   AC025710   948    1-561       HRAEC03   167   923401   AL359353   949    1-561       HRAEC03   167   923401   AC025710   950    1-47                           2659-3236                           4025-6604       HRAEC03   167   923401   AL359353   951    1-47                           2659-3236                           4025-6604       HRAEC03   167   923401   AC025710   952    1-389       HRAEC03   167   923401   AL359353   953    1-390       HRKAB10   168   968272   AC018431   954    1-459       HRKAB10   168   968272   AL117354   955    1-201                           318-397                           1689-2518                           2909-3252                           3296-4192                           4457-4937                           5239-5389                           8114-8209                           9102-9579                           10318-10448       HRKAB10   168   968272   AL117354   956    1-160       HRKAB10   168   968272   AL117354   957    1-121       HRKAF31   171   698347   AC068942   958    1-597                           1981-2374                           2510-2735                           3032-3130                           3193-4169                           4618-4792       HRKAF31   171   698347   AC016590   959    1-976       HRKAF31   171   698347   AC012309   960    1-491                            594-1632                           3019-3412                           3548-3774                           4071-4169                           4232-5207                           5656-5830       HRKAF31   171   698347   AC068942   961    1-304       HRKAF31   171   698347   AC016590   962    1-99       HRKAF31   171   698347   AC016590   963    1-304       HRKAF31   171   698347   AC012309   964    1-148       HRKAF31   171   698347   AC012309   965    1-304       HRKAC62   173   742429   AC015919   966    1-293       HRKAC62   173   742429   AC015919   967    1-293       HRKAC62   173   742429   AC007763   968    1-366                           376-740       HRKAC62   173   742429   AC016704   969    1-366                           376-740       HRKAC62   173   742429   AC015920   970    1-366                           376-668       HRKAC62   173   742429   AC007763   971    1-266                           1286-1478       HRKAC62   173   742429   AC007763   972    1-87       HRKAC62   173   742429   AC016704   973    1-266                           1284-1490                           3464-3826                           5158-5320                           6212-6300                           7623-7838       HRKAC62   173   742429   AC016704   974    1-87       HRKAC62   173   742429   AC015920   975    1-87       HRKAA82   175   880783   AC026556   976     1-1168       HRKAA82   175   880783   AC068243   977     1-1168       HRKAA82   175   880783   AC026556   978    1-626       HRKAA82   175   880783   AC026556   979    1-294       HRKAA82   175   880783   AC068243   980    1-626       HRKAA82   175   880783   AC068243   981    1-279       HRAED30   177   867176   AC040169   982    1-143                           1045-1358                           1402-2764                           3033-3632                           3711-4143                           6385-7445                           8802-9689       HRAEB43   178   714842   AP000096   983     1-2486                           3072-3458                           3479-3937                           5086-5458       HRAEB43   178   714842   AP000200   984     1-2486                           3072-3458                           3479-3937                           5086-5458       HRAEB43   178   714842   AP000240   985    1-387                           408-866       HRAEB43   178   714842   AP000096   986    1-89       HRAEB43   178   714842   AP000200   987    1-89       HRAEB43   178   714842   AP000240   988     1-2486       HRAEB43   178   714842   AP000240   989    1-357       HRAEB29   179   690179   AC024885   990     1-3448       HRADR43   183   714857   AL359997   991     1-1563       HRADR21   184   830039   AC007386   992    1-391       HRADK79   187   774597   AC016400   993    1-61                            960-1187                           1265-1372                           1519-1584                           1853-2385                           2428-2786                           3031-4137       HRADK79   187   774597   AC016400   994    1-337       HRADE49   188   722595   AL136109   995     1-3030                           3212-3814                           9089-9408                           11724-12242                           12308-12959                           23153-23254                           24314-26013       HRADE49   188   722595   AC023147   996     1-3041                           3223-3825                           9096-9415                           11730-12248                           12314-12965                           23152-23259                           24319-26018       HRADE49   188   722595   AC022219   997     1-3030                           3212-3814                           9084-9403                           11717-12235                           12301-12952                           23145-23246                           24307-26006       HRADE49   188   722595   AL136109   998    1-344       HRADE49   188   722595   AL136109   999    1-174       HRADE49   188   722595   AC023147   1000    1-122       HRADE49   188   722595   AC022219   1001    1-191       HRADE49   188   722595   AC022219   1002    1-344       HRADA93   190   792001   AC010463   1003    1-56                           380-483                           579-900                           1742-1988       HRADA93   190   792001   AC010463   1004    1-27                            934-1247                           2557-2685                           2850-2960       HRACV73   193   764141   AC013322   1005    1-421       HRACV73   193   764141   AC006038   1006    1-421       HRACV73   193   764141   AC013322   1007    1-308       HRACV73   193   764141   AC013322   1008    1-447       HRACV73   193   764141   AC006038   1009    1-311       HRACV73   193   764141   AC006038   1010    1-447       HRACR57   196   745443   AC055863   1011    1-946       HRACR57   196   745443   AC073922   1012    1-566       HRACR57   196   745443   AC055863   1013    1-284       HRACR49   197   722524   AC009568   1014    1-297       HRACR49   197   722524   AC011633   1015    1-297       HRACR49   197   722524   AC011633   1016    1-335       HRACF04   200   615036   AL354833   1017    1-316                            564-1413                           1607-1800                           2119-2419                           3091-4057                           4252-4680                           7398-7790                           8083-8259                           8450-8642                            9096-11423                           11866-13435       HRACF04   200   615036   AL354833   1018    1-121       HRACD65   201   918345   AL031297   1019    1-131                           679-912                           1349-1654                           5029-5252                           9376-9493                            9736-10204                           10953-11302                           11525-12122                           16952-17243                           20848-21153                           21457-22062                           25001-25396                           26949-27023                           28082-28430                           29411-29548                           29680-30123                           30797-30981                           31120-31308                           31959-32425                           34705-34876                           35061-35527                           37354-37502                           37933-38190                           38381-39650                           39839-41256                           41488-41511                           41519-41916                           41983-42104                           42275-42855                           43391-43461                           43574-43656                           43857-44292                           44317-44421                           46115-46231                           47800-48512                           48841-49208                           50149-50247                           51377-51502                           52685-52984                           53118-53307                           56807-56996                           61413-61503                           63173-63224                           63579-63659                           64464-64659                           66082-66208                           66720-66871                           67311-67472                           70450-70513                           71257-71408                           72162-72215       HRACD65   201   918345   AL031297   1020    1-648       HRACC06   202   867214   AC006347   1021    1-544       HRACC06   202   867214   AC006347   1022    1-532                           750-1892       HRACC06   202   867214   AC006347   1023    1-806       HRABZ67   206   751496   AC004542   1024     1-4332                            4401-10126       HRABZ67   206   751496   AC004542   1025    1-195       HRABR30   207   691157   AL161447   1026    1-611       HRABR30   207   691157   AL161447   1027    1-368       HRABR30   207   691157   AL161447   1028    1-247       HRABO60   208   871380   AL359538   1029    1-548       HRABO60   208   871380   AC013721   1030    1-155                           789-836                            978-1056                           1143-1690                           1707-1999                           3621-3762                           3849-4168                           4886-5085                           5994-6080                           6441-6513                           7498-8147                           8651-9220                           10275-10381                           10687-10988                           12904-13077                           13332-13417                           13623-14029                           16366-16446                           17409-17507                           18127-18230                           18280-18693                           18709-19020                           20417-20713                           24618-25701                           27490-28016                           28378-28720                           29486-29516                           30017-30581                           30641-31070                           31505-31744                           32436-32725                           33178-33363                           33487-33630                           34031-34157                           34251-34807                           35077-35422                           35460-35863                           36979-37467                           37750-38006                           38169-39169       HRABO60   208   871380   AL359763   1031    1-155                           789-836                            978-1056                           1143-1690                           1702-1992                           3622-3763                           3850-4170                           4888-5087                           5996-6082                           6443-6515                           7500-8149                           8653-9222                           10281-10387                           10687-10994                           12910-13083                           13338-13423                           13629-14035                           16372-16452                           17415-17511                           18133-18236                           18286-18700                           18716-19027                           20424-20720                           24625-25708                           27497-28023                           28078-28194                           28385-28727                           29493-29523                           30024-30588                           30648-31077                           31512-31751                           32443-32732                           33168-33347                           33494-33637                           34038-34164                           34258-34814                           35084-35429                           35467-35870                           36985-37473                           37756-38012                           38175-39175       HRABO60   208   871380   AL359538   1032    1-299       HRABO60   208   871380   AC013721   1033    1-397       HRABO60   208   871380   AC013721   1034    1-439       HRABO60   208   871380   AL359763   1035    1-439       HRABO60   208   871380   AL359763   1036    1-397       HRABO08   209   959104   AC025597   1037    1-547       HRABO08   209   959104   AL355834   1038    1-547       HRABO08   209   959104   AL161804   1039    1-547       HRABO08   209   959104   AC025597   1040    1-428                            550-1154       HRABO08   209   959104   AL355834   1041    1-439                           1615-2106       HRABO08   209   959104   AL355834   1042    1-428                            550-1154       HRABO08   209   959104   AL161804   1043    1-428                            550-1008       HRABO08   209   959104   AL161804   1044    1-439                           1615-2106       HRABM45   210   875735   AC003663   1045     1-1827       HRABM45   210   875735   AC003663   1046    1-559       HRABM45   210   875735   AC003663   1047    1-250                           1981-2340                           2645-2782                           3859-4046                           4073-4241                           6066-6166                           6314-6452                           10021-10278                           10529-10697                           11001-11141                           11615-11751                           11925-12464                           12728-15037       HRABD15   211   867228   AC024944   1048    1-573                            670-1471                           1710-2231                           2681-2716       HRABD15   211   867228   AC024911   1049    1-573                            670-1471                           1710-2231                           2681-2716       HRABD15   211   867228   AC024944   1050    1-545       HRABD15   211   867228   AC024911   1051    1-315       HRABC08   212   959124   AC026840   1052    1-503       HRABC08   212   959124   AC007897   1053    1-453                           1564-2870       HRABC08   212   959124   AC022221   1054     1-1294       HRABC08   212   959124   AC007897   1055    1-129       HRABC08   212   959124   AC007897   1056    1-438       HRABC08   212   959124   AC022221   1057    1-438       HRABA59   213   867239   AC072049   1058    1-531       HRABA59   213   867239   AC072049   1059    1-357       HRAAW62   215   742631   AC034115   1060    1-615       HRAAW62   215   742631   AC036108   1061     1-1763       HRAAW62   215   742631   AC018999   1062     1-1766       HRAAW62   215   742631   AC036108   1063    1-146       HRAAW62   215   742631   AC018999   1064    1-307       HRAAM31   217   945071   AC073991   1065     1-1177       HRAAM31   217   945071   AC006230   1066     1-1177       HRAAH86   220   785398   AL139331   1067    1-534       HRAAH86   220   785398   AL157697   1068    1-534       HRAAH86   220   785398   AL157697   1069    1-648       HRAAH86   220   785398   AL139331   1070    1-648       HRAAD24   221   676567   AC006208   1071    1-442                           516-699                           770-945                           1607-1777                           1779-2240                           2748-3680                           4220-4397       HRAAD24   221   676567   AC024148   1072    1-148                           263-423                           1284-1509                           1650-1931                           3343-3483                           3737-3879                           4128-4290                           4371-4503                           4924-5365                           5439-5622                           5693-5868                           6530-6700                           6702-7164                           7281-7394                           7672-8603                           9143-9320       HRAAD24   221   676567   AC006208   1073    1-141                           395-537                           786-948                           1029-1161       HRAAD24   221   676567   AC006208   1074     1-1425                           1603-1678                           1783-1875                           2028-3154                           3258-3740                           3768-4488                           4764-4913                           5252-5382                           5827-5905                           6172-6319                           6397-6466                           6957-7076                           7473-7606                           8554-8608                           8714-8741                           8840-8984       HKPMB95   225   795060   AL031650   1075    1-423       HKPMB95   225   795060   AC068624   1076    1-336                            838-1776                           1968-2081       HKPMB95   225   795060   AL121751   1077    1-423       HKPMB95   225   795060   AC068624   1078    1-256       HKPMB95   225   795060   AL031650   1079     1-1839       HKPMB95   225   795060   AC068624   1080     1-1574       HKPMB95   225   795060   AL121751   1081    1-921                           1179-2159       HKMNC21   231   575816   AL035070   1082    1-445       HKMNC21   231   575816   AL035070   1083    1-589       HKMMY63   232   745145   AL031985   1084    1-703                           1291-1889       HKMMY63   232   745145   AL031985   1085    1-129                           402-491                           5473-5683                           6349-6775       HKMMX31   233   731638   AC008145   1086     1-1165                           1183-1440                           1929-3571                           4290-4866                           5620-5991                           6223-7048                           7820-7972                           8559-9062                           9224-9674                           10540-10878                           11255-11932                           12172-12614       HKMMX31   233   731638   AC008145   1087     1-2343       HKMMX31   233   731638   AC008145   1088     1-1002       HKMMU45   234   871759   AC009869   1089     1-1230                           1307-2148                           2168-3029       HKMMU45   234   871759   AC009869   1090    1-507       HKMMU45   234   871759   AC009869   1091     1-2222       HKMMR58   235   736099   AL162501   1092    1-373       HKMMR58   235   736099   AL353729   1093    1-373       HKMMR58   235   736099   AL353729   1094    1-116       HKMMR58   235   736099   AL353729   1095    1-546       HKMMJ41   236   920910   AC011714   1096    1-108                           1971-2651                           2708-3803       HKMMJ41   236   920910   AC011714   1097     1-1481       HKMMJ41   236   920910   AC011714   1098    1-644       HKMMB27   237   575799   AC007899   1099    1-78                            911-1060                           1125-1525                           3006-3125                           5016-5230                           7331-7408       HKMLY45   239   575805   AC021959   1100    1-418       HKMLO33   240   859903   AC027164   1101    1-680       HKMLO33   240   859903   AC024388   1102    1-680       HKMLO33   240   859903   AC027164   1103    1-93       HKMLO33   240   859903   AC024388   1104    1-93       HKMLO33   240   859903   AC027164   1105    1-119       HKMLO33   240   859903   AC024388   1106    1-119       HKMLF28   243   705533   AC008488   1107     1-1307                           1691-2527       HKMLF28   243   705533   AC026424   1108    1-374                           1299-2384                           3050-3444                           3536-3708                           4988-5557                           5619-5841                           5882-6842                           7078-9586                            9970-10806       HKMLF28   243   705533   AC008587   1109    1-164                           2264-2301                           2816-3276                           4686-4842                           5583-5956                           6881-7966                           8617-9026                           9118-9290                           10569-11138                           11200-11422                           11463-12423                           12659-15166                           15550-16386       HKMLF28   243   705533   AC026424   1110    1-157       HKMLF28   243   705533   AC008488   1111    1-355       HKMLF28   243   705533   AC026424   1112    1-355       HKMLF28   243   705533   AC008587   1113    1-355       HKMLF28   243   705533   AC008587   1114    1-212                           3498-4246                           4457-4587                           7496-7691                           11928-12166                           13527-13685                           14011-14103       HKMLD21   244   671010   AC009673   1115    1-438       HKMLD21   244   671010   AC024930   1116    1-439                            999-1481       HKMLD21   244   671010   AC019322   1117    1-438       HKMLD21   244   671010   AC009673   1118    1-115       HKMLD21   244   671010   AC019322   1119    1-297       HKMLC56   246   733473   AC005037   1120    1-642       HKMLC56   246   733473   AC005037   1121    1-404       HKMLC56   246   733473   AC005037   1122    1-310       HKMBC21   249   670144   AP000718   1123    1-435       HKMBC21   249   670144   AC026851   1124    1-435                            735-1154       HKMBC21   249   670144   AP001351   1125    1-435                            734-1157       HKMBC21   249   670144   AP001351   1126    1-613       HKMBC21   249   670144   AP000718   1127    1-613       HKMBC21   249   670144   AC026851   1128    1-613       HKMBA94   250   793011   AC007737   1129    1-924       HKMBA94   250   793011   AC007556   1130    1-925       HKMBA94   250   793011   AC007737   1131    1-74                            243-1037       HKMBA94   250   793011   AC007556   1132    1-640                           1526-1768                           3142-3412                           4485-4610                           6381-6484                           8584-9086                           9503-9635                           11363-11561                           15129-15311                           17376-17893                           18236-18646                           21077-21228                           21777-21948                           23054-23493                           23662-23902                           25370-25589                           26807-26985                           28007-28203                           29232-29477                           30172-30300                           31261-31381                           32224-32440                           32729-32844                           33577-33694                           34720-34857                           37342-37464                           40796-40924                           45893-46023                           46989-47124                           48792-48938                           50432-50598                           52368-52497                           55908-56280                           56436-56657                           57473-57649                           59906-60018                           60603-60722                           62851-62943                           63788-63853                           64025-64143                           64688-64819                           65902-66001                           66584-67062                           67143-67869                           68004-68496                           68545-69613                           70712-70820                           73163-73483                           74310-74383                           74552-75346       HKIYT69   251   843327   AL031228   1133    1-352       HKIYT69   251   843327   AL031228   1134    1-325       HKIYT69   251   843327   AL031228   1135    1-113       HKIYS82   252   779904   AC015589   1136     1-1206                           1256-4224       HKIYS82   252   779904   AC010328   1137    1-82                           355-795                           871-998                           1300-1582                           1629-2248                           2727-2918                           4474-4729                           4876-6190                           6240-9439       HKIYS82   252   779904   AC015589   1138    1-299       HKIYS82   252   779904   AC010328   1139    1-179       HKIYS82   252   779904   AC010328   1140    1-570       HKIYN76   253   770080   AL161910   1141     1-1421       HKIYF03   256   924241   AC022542   1142     1-2074       HKIYF03   256   924241   AC005384   1143     1-1037       HKIYF03   256   924241   AC022542   1144    1-680       HKIYF03   256   924241   AC005384   1145    1-680       HKIYC59   257   868263   AL137066   1146    1-855                            873-1230       HKIYC59   257   868263   AL137066   1147    1-243       HKIYC59   257   868263   AL137066   1148    1-525       HKIXQ80   260   775405   AC011921   1149    1-443       HKIXQ80   260   775405   AC025515   1150    1-443       HKIXQ80   260   775405   AC011921   1151    1-149       HKIXQ80   260   775405   AC025515   1152    1-149       HKIXQ47   261   720373   AC068282   1153    1-386                            426-1484                           1594-1896       HKIXQ47   261   720373   AC068282   1154    1-238       HKIXB15   262   660458   AC022211   1155    1-33                           1164-1278                           1567-2052                           3306-3473       HKIXB15   262   660458   AC022211   1156    1-252       HKIMG64   265   857190   AC013647   1157    1-405       HKIMG64   265   857190   AC010741   1158    1-413       HKIMG64   265   857190   AL161790   1159    1-413       HKIMG64   265   857190   AC010741   1160    1-638       HKIMG64   265   857190   AL161790   1161    1-638       HKIMG64   265   857190   AC010741   1162    1-351       HKIMG64   265   857190   AL161790   1163    1-351       HKIBB62   267   742526   AC009509   1164    1-619       HKIBB62   267   742526   AC009509   1165    1-97                            978-1034                           2318-2377                           4978-5150                           5615-5647       HKIBB62   267   742526   AC009509   1166    1-389       HFKLK34   269   907556   AC022576   1167    1-722       HFKLK34   269   907556   AC022576   1168    1-321       HFKGB24   272   677402   AC007104   1169    1-802                           2342-2695                           3074-3189                           5319-5633                           7248-8571       HFKGB24   272   677402   AC069497   1170    1-117                           2470-3367                           4908-5262                           5641-5756                           7886-8200                            9815-11138       HFKGB24   272   677402   AC007104   1171    1-453       HFKGB24   272   677402   AC069497   1172    1-453       HFKFI46   274   586801   AC005586   1173    1-337                           345-870                           1023-1553                           2148-3037                           3212-3335       HFKFI46   274   586801   AC005586   1174     1-1438                           2411-2511       HFKDF03   277   960977   AC019131   1175     1-4679                           4858-5322                           7433-7916                           7918-8276                           11359-11661                           13034-13322                           14921-15217                           19170-19416                           20116-23855       HFKDF03   277   960977   AP002026   1176    1-484       HFKCO51   279   725968   AC074386   1177    1-470       HFKCO51   279   725968   AC004889   1178    1-470       HFKCO51   279   725968   AC074386   1179    1-527                           4449-4476       HFKCO51   279   725968   AC004889   1180    1-527                           4447-4552                           4726-4968       HFKCG41   283   712718   AP002784   1181    1-654                           1182-2920                           3315-5990       HFKCC73   284   742991   AL161451   1182    1-37                           873-980                           1129-1342                           1521-1731                           3705-3985                           4040-4126                           5368-5773                           5825-6649       HFKCC73   284   742991   AL365502   1183    1-406                           &gt;458-1282       HFKCC73   284   742991   AL365502   1184    1-245       HFKCC73   284   742991   AL161451   1185    1-245       HFKBC08   286   960526   AC025597   1186    1-966                           2536-2698                           3500-3602                           5005-5242       HFKBC08   286   960526   AL161804   1187    1-966                           2536-2698                           3500-3602                           5005-5242       HFKBC08   286   960526   AL355834   1188    1-966                           2534-2696                           3498-3600                           5003-5240       HFKBC08   286   960526   AC025597   1189    1-200       HFKBC08   286   960526   AL161804   1190    1-200       HFKBC08   286   960526   AL355834   1191    1-200       HCKAA51   287   534949   AL022325   1192    1-154                           1810-1865                           1947-2233                           2391-2757                           2828-4196                           4215-4421                           4990-5074                           5133-5294                           5676-6489                           6529-7035       HCKAA51   287   534949   AL031588   1193    1-154                           1810-1865                           1947-2233                           2391-2757                           2828-4196                           4215-4421                           4990-5074                           5133-5294                           5676-6489                           6529-7035       HCKAA51   287   534949   AL022325   1194    1-875       HCKAA51   287   534949   AL031588   1195    1-875       HBAMD83   288   573369   AC044821   1196    1-326       HBAMD83   288   573369   AC044821   1197    1-155       HBAMD79   290   573373   AC011025   1198    1-263       HBAMD79   290   573373   AC011954   1199    1-263       HBAMD74   291   573372   AC064850   1200    1-384       HBAMD74   291   573372   AC064850   1201    1-450       HBAMD66   293   750532   AC001228   1202    1-646       HBAMD66   293   750532   AC001228   1203    1-144       HBAMD66   293   750532   AC001228   1204    1-611       HBAMD57   294   573370   AL133224   1205    1-359       HBAMD50   295   864379   AP000648   1206     1-1521       HBAMD50   295   864379   AP001769   1207    1-797                           1056-2966                           3062-3615       HBAMD50   295   864379   AP000827   1208    1-782                            893-1689                           1948-3858                           3954-4507       HBAMD50   295   864379   AP001769   1209    1-70                           111-298       HBAMD50   295   864379   AP000648   1210    1-781                            892-1688       HBAMD50   295   864379   AP000827   1211     1-1045       HBAMD41   296   573374   AC024610   1212    1-263       HBAMD36   297   573367   AC009670   1213    1-442       HBAMD35   298   571354   AC017062   1214    1-383       HBAMD33   299   573365   AC025734   1215    1-301       HBAMD33   299   573365   AC013294   1216    1-301       HBAMD33   299   573365   AC025734   1217    1-88       HBAMD33   299   573365   AC013294   1218    1-88       HBAMD32   300   573362   AL354950   1219    1-369       HBAMC66   303   575218   AC026982   1220    1-213       HBAMC66   303   575218   AC026982   1221    1-120       HBAMC65   304   750405   AL359212   1222    1-381       HBAMC65   304   750405   AL359332   1223    1-381       HBAMC65   304   750405   AL359332   1224    1-380       HBAMC63   305   572936   AC010142   1225    1-402       HBAMC63   305   572936   AL121823   1226    1-402       HBAMC63   305   572936   AL121823   1227    1-109       HBAMC62   306   572927   AL354747   1228    1-361       HBAMC62   306   572927   AL354747   1229    1-705       HBAMC51   308   572929   AC027561   1230    1-741       HBAMC42   309   572938   AL133419   1231    1-150       HBAMC23   312   572946   AL163151   1232    1-451       HBAMC05   313   932234   AL356019   1233    1-795                           3029-3404                           5031-5269                           6359-6575                           6757-6902                           7437-7493                           9843-9935                           10345-10498                           11221-11501                           11654-11866                           12881-13014                           14133-14247                           16803-17149                           17484-17858       HBAMC05   313   932234   AL356019   1234    1-368       HBAMC05   313   932234   AL356019   1235    1-107       HBAGW31   314   960146   AC019194   1236     1-2243                           2706-3044                           3147-3252                           3286-3441                           4820-4941                           6238-6536                           6929-7332                           8567-9048                           9388-9684                            9981-10341                           12293-13505                           13876-13926                           14318-14400                           14800-15308                           15715-16364                           16560-16748                           17222-17571                           18347-18756                           19156-19615                           19666-19982                           21112-21428                           22550-22693                           28745-29143                           29809-31336                           32109-32397                           32731-33181                           35845-36323                           39352-39743                           40047-40483                           40677-40972                           44642-44840       HBAGW31   314   960146   AC020759   1237     1-1528       HBAGW31   314   960146   AC005632   1238     1-1528       HBAGW31   314   960146   AC020759   1239    1-399       HBAGW31   314   960146   AC020759   1240    1-289       HBAGW31   314   960146   AC005632   1241    1-289       HBAGW31   314   960146   AC005632   1242    1-399       HBAGR76   315   864389   AC013400   1243    1-476       HBAGR76   315   864389   AC013400   1244    1-760       HBAGH38   316   487933   AC020659   1245    1-671                            703-3178       HBAGH38   316   487933   AC020659   1246    1-309       HBAGH38   316   487933   AC020659   1247    1-276       HBAFU01   318   916248   AL355296   1248    1-474       HBAFU01   318   916248   AL355296   1249    1-320       HBAFU01   318   916248   AL355296   1250    1-143       HBAFP29   319   690521   AL353807   1251    1-957       HBAFP29   319   690521   AL353807   1252    1-155       HBAFF55   321   753801   AC021162   1253    1-967       HBAFF55   321   753801   AC021162   1254     1-1542       HBAFF55   321   753801   AC021162   1255    1-178       HAKAD91   324   509854   AC011875   1256    1-510       HAKAD91   324   509854   AP000848   1257    1-510       HAKAD91   324   509854   AP000663   1258    1-509       HAKAD91   324   509854   AP001320   1259    1-506       HAKAD91   324   509854   AP000848   1260    1-610       HAKAD91   324   509854   AC011875   1261    1-610       HAKAD91   324   509854   AP000848   1262    1-231       HAKAD91   324   509854   AP000663   1263    1-610       HAKAD91   324   509854   AP001320   1264    1-231       HAKAD91   324   509854   AP001320   1265    1-610       HAKAD72   325   509855   AP000425   1266    1-405       HAKAD72   325   509855   AP000425   1267    1-451                  
 
       [0066] Table 1B summarizes additional polynucleotides encompassed by the invention (including cDNA clones related to the sequences (Clone ID NO: Z), contig sequences (contig identifier (Contig ID:) contig nucleotide sequence identifiers (SEQ ID NO: X)), and genomic sequences (SEQ ID NO: B). The first column provides a unique clone identifier, “Clone ID NO: Z”, for a cDNA clone related to each contig sequence. The second column provides the sequence identifier, “SEQ ID NO: X”, for each contig sequence. The third column provides a unique contig identifier, “Contig ID:” for each contig sequence. The fourth column, provides a BAC identifier “BAC ID NO:A” for the BAC clone referenced in the corresponding row of the table. The fifth column provides the nucleotide sequence identifier, “SEQ ID NO: B” for a fragment of the BAC clone identified in column four of the corresponding row of the table. The sixth column, “Exon From-To”, provides the location (i.e., nucleotide position numbers) within the polynucleotide sequence of SEQ ID NO: B which delineate certain polynucleotides of the invention that are also exemplary members of polynucleotide sequences that encode polypeptides of the invention (e.g., polypeptides containing amino acid sequences encoded by the polynucleotide sequences delineated in column six, and fragments and variants thereof).  
                                               TABLE 2                               SEQ           PFam/NR   Score/               Clone ID   Contig   ID   Analysis       Accession   Percent   NT   NT       NO: Z   ID:    NO: X   Method   PFam/NR Description   Number   Identity   From   To                                                                    HFKEJ40   909830   28   HMMER   PFAM: RhoGAP domain   PF00620   21.6   59   127                   2.1.1       HFKEN74   974309   32   blastx.2   (AK002129) unnamed   dbj|BAA92096.1|   47%   385   594                       protein product [ Homo                           sapiens ]       HFKFI14   670322   43   blastx.2   (AF047437) sperm   gb|AAC39888.1|   73%   87   368                       acrosomal protein [ Homo                           sapiens ]       HFKFI44   929786   45   blastx.2   The ha0936 gene product   dbj|BAA07551.1|   95%   8   142                       is novel. [ Homo sapiens ]       48%   136   249                               45%   180   296       HFKGA94   855099   52   blastx.2   alternatively spliced   gb|AAB49034.1|   94%   168   221                       product using exon 13A       54%   79   144                       [ Homo sapiens ]       61%   242   304       HFKHB46   965767   56   blastx.2   (AL035405) dJ21O18.2   emb|CAB46021.1|   80%   187   312                       (protein similar to       90%   312   344                       collagen) [ Homo sapiens ]       HFKHE67   881093   61   blastx.2   (AL117662) hypothetical   emb|CAB56033.1|   60%   121   339                       protein [ Homo sapiens ]       HFKHG06   965906   63   blastx.2   (AK000575) unnamed   dbj|BAA91265.1|   63%   64   198                       protein product [ Homo                           sapiens ]       HFKHH68   961433   64   blastx.2   (AK000031) unnamed   dbj|BAA90894.1|   92%   249   503                       protein product [ Homo                           sapiens ]       HFKIP07   924825   74   blastx.2   (AB026288) pharbin   dbj|BAA82150.1|   78%   214   339                       [ Rattus norvegicus ]       HFKIP11   965072   75   HMMER   PFAM: Domain of   PF01958   55.5   94   384                   2.1.1   unknown function                   blastx.2   cDNA EST   emb|CAA84799.1|   46%   94   384                       EMBL: D67419 comes                       from this gene; cDNA                       EST 11 yk234a7.5 comes                       from this gene; cDNA                       EST yk299a6.3 comes                       from th       HFKIR40   883093   76   blastx.2   (AF151078) HSPC244   gb|AAF36164.1|   100%   287   397                       [ Homo sapiens ]   AF151078_1   96%   414   503                               73%   214   258       HFKIS93   854862   77   blastx.2   (AL050318) dJ977B1.4   emb|CAB75368.1|   76%   3   221                       (novel protein similar to                       TGIF 1       HFKIW31   918243   79   HMMER   PFAM: Cyclic nucleotide-   PF00027   45.5   79   231                   2.1.1   binding domain                   blastx.2   (AB022697) BEC1   dbj|BAA83591.1|   97%   94   366                       [ Rattus norvegicus ]       68%   348   413       HFKJL17   854829   83   blastx.2   (AK000385) unnamed   dbj|BAA91131.1|   58%   123   221                       protein product [ Homo         90%   215   244                         sapiens ]       62%   40   63       HFKJL36   930422   84   blastx.2   (AK000496) unnamed   dbj|BAA91205.1|   75%   301   122                       protein product [ Homo         53%   413   297                         sapiens ]       HFKKS48   854927   92   blastx.2   (AF118082) PRO1902   gb|AAF22026.1|   40%   348   539                       [ Homo sapiens ]   AF118094_21       HFKKU68   854913   93   blastx.2   (AF090942) PRO0657   gb|AAF24054.1|   73%   411   500                       [ Homo sapiens ]   AF090942_1   81%   308   355                               68%   361   408       HFKLD11   965830   94   HMMER   PFAM: PH domain   PF00169   25.2   414   530                   2.1.1                   blastx.2   IDN4-GGTR14   sp|Q9Y6Y5|Q9Y6Y5   91%   1   102                       PROTEIN.       HFKLX38   880220   99   HMMER   PFAM: PMP-   PF00822   103.9   9   299                   2.1.1   22/EMP/MP20/Claudin                       family                   blastx.2   (AF087825) claudin-7   gb|AAD09760.1|   44%   3   299                       [ Mus musculus ]       HKDAF34   703405   103   blastx.2   (AK000496) unnamed   dbj|BAA91205.1|   60%   18   167                       protein product [ Homo         75%   175   234                         sapiens ]       HKDAF84   781937   104   blastx.2   alternatively spliced   gb|AAB49034.1|   72%   394   320                       product using exon 13A       67%   284   192                       [ Homo sapiens ]       50%   195   142       HKIXA37   735445   112   blastx.2   (AF091083) unknown   gb|AAC72952.1|   71%   8   349                       [ Homo sapiens ]       HKIXB03   924636   113   HMMER   PFAM: FAD/NAD-   PF00175   31.48   192   326                   1.8   binding domain in                       oxidoreductases                   blastx.2   (AL133582) hypothetical   emb|CAB63726.1|   85%   144   371                       protein [ Homo sapiens ]       HKIXG58   464241   117   HMMER   PFAM: Phorbol esters/   PF00130   3.59   84   137                   1.8   diacylglycerol binding                       domain       HKIXY04   736085   125   blastx.2   homeotic protein Gtx-   pir|S35304|S35304   100%   5   184                       mouse       HKIYF45   970756   126   blastx.2   (AF010144) neuronal   gb|AAC08737.1|   56%   68   376                       thread protein AD7c-NTP       67%   189   377                       [ Homo sapiens ]       50%   92   334                               61%   249   371                               40%   155   256                               47%   322   372       HKIYQ89   625636   130   blastx.2   (AF079765) enhancer of   gb|AAC64272.1|   63%   8   214                       polycomb [ Mus musculus ]       50%   215   238       HKMAA07   954358   131   blastx.2   zinc finger protein [ Homo     gb|AAA59469.1|   79%   149   48                         sapiens ]       HKMMF21   969002   142   blastx.2   p82 [ Homo sapiens ]   gb|AAC50926.1|   45%   242   856                               61%   48   233       HKMMG47   720379   143   blastx.2     C. elegans  mec-2   gb|AAA82333.1|   41%   2   271                       (GB: U26735)                       [ Caenorhabditis elegans ]       HKMMJ67   575750   144   blastx.2   (AF090931) PRO0483   gb|AAF24046.1|   81%   104   6                       [ Homo sapiens ]   AF090931_1       HRACL64   674012   155   blastx.2   (AC007055) unknown   gb|AAD31939.1|   88%   3   164                       [ Homo sapiens ]   AC007055_4       HRADN24   877323   164   blastx.2   (AB023811) TU3A   dbj|BAA82845.1|   69%   240   347                       [ Homo sapiens ]       HRKAB10   968272   168   blastx.2   metal response element   gb|AAC34714.1|   54%   156   248                       DNA-binding protein       85%   268   309                       M96 [ Mus musculus ]       HRKAB80   930473   174   blastx.2   alternate gene name ygcB;   gb|AAA69271.1|   98%   2   355                       ORF f888 [ Escherichia                           coli ]       HRADM45   717358   186   HMMER   PFAM: Eukaryotic protein   PF00069   23.7   14   124                   1.8   kinase domain                   blastx.2   (AJ271722) putative   emb|CAB71146.1|   98%   2   469                       serine/threonine protein                       kinase MAK-V [ Homo                           sapiens ]       HRACX37   711466   192   blastx.2   (AF100753) ancient   gb|AAD43017.1|   97%   3   104                       ubiquitous 46 kDa protein       60%   200   382                       AUP1 [ Homo sapiens ]       42%   348   425       HRACV26   793997   194   blastx.2   (AK000385) unnamed   dbj|BAA91131.1|   68%   46   198                       protein product [ Homo         71%   179   241                         sapiens ]       92%   246   287       HRACR57   745443   196   blastx.2   (AK000249) unnamed   dbj|BAA91030.1|   100%   361   459                       protein product [ Homo         94%   462   512                         sapiens ]       HRACD65   918345   201   blastx.2   (AL117233) hypothetical   emb|CAB55300.1|   97%   246   377                       protein [ Homo sapiens ]       86%   419   463                               100%   379   417       HRAAI91   790090   219   HMMER   PFAM: Zinc-binding   PF00099   2.96   343   384                   1.8   metalloprotease domain       HRAAD24   676567   221   blastx.2   (AL117428) hypothetical   emb|CAB55917.1|   99%   135   491                       protein [ Homo sapiens ]       HKPBA75   767550   226   blastx.2   (AF090894) PRO0113   gb|AAF24018.1|   52%   294   94                       [ Homo sapiens ]   AF090894_1       HKIYS82   779904   252   blastx.2   (AK000385) unnamed   dbj|BAA91131.1|   82%   185   102                       protein product [ Homo         84%   96   40                         sapiens ]       HKIYC29   725699   258   blastx.2   Contains C3HC4 type   dbj|BAA13392.1|   78%   131   463                       zinc finger signature       84%   3   161                       [ Homo sapiens ]       HKISA86   785613   264   blastx.2   (AL031290) dJ774I24.2   emb|CAA20359.1|   91%   79   150                       (NEURONAL                       MIGRATION PROTEIN                       ASTROTACTIN) [ Homo                           sapiens ]       HKIMG03   924745   266   blastx.2   (AK000531) unnamed   dbj|BAA91235.1|   52%   295   501                       protein product [ Homo                           sapiens ]       HFKLC10   963164   270   blastx.2   unnamed protein product   emb|CAB42187.1|   100%   1   87                       [unidentified]       HFKJP91   836476   271   blastx.2   UDP-GalNAc: polypeptide   emb|CAA59381.1|   62%   1   537                       N-acetylgalactosaminyl                       transferase [ Homo                           sapiens ]       HFKDE75   766436   278   blastx.2   (AL117424) hypothetical   emb|CAB55916.1|   72%   43   378                       protein [ Homo sapiens ]       66%   2   37       HFKCO02   917279   280   blastx.2   truncated protein   gb|AAB31222.1|   84%   97   20                       [ Saccharomyces                           cerevisiae ]       HFKBC11   967999   285   blastx.2   (AK000385) unnamed   dbj|BAA91131.1|   69%   67   183                       protein product [ Homo         62%   3   74                         sapiens ]       HFKBC08   960526   286   blastx.2   (AK001512) unnamed   dbj|BAA91732.1|   94%   150   518                       protein product [ Homo                           sapiens ]       HBAMD41   573374   296   blastx.2   (AK000496) unnamed   dbj|BAA91205.1|   60%   198   55                       protein product [ Homo         32%   299   207                         sapiens ]       HBAMC62   572927   306   blastx.2   (AF113685) PRO0974   gb|AAF29584.1|   51%   2   235                       [ Homo sapiens ]   AF113685_1       HBAMC52   572935   307   blastx.2   putative p150 [ Homo     gb|AAC51271.1|   70%   77   196                         sapiens ]       61%   12   74       HBAFV71   932783   317   blastx.2   (AB010441) UDP-   dbj|BAA75219.1|   96%   68   310                       glucuronyltransferase-S       89%   402   488                       [ Rattus norvegicus ]       75%   1   75                               84%   48   86                               60%   304   333       HBAFF09   926667   322   blastx.2   (AF184967) heparanase   gb|AAF04563.1|   51%   16   633                       [ Rattus norvegicus ]   AF184967_1                  
 
       [0067] Table 2 further characterizes certain encoded polypeptides of the invention, by providing the results of comparisons to protein and protein family databases. The first column provides a unique clone identifier, “Clone ID NO:”, corresponding to a cDNA clone disclosed in Table 1A. The second column provides the unique contig indentifier, “Contig ID:” which allows correlation with the information in Table 1A. The third column provides the sequence identifier, “SEQ ID NO: X”, for the contig polynucleotide sequences. The fourth column provides the analysis method by which the homology/identity disclosed in the row was determined. The fifth column provides a description of PFam/NR hits having significant matches identified by each analysis. Column six provides the accession number of the PFam/NR hit disclosed in the fifth column. Column seven, “Score/Percent Identity”, provides a quality score or the percent identity, of the hit disclosed in column five. Comparisons were made between polypeptides encoded by polynucleotides of the invention and a non-redundant protein database (herein referred to as “NR”), or a database of protein families (herein referred to as “PFam”), as described below.  
       [0068] The NR database, which comprises the NBRF PIR database, the NCBI GenPept database, and the SIB SwissProt and TrEMBL databases, was made non-redundant using the computer program nrdb2 (Warren Gish, Washington University in Saint Louis). Each of the polynucleotides shown in Table 1A, column 3 (e.g., SEQ ID NO: X or the ‘Query’ sequence) was used to search against the NR database. The computer program BLASTX was used to compare a 6-frame translation of the Query sequence to the NR database (for information about the BLASTX algorithm please see Altshul et al., J. Mol. Biol. 215:403-410 (1990), and Gish et al., Nat. Genet. 3:266-272 (1993)). A description of the sequence that is most similar to the Query sequence (the highest scoring ‘Subject’) is shown in column five of Table 2 and the database accession number for that sequence is provided in column six. The highest scoring ‘Subject’ is reported in Table 2 if (a) the estimated probability that the match occurred by chance alone is less than 1.0e-07, and (b) the match was not to a known repetitive element. BLASTX returns alignments of short polypeptide segments of the Query and Subject sequences which share a high degree of similarity; these segments are known as High-Scoring Segment Pairs or HSPs. Table 2 reports the degree of similarity between the Query and the Subject for each HSP as a percent identity in Column 7. The percent identity is determined by dividing the number of exact matches between the two aligned sequences in the HSP, dividing by the number of Query amino acids in the HSP and multiplying by 100. The polynucleotides of SEQ ID NO: X which encode the polypeptide sequence that generates an HSP are delineated by columns 8 and 9 of Table 2.  
       [0069] The PFam database, PFam version 5.2, (Sonnhammer et al., Nucl. Acids Res., 26:320-322, (1998)) consists of a series of multiple sequence alignments; one alignment for each protein family. Each multiple sequence alignment is converted into a probability model called a Hidden Markov Model, or HMM, that represents the position-specific variation among the sequences that make up the multiple sequence alignment (see, e.g., R. Durbin et al.,  Biological sequence analysis: probabilistic models of proteins and nucleic acids,  Cambridge University Press, 1998 for the theory of HMMs). The program HMMER version 1.8 (Sean Eddy, Washington University in Saint Louis) was used to compare the predicted protein sequence for each Query sequence (SEQ ID NO: Y in Table 1A) to each of the HMMs derived from PFam version 5.2. A HMM derived from PFam version 5.2 was said to be a significant match to a polypeptide of the invention if the score returned by HMMER 1.8 was greater than 0.8 times the HMMER 1.8 score obtained with the most distantly related known member of that protein family. The description of the PFam family which shares a significant match with a polypeptide of the invention is listed in column 5 of Table 2, and the database accession number of the PFam hit is provided in column 6. Column 7 provides the score returned by HMMER version 1.8 for the alignment. Columns 8 and 9 delineate the polynucleotides of SEQ ID NO: X which encode the polypeptide sequence which shows a significant match to a PFam protein family.  
       [0070] As mentioned, columns 8 and 9 in Table 2, “NT From” and “NT To”, delineate the polynucleotides of “SEQ ID NO: X” that encode a polypeptide having a significant match to the PFam/NR database as disclosed in the fifth column of Table 2. In one embodiment, the invention provides a protein comprising, or alternatively consisting of, a polypeptide encoded by the polynucleotides of SEQ ID NO: X delineated in columns 8 and 9 of Table 2. Also provided are polynucleotides encoding such proteins, and the complementary strand thereto.  
       [0071] The nucleotide sequence SEQ ID NO: X and the translated SEQ ID NO: Y are sufficiently accurate and otherwise suitable for a variety of uses well known in the art and described further below. For instance, the nucleotide sequences of SEQ ID NO: X are useful for designing nucleic acid hybridization probes that will detect nucleic acid sequences contained in SEQ ID NO: X or the cDNA contained in Clone ID NO: Z. These probes will also hybridize to nucleic acid molecules in biological samples, thereby enabling immediate applications in chromosome mapping, linkage analysis, tissue identification and/or typing, and a variety of forensic and diagnostic methods of the invention. Similarly, polypeptides identified from SEQ ID NO: Y may be used to generate antibodies which bind specifically to these polypeptides, or fragments thereof, and/or to the polypeptides encoded by the cDNA clones identified in, for example, Table 1A.  
       [0072] Nevertheless, DNA sequences generated by sequencing reactions can contain sequencing errors. The errors exist as misidentified nucleotides, or as insertions or deletions of nucleotides in the generated DNA sequence. The erroneously inserted or deleted nucleotides cause frame shifts in the reading frames of the predicted amino acid sequence. In these cases, the predicted amino acid sequence diverges from the actual amino acid sequence, even though the generated DNA sequence may be greater than 99.9% identical to the actual DNA sequence (for example, one base insertion or deletion in an open reading frame of over 1000 bases).  
       [0073] Accordingly, for those applications requiring precision in the nucleotide sequence or the amino acid sequence, the present invention provides not only the generated nucleotide sequence identified as SEQ ID NO: X, and a predicted translated amino acid sequence identified as SEQ ID NO: Y, but also a sample of plasmid DNA containing cDNA Clone ID NO: Z (deposited with the ATCC on Oct. 5, 2000, and receiving ATCC designation numbers PTA 2574 and PTA 2575; deposited with the ATCC on Jan. 5, 2001, having the depositor reference numbers TS-1, TS-2, AC-1, and AC-2; and/or as set forth, for example, in Table 1A, 6 and 7). The nucleotide sequence of each deposited clone can readily be determined by sequencing the deposited clone in accordance with known methods. Further, techniques known in the art can be used to verify the nucleotide sequences of SEQ ID NO: X.  
       [0074] The predicted amino acid sequence can then be verified from such deposits. Moreover, the amino acid sequence of the protein encoded by a particular clone can also be directly determined by peptide sequencing or by expressing the protein in a suitable host cell containing the deposited human cDNA, collecting the protein, and determining its sequence.  
       [0075] RACE Protocol For Recovery of Full-Length Genes  
       [0076] Partial cDNA clones can be made full-length by utilizing the rapid amplification of cDNA ends (RACE) procedure described in Frohman, M. A., et al., Proc. Nat&#39;l. Acad. Sci. USA, 85:8998-9002 (1988). A cDNA clone missing either the 5′ or 3′ end can be reconstructed to include the absent base pairs extending to the translational start or stop codon, respectively. In some cases, cDNAs are missing the start codon of translation. The following briefly describes a modification of this original 5′ RACE procedure. Poly A+ or total RNA is reverse transcribed with Superscript II (Gibco/BRL) and an antisense or complementary primer specific to the cDNA sequence. The primer is removed from the reaction with a Microcon Concentrator (Amicon). The first-strand cDNA is then tailed with dATP and terminal deoxynucleotide transferase (Gibco/BRL). Thus, an anchor sequence is produced which is needed for PCR amplification. The second strand is synthesized from the dA-tail in PCR buffer, Taq DNA polymerase (Perkin-Elmer Cetus), an oligo-dT primer containing three adjacent restriction sites (XhoI, SalI and ClaI) at the 5′ end and a primer containing just these restriction sites. This double-stranded cDNA is PCR amplified for 40 cycles with the same primers as well as a nested cDNA-specific antisense primer. The PCR products are size-separated on an ethidium bromide-agarose gel and the region of gel containing cDNA products the predicted size of missing protein-coding DNA is removed. cDNA is purified from the agarose with the Magic PCR Prep kit (Promega), restriction digested with XhoI or SalI, and ligated to a plasmid such as pBluescript SKII (Stratagene) at XhoI and EcoRV sites. This DNA is transformed into bacteria and the plasmid clones sequenced to identify the correct protein-coding inserts. Correct 5′ ends are confirmed by comparing this sequence with the putatively identified homologue and overlap with the partial cDNA clone. Similar methods known in the art and/or commercial kits are used to amplify and recover 3′ ends.  
       [0077] Several quality-controlled kits are commercially available for purchase. Similar reagents and methods to those above are supplied in kit form from Gibco/BRL for both 5′ and 3′ RACE for recovery of full length genes. A second kit is available from Clontech which is a modification of a related technique, SLIC (single-stranded ligation to single-stranded cDNA), developed by Dumas et al., Nucleic Acids Res., 19:5227-32 (1991). The major differences in procedure are that the RNA is alkaline hydrolyzed after reverse transcription and RNA ligase is used to join a restriction site-containing anchor primer to the first-strand cDNA. This obviates the necessity for the dA-tailing reaction which results in a polyT stretch that is difficult to sequence past.  
       [0078] An alternative to generating 5′ or 3′ cDNA from RNA is to use cDNA library double-stranded DNA. An asymmetric PCR-amplified antisense cDNA strand is synthesized with an antisense cDNA-specific primer and a plasmid-anchored primer. These primers are removed and a symmetric PCR reaction is performed with a nested cDNA-specific antisense primer and the plasmid-anchored primer.  
       [0079] RNA Ligase Protocol for Generating the 5′ or 3′ End Sequences to Obtain Full Length Genes  
       [0080] Once a gene of interest is identified, several methods are available for the identification of the 5′ or 3′ portions of the gene which may not be present in the original cDNA plasmid. These methods include, but are not limited to, filter probing, clone enrichment using specific probes and protocols similar and identical to 5′ and 3′ RACE. While the full length gene may be present in the library and can be identified by probing, a useful method for generating the 5′ or 3′ end is to use the existing sequence information from the original cDNA to generate the missing information. A method similar to 5′ RACE is available for generating the missing 5′ end of a desired full-length gene. (This method was published by Fromont-Racine et al., Nucleic Acids Res., 21(7):1683-1684 (1993)). Briefly, a specific RNA oligonucleotide is ligated to the 5′ ends of a population of RNA presumably containing full-length gene RNA transcript. A primer set containing a primer specific to the ligated RNA oligonucleotide and a primer specific to a known sequence of the gene of interest, is used to PCR amplify the 5′ portion of the desired full length gene which may then be sequenced and used to generate the full length gene. This method starts with total RNA isolated from the desired source, poly A RNA may be used but is not a prerequisite for this procedure. The RNA preparation may then be treated with phosphatase if necessary to eliminate 5′ phosphate groups on degraded or damaged RNA, which may interfere with the later RNA ligase step. The phosphatase, if used, is then inactivated and the RNA is treated with tobacco acid pyrophosphatase in order to remove the cap structure present at the 5′ ends of messenger RNAs. This reaction leaves a 5′ phosphate group at the 5′ end of the cap cleaved RNA which can then be ligated to an RNA oligonucleotide using T4 RNA ligase. This modified RNA preparation can then be used as a template for first strand cDNA synthesis using a gene specific oligonucleotide. The first strand synthesis reaction can then be used as a template for PCR amplification of the desired 5′ end using a primer specific to the ligated RNA oligonucleotide and a primer specific to the known sequence of the excretory system antigen of interest. The resultant product is then sequenced and analyzed to confirm that the 5′ end sequence belongs to the relevant excretory system antigen.  
       [0081] The present invention also relates to vectors or plasmids, which include such DNA sequences, as well as the use of the DNA sequences. The material deposited with the ATCC (deposited with the ATCC on Oct. 5, 2000, and receiving ATCC designation numbers PTA 2574 and PTA 2575; deposited with the ATCC on Jan. 5, 2001, having the depositor reference numbers TS-1, TS-2, AC-1, and AC-2; and/or as set forth, for example, in Table 1A, 6 and 7) is a mixture of cDNA clones derived from a variety of human tissue and cloned in either a plasmid vector or a phage vector, as shown, for example, in Table 7. These deposits are referred to as “the deposits” herein. The tissues from which some of the clones were derived are listed in Table 7, and the vector in which the corresponding cDNA is contained is also indicated in Table 7. The deposited material includes cDNA clones corresponding to SEQ ID NO: X described, for example, in Table 1A (Clone ID NO: Z). A clone which is isolatable from the ATCC Deposits by use of a sequence listed as SEQ ID NO: X, may include the entire coding region of a human gene or in other cases such clone may include a substantial portion of the coding region of a human gene. Furthermore, although the sequence listing may in some instances list only a portion of the DNA sequence in a clone included in the ATCC Deposits, it is well within the ability of one skilled in the art to sequence the DNA included in a clone contained in the ATCC Deposits by use of a sequence (or portion thereof) described in, for example Tables 1A or 2 by procedures hereinafter further described, and others apparent to those skilled in the art.  
       [0082] Also provided in Table 7 is the name of the vector which contains the cDNA clone. Each vector is routinely used in the art. The following additional information is provided for convenience.  
       [0083] Vectors Lambda Zap (U.S. Pat. Nos. 5,128,256 and 5,286,636), Uni-Zap XR (U.S. Pat. Nos. 5,128,256 and 5,286,636), Zap Express (U.S. Pat. Nos. 5,128,256 and 5,286,636), pBluescript (pBS) (Short, J. M. et al.,  Nucleic Acids Res.  16:7583-7600 (1988); Alting-Mees, M. A. and Short, J. M.,  Nucleic Acids Res.  17:9494 (1989)) and pBK (Alting-Mees, M. A. et al.,  Strategies  5:58-61 (1992)) are commercially available from Stratagene Cloning Systems, Inc., 11011 N. Torrey Pines Road, La Jolla, Calif., 92037. pBS contains an ampicillin resistance gene and pBK contains a neomycin resistance gene. Phagemid pBS may be excised from the Lambda Zap and Uni-Zap XR vectors, and phagemid pBK may be excised from the Zap Express vector. Both phagemids may be transformed into  E. coli  strain XL-1 Blue, also available from Stratagene.  
       [0084] Vectors pSport1, pCMVSport 1.0, pCMVSport 2.0 and pCMVSport 3.0, were obtained from Life Technologies, Inc., P.O. Box 6009, Gaithersburg, Md. 20897. All Sport vectors contain an ampicillin resistance gene and may be transformed into  E. coli  strain DH10B, also available from Life Technologies. See, for instance, Gruber, C. E., et al.,  Focus  15:59-(1993). Vector lafmid B A (Bento Soares, Columbia University, New York, N.Y.) contains an ampicillin resistance gene and can be transformed into  E. coli  strain XL-1 Blue. Vector pCR® 2.1, which is available from Invitrogen, 1600 Faraday Avenue, Carlsbad, Calif. 92008, contains an ampicillin resistance gene and may be transformed into  E. coli  strain DH10B, available from Life Technologies. See, for instance, Clark, J. M., Nuc. Acids Res. 16:9677-9686 (1988) and Mead, D. et al., Bio/Technology 9: (1991).  
       [0085] The present invention also relates to the genes corresponding to SEQ ID NO: X, SEQ ID NO: Y, and/or the deposited clone (Clone ID NO: Z). The corresponding gene can be isolated in accordance with known methods using the sequence information disclosed herein. Such methods include preparing probes or primers from the disclosed sequence and identifying or amplifying the corresponding gene from appropriate sources of genomic material.  
       [0086] Also provided in the present invention are allelic variants, orthologs, and/or species homologs. Procedures known in the art can be used to obtain full-length genes, allelic variants, splice variants, full-length coding portions, orthologs, and/or species homologs of excretory system associated genes corresponding to SEQ ID NO: X or the complement thereof, polypeptides encoded by SEQ ID NO: X or the complement thereof, and/or the cDNA contained in Clone ID NO: Z, using information from the sequences disclosed herein or the clones deposited with the ATCC. For example, allelic variants and/or species homologs may be isolated and identified by making suitable probes or primers from the sequences provided herein and screening a suitable nucleic acid source for allelic variants and/or the desired homologue.  
       [0087] The polypeptides of the invention can be prepared in any suitable manner. Such polypeptides include isolated naturally occurring polypeptides, recombinantly produced polypeptides, synthetically produced polypeptides, or polypeptides produced by a combination of these methods. Means for preparing such polypeptides are well understood in the art.  
       [0088] The polypeptides may be in the form of the secreted protein, including the mature form, or may be a part of a larger protein, such as a fusion protein (see below). It is often advantageous to include an additional amino acid sequence which contains secretory or leader sequences, pro-sequences, sequences which aid in purification, such as multiple histidine residues, or an additional sequence for stability during recombinant production.  
       [0089] The polypeptides of the present invention are preferably provided in an isolated form, and preferably are substantially purified. A recombinantly produced version of a polypeptide, including the secreted polypeptide, can be substantially purified using techniques described herein or otherwise known in the art, such as, for example, by the one-step method described in Smith and Johnson, Gene 67:31-40 (1988). Polypeptides of the invention also can be purified from natural, synthetic or recombinant sources using techniques described herein or otherwise known in the art, such as, for example, antibodies of the invention raised against the excretory system polypeptides of the present invention in methods which are well known in the art.  
       [0090] The present invention provides a polynucleotide comprising, or alternatively consisting of, the nucleic acid sequence of SEQ ID NO: X, and/or the cDNA sequence contained in Clone ID NO: Z. The present invention also provides a polypeptide comprising, or alternatively, consisting of, the polypeptide sequence of SEQ ID NO: Y, a polypeptide encoded by SEQ ID NO: X or a complement thereof, a polypeptide encoded by the cDNA contained in Clone ID NO: Z, and/or the polypeptide sequence encoded by a nucleotide sequence in SEQ ID NO: B as defined in column 6 of Table 1B. Polynucleotides encoding a polypeptide comprising, or alternatively consisting of the polypeptide sequence of SEQ ID NO: Y, a polypeptide encoded by SEQ ID NO: X, a polypeptide encoded by the cDNA contained in Clone ID NO: Z and/or a polypeptide sequence encoded by a nucleotide sequence in SEQ ID NO: B as defined in column 6 of Table 1B are also encompassed by the invention. The present invention further encompasses a polynucleotide comprising, or alternatively consisting of, the complement of the nucleic acid sequence of SEQ ID NO: X, a nucleic acid sequence encoding a polypeptide encoded by the complement of the nucleic acid sequence of SEQ ID NO: X, and/or the cDNA contained in Clone ID NO: Z.  
       [0091] Moreover, representative examples of polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the sequences delineated in Table 1B column 6, or any combination thereof. Additional, representative examples of polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the complementary strand(s) of the sequences delineated in Table 1B column 6, or any combination thereof. In further embodiments, the above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in Table 1B, column 6, and have a nucleic acid sequence which is different from that of the BAC fragment having the sequence disclosed in SEQ ID NO: B (see Table 1B, column 5). In additional embodiments, the above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in Table 1B, column 6, and have a nucleic acid sequence which is different from that published for the BAC clone identified as BAC ID NO:A (see Table 1B, column 4). In additional embodiments, the above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in Table 1B, column 6, and have a nucleic acid sequence which is different from that contained in the BAC clone identified as BAC ID NO: A (see Table 1B, column 4). Polypeptides encoded by these polynucleotides, other polynucleotides that encode these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides and polypeptides are also encompassed by the invention.  
       [0092] Further, representative examples of polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the sequences delineated in column 6 of Table 1B which correspond to the same Clone ID NO: Z (see Table 1B, column 1), or any combination thereof. Additional, representative examples of polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the complementary strand(s) of the sequences delineated in column 6 of Table 1B which correspond to the same Clone ID NO: Z (see Table 1B, column 1), or any combination thereof. In further embodiments, the above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in column 6 of Table 1B which correspond to the same Clone ID NO: Z (see Table 1B, column 1) and have a nucleic acid sequence which is different from that of the BAC fragment having the sequence disclosed in SEQ ID NO: B (see Table 1B, column 5). In additional embodiments, the above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in column 6 of Table 1B which correspond to the same Clone ID NO: Z (see Table 1B, column 1) and have a nucleic acid sequence which is different from that published for the BAC clone identified as BAC ID NO: A (see Table 1B, column 4). In additional embodiments, the above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in column 6 of Table 1B which correspond to the same Clone ID NO: Z (see Table 1B, column 1) and have a nucleic acid sequence which is different from that contained in the BAC clone identified as BAC ID NO: A (see Table 1B, column 4). Polypeptides encoded by these polynucleotides, other polynucleotides that encode these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides and polypeptides are also encompassed by the invention.  
       [0093] Further, representative examples of polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the sequences delineated in column 6 of Table 1B which correspond to the same contig sequence identifer SEQ ID NO: X (see Table 1B, column 2), or any combination thereof. Additional, representative examples of polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the complementary strand(s) of the sequences delineated in column 6 of Table 1B which correspond to the same contig sequence identifer SEQ ID NO: X (see Table 1B, column 2), or any combination thereof. In further embodiments, the above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in column 6 of Table 1B which correspond to the same contig sequence identifer SEQ ID NO: X (see Table 1B, column 2) and have a nucleic acid sequence which is different from that of the BAC fragment having the sequence disclosed in SEQ ID NO: B (see Table 1B, column 5). In additional embodiments, the above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in column 6 of Table 1B which correspond to the same contig sequence identifer SEQ ID NO: X (see Table 1B, column 2) and have a nucleic acid sequence which is different from that published for the BAC clone identified as BAC ID NO: A (see Table 1B, column 4). In additional embodiments, the above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in column 6 of Table 1B which correspond to the same contig sequence identifer SEQ ID NO: X (see Table 1B, column 2) and have a nucleic acid sequence which is different from that contained in the BAC clone identified as BAC ID NO: A (See Table 1B, column 4). Polypeptides encoded by these polynucleotides, other polynucleotides that encode these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides and polypeptides are also encompassed by the invention.  
       [0094] Moreover, representative examples of polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the sequences delineated in the same row of Table 1B column 6, or any combination thereof. Additional, representative examples of polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the complementary strand(s) of the sequences delineated in the same row of Table 1B column 6, or any combination thereof. In preferred embodiments, the polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the complementary strand(s) of the sequences delineated in the same row of Table 1B column 6, wherein sequentially delineated sequences in the table (i.e. corresponding to those exons located closest to each other) are directly contiguous in a 5′ to 3′ orientation. In further embodiments, above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in the same row of Table 1B, column 6, and have a nucleic acid sequence which is different from that of the BAC fragment having the sequence disclosed in SEQ ID NO: B (see Table 1B, column 5). In additional embodiments, the above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in the same row of Table 1B, column 6, and have a nucleic acid sequence which is different from that published for the BAC clone identified as BAC ID NO: A (see Table 1B, column 4). In additional embodiments, the above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in the same row of Table 1B, column 6, and have a nucleic acid sequence which is different from that contained in the BAC clone identified as BAC ID NO: A (see Table 1B, column 4). Polypeptides encoded by these polynucleotides, other polynucleotides that encode these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention.  
       [0095] In additional specific embodiments, polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the sequences delineated in column 6 of Table 1B, and the polynucleotide sequence of SEQ ID NO: X (e.g., as defined in Table 1B, column 2) or fragments or variants thereof. Polypeptides encoded by these polynucleotides, other polynucleotides that encode these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention.  
       [0096] In additional specific embodiments, polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the sequences delineated in column 6 of Table 1B which correspond to the same Clone ID NO: Z (see Table 1B, column 1), and the polynucleotide sequence of SEQ ID NO: X (e.g., as defined in Table 1A or 1B) or fragments or variants thereof. In preferred embodiments, the delineated sequence(s) and polynucleotide sequence of SEQ ID NO: X correspond to the same Clone ID NO: Z. Polypeptides encoded by these polynucleotides, other polynucleotides that encode these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention  
       [0097] In further specific embodiments, polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the sequences delineated in the same row of column 6 of Table 1B, and the polynucleotide sequence of SEQ ID NO: X (e.g., as defined in Table 1A or 1B) or fragments or variants thereof. In preferred embodiments, the delineated sequence(s) and polynucleotide sequence of SEQ ID NO: X correspond to the same row of column 6 of Table 1B. Polypeptides encoded by these polynucleotides, other polynucleotides that encode these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention.  
       [0098] In additional specific embodiments, polynucleotides of the invention comprise, or alternatively consist of a polynucleotide sequence in which the 3′ 10 polynucleotides of one of the sequences delineated in column 6 of Table 1B and the 5′ 10 polynucleotides of the sequence of SEQ ID NO: X are directly contiguous. Nucleic acids which hybridize to the complement of these 20 contiguous polynucleotides under stringent hybridization conditions or alternatively, under lower stringency conditions, are also encompassed by the invention. Polypeptides encoded by these polynucleotides and/or nucleic acids, other polynucleotides and/or nucleic acids that encode these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides, nucleic acids, and polypeptides are also encompassed by the invention.  
       [0099] In additional specific embodiments, polynucleotides of the invention comprise, or alternatively consist of, a polynucleotide sequence in which the 3′ 10 polynucleotides of one of the sequences delineated in column 6 of Table 1B and the 5′ 10 polynucleotides of a fragment or variant of the sequence of SEQ ID NO: X are directly contiguous Nucleic acids which hybridize to the complement of these 20 contiguous polynucleotides under stringent hybridization conditions or alternatively, under lower stringency conditions, are also encompassed by the invention. Polypeptides encoded by these polynucleotides and/or nucleic acids, other polynucleotides and/or nucleic acids encoding these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides, nucleic acids, and polypeptides are also encompassed by the invention.  
       [0100] In specific embodiments, polynucleotides of the invention comprise, or alternatively consist of, a polynucleotide sequence in which the 3′ 10 polynucleotides of the sequence of SEQ ID NO: X and the 5′ 10 polynucleotides of the sequence of one of the sequences delineated in column 6 of Table 1B are directly contiguous. Nucleic acids which hybridize to the complement of these 20 contiguous polynucleotides under stringent hybridization conditions or alternatively, under lower stringency conditions, are also encompassed by the invention. Polypeptides encoded by these polynucleotides and/or nucleic acids, other polynucleotides and/or nucleic acids encoding these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides, nucleic acids, and polypeptides are also encompassed by the invention.  
       [0101] In specific embodiments, polynucleotides of the invention comprise, or alternatively consist of, a polynucleotide sequence in which the 3′ 10 polynucleotides of a fragment or variant of the sequence of SEQ ID NO: X and the 5′ 10 polynucleotides of the sequence of one of the sequences delineated in column 6 of Table 1B are directly contiguous. Nucleic acids which hybridize to the complement of these 20 contiguous polynucleotides under stringent hybridization conditions or alternatively, under lower stringency conditions, are also encompassed by the invention. Polypeptides encoded by these polynucleotides and/or nucleic acids, other polynucleotides and/or nucleic acids encoding these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides, nucleic acids, and polypeptides, are also encompassed by the invention.  
       [0102] In further specific embodiments, polynucleotides of the invention comprise, or alternatively consist of, a polynucleotide sequence in which the 3′ 10 polynucleotides of one of the sequences delineated in column 6 of Table 1B and the 5′ 10 polynucleotides of another sequence in column 6 are directly contiguous. Nucleic acids which hybridize to the complement of these 20 contiguous polynucleotides under stringent hybridization conditions or alternatively, under lower stringency conditions, are also encompassed by the invention. Polypeptides encoded by these polynucleotides and/or nucleic acids, other polynucleotides and/or nucleic acids encoding these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides, nucleic acids, and polypeptides are also encompassed by the invention.  
       [0103] In specific embodiments, polynucleotides of the invention comprise, or alternatively consist of, a polynucleotide sequence in which the 3′ 10 polynucleotides of one of the sequences delineated in column 6 of Table 1B and the 5′ 10 polynucleotides of another sequence in column 6 corresponding to the same Clone ID NO: Z (see Table 1B, column 1) are directly contiguous. Nucleic acids which hybridize to the complement of these 20 lower stringency conditions, are also encompassed by the invention. Polypeptides encoded by these polynucleotides and/or nucleic acids, other polynucleotides and/or nucleic acids encoding these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides, nucleic acids, and polypeptides are also encompassed by the invention.  
       [0104] In specific embodiments, polynucleotides of the invention comprise, or alternatively consist of, a polynucleotide sequence in which the 3′ 10 polynucleotides of one sequence in column 6 corresponding to the same contig sequence identifer SEQ ID NO: X (see Table 1B, column 2) are directly contiguous. Nucleic acids which hybridize to the complement of these 20 contiguous polynucleotides under stringent hybridization conditions or alternatively, under lower stringency conditions, are also encompassed by the invention. Polypeptides encoded by these polynucleotides and/or nucleic acids, other polynucleotides and/or nucleic acids encoding these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides, nucleic acids, and polypeptides are also encompassed by the invention.  
       [0105] In specific embodiments, polynucleotides of the invention comprise, or alternatively consist of a polynucleotide sequence in which the 3′ 10 polynucleotides of one of the sequences delineated in column 6 of Table 1B and the 5′ 10 polynucleotides of another sequence in column 6 corresponding to the same row are directly contiguous. In preferred embodiments, the 3′ 10 polynucleotides of one of the sequences delineated in column 6 of Table 1B is directly contiguous with the 5′ 10 polynucleotides of the next sequential exon delineated in Table 1B, column 6. Nucleic acids which hybridize to the complement of these 20 contiguous polynucleotides under stringent hybridization conditions or alternatively, under lower stringency conditions, are also encompassed by the invention. Polypeptides encoded by these polynucleotides and/or nucleic acids, other polynucleotides and/or nucleic acids encoding these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides, nucleic acids, and polypeptides are also encompassed by the invention.  
       [0106] Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. Accordingly, for each contig sequence (SEQ ID NO: X) listed in the third column of Table 1A, preferably excluded are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a−b, where a is any integer between 1 and the final nucleotide minus 15 of SEQ ID NO: X, b is an integer of 15 to the final nucleotide of SEQ ID NO: X, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO: X, and where b is greater than or equal to a+14. More specifically, preferably excluded are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a−b, where a and b are integers as defined in columns 4 and 5, respectively, of Table 3. In specific embodiments, the polynucleotides of the invention do not consist of at least one, two, three, four, five, ten, or more of the specific polynucleotide sequences referenced by the Genbank Accession No. as disclosed in column 6 of Table 3 (including for example, published sequence in connection with a particular BAC clone). In further embodiments, preferably excluded from the invention are the specific polynucleotide sequence(s) contained in the clones corresponding to at least one, two, three, four, five, ten, or more of the available material having the accession numbers identified in the sixth column of this Table (including for example, the actual sequence contained in an identified BAC clone). In no way is this listing meant to encompass all of the sequences which may be excluded by the general formula, it is just a representative example. All references available through these accessions are hereby incorporated by reference in their entirety.  
                               TABLE 3                          Clone ID   SEQ ID   Contig   EST Disclaimer                                         NO: Z   NO: X   ID:   Range of a   Range of b   Accession #&#39;s                                             H7MBA84   11   625386   1-212   15-226           H7MBC38   12   705707   1-121   15-135   AL035088.       H7MBD34   13   928552   1-60   15-74       HBAFB96   14   573392   1-332   15-346   AC004049.       HBAGJ74   15   945133   1-401   15-415       HBAGK69   16   881903   1-521   15-535   Z28716, AA092179, and C04832.       HBAGU08   17   959191   1-363   15-377   AL134524, AL045328, AL047163, AL038838, AL037343, AL037436,                           AL038983, AL037335, AI142134, AL037323, AL044125, AL040193,                           AL037443, AL042898, AL037727, AL038532, AL044162, AL041347,                           AL040621, AL043538, AL043496, AL041324, AL038822, AL047012,                           AL041098, AL037435, AL038761, AL041246, AL041238, AL040464,                           AL044186, AL040463, AL040617, AL043923, AL047170, AL043814,                           AL044037, AL043845, AL047219, AL040625, AL041635, AL040294,                           AL040075, AL045684, AL041296, AL040576, AL044064, AL041752,                           AL041459, AL041577, AL134110, AL045753, AL040510, AL043467,                           AL047183, AL041086, AL043677, AL040839, AL046850, AL043492,                           AL041602, AL040052, AL040444, AL040768, AL044074, AL046994,                           AL041730, AL041523, AL043627, AL046914, AL041374, AL040472,                           AL043848, AL041163, AL043570, AL041133, AL042135, AL046442,                           AL041096, AL040322, AL041955, AL037295, AL041233, AL040119,                           AL045671, AL039316, AL040149, AL046392, AL039360, AL079852,                           AL044272, AL039643, AL041168, AL044258, AL041159, AL041358,                           AL047057, AL042096, AL045920, AL040148, AL041346, AL049018,                           AL041292, AL040458, AL044187, AL044199, AL041142, AL045990,                           AL040332, AL040571, AL041197, AL040529, AL046330, AL039338,                           AL079878, AL040745, AL040370, AI547295, AL040128, AL044274,                           AL047036, AL037341, AL045327, AL041277, AL040342, AL040553,                           AL041186, AL039744, AL040414, AL040155, AL040285, AL047037,                           AL040091, AL045989, AL044165, AL041131, AL040090, AL041051,                           AL046327, AL038745, AL040168, AL043775, AL043444, AL045817,                           AL040253, AL041227, AL040082, AL045857, AL040329, AL039432,                           AL041278, AL043941, AL040238, AL040263, AL037279, AL040255,                           AL044201, AL038651, D29033, AL048677, AL038878, AI547291,                           AI318479, AL079977, AA585098, AL045725, AL041344, AL039915,                           AI547039, AL043612, AI546971, U46344, AL045211, AI541383,                           AL044529, AI526113, AL038024, AL135012, AL048714, AL047340,                           T19407, AI541524, AL048657, AL049069, AI541527, T18597, AL045494,                           C06219, AI557039, AA585439, AL042523, AI525500, AI557864,                           AI541356, AI540920, AI557084, AI541205, AL042420, D59436, R28895,                           AI541346, AA283326, AL042468, T10982, AL038040, AI547250,                           AI557262, AI526186, D60844, R29262, AI526078, C16293, AW363350,                           R28892, AA585325, AL038041, AR064707, AJ238010, AR066494, A93923,                           D17247, A93916, U94592, A93931, A22739, A85203, Y16359, AL133053,                           AI6035, AL122101, AR023813, Z32836, AL133074, AR054723, AF082186,                           I05558, D50010, D13509, AJ244003, AJ244004, AJ244005, X81969,                           A98767, A20702, A93963, A93964, AR062872, I63120, AR062871,                           AR017907, A43189, AR062873, A43188, A20700, A25909, A98420,                           A98423, A98432, A98436, A98417, A98427, D78345, E03627, I48927,                           E17098, I06859, AI8050, A23334, A75888, I70384, A60111, A23633,                           AR007512, AL133049, AR038855, and A81878.       HBAMC12   18   968816   1-375   15-389       HBAMC47   19   854049   1-545   15-559   AP000523.       HBAMC68   20   849402   1-390   15-404       HBAMC92   21   572947   1-435   15-449       HCKAA13   22   534965   1-370   15-384       HCKAA41   23   694397   1-352   15-366       HFKCJ86   24   504445   1-326   15-340   AA341129, and AA341247.       HFKEA55   25   530256   1-341   15-355   AA741056.       HFKEA65   26   932094   1-639   15-653   AC002366.       HFKEH40   27   523591   1-253   15-267       HFKEJ40   28   909830   1-309   15-323   AA351412, AW369782, AI968585, R13131, R71556, H59671, AA732740,                           R35566, and AB018325.       HFKEJ77   29   529919   1-233   15-247       HFKEM26   30   573949   1-170   15-184   AC004982.       HFKEM70   31   963178   1-313   15-327       HFKEN74   32   974309   1-626   15-640   AW023938, AI554747, AA459899, AA074393, AL022330, AL009174,                           AC002073, AC005777, AC004143, AC004447, AC006013, AP000501,                           AC000054, AC005527, AC004032, AC004918, AC004893, AC005529,                           AJ003147, AC005005, AC004231, and AL096794.       HFKER27   33   926744   1-290   15-304       HFKER69   34   918290   1-490   15-504       HFKEU09   35   855045   1-441   15-455       HFKEW23   36   854952   1-713   15-727   AI821974, and AA873801.       HFKFB18   37   935988   1-506   15-520       HFKFB23   38   675175   1-410   15-424   H29841.       HFKFB42   39   522037   1-374   15-388   AL109839.       HFKFE05   40   932306   1-309   15-323   W86926, AL049775, AC004741, AC008163, AL031734, and AL031274.       HFKFE23   41   881475   1-600   15-614   AW247495, AA187097, AA172364, AI815484, AA169457, and AA148993.       HFKFE59   42   854991   1-546   15-560       HFKFI14   43   670322   1-512   15-526   AI635635, AW029406, AW301134, AI439214, AI222373, AI160043,                           AI936133, AA604994, AI088166, AI620579, AI807864, AW087927,                           F18815, AI933350, AA971094, AA679494, F19202, C00780, AA516052,                           F35328, AI422053, AI378846, AI422054, AI467881, AA505330, AI160683,                           AI382047, AA747782, AI382048, AA838645, AI685868, AI089313,                           AI200403, AI222097, AA836800, AA233797, AI565857, F26915,                           AI367842, AI651466, AA114906, AA902486, AA302447, R14860, F16986,                           AA931620, F28409, AI744468, N64170, W22033, Z25239, C17445, F27592,                           AI672619, F17310, AW316769, AA838451, T57851, R11362, AA233828,                           T81626, AI541422, AI085169, AI364052, AA114905, AI003676,                           AA903573, F18512, R10508, AA352749, AF047437, and AC004771.       HFKFI22   44   930982   1-318   15-332       HFKFI44   45   929786   1-298   15-312   AI366196, AA224540, and D38548.       HFKFJ12   46   582587   1-355   15-369       HFKFJ14   47   787260   1-332   15-346   Z68324.       HFKFJ25   48   963144   1-671   15-685   T26651, AI860719, Z43590, F06052, and AC004017.       HFKFN66   49   511046   1-570   15-584   AA662296, T90222, and T83027.       HFKFO75   50   573840   1-323   15-337       HFKFQ24   51   530222   1-172   15-186   AL136295.       HFKGA94   52   855099   1-309   15-323   AA368329, AA825954, R39295, T12047, AA831913, AI919048,                           AA362440, AA557945, AA012987, AI732911, AA362439, R33091,                           AA640305, AA731008, AA350081, AA569206, AA385094, AA809787,                           AI002863, AA558377, AA219166, AI279693, AI049630, R79396,                           AI668566, AW028376, AW268090, AA360139, AA832104, T54173,                           AI003474, AA367672, AA598497, AA364082, AA219651, R64110,                           AA310557, AA668421, AA658320, AA368659, R92703, AI884404,                           AI281622, AI567676, AW022796, AI003068, H86399, AA047842,                           AW407007, AA601336, AC005089, AL023575, AL035405, AC005839,                           AC003109, AL008726, AF108083, AC006088, AL109798, AC004477,                           AC004253, AC007993, AL080317, AC008372, Z83843, AL009181,                           AL132712, U91326, Z98036, Z98884, AC004974, AL049569, AC002544,                           AC007546, AC002073, AL049869, AF196779, AC005409, AC000039,                           AL022323, AC006441, AC007226, AC004686, Z99716, AC006257,                           AC007298, AC005486, AL022393, AL035443, AL121658, AC006578,                           AC006536, AF196972, AL034379, U91322, U95742, AF111168,                           AC004895, AC006023, AL121603, AP000355, AC005920, AL049830,                           AC004815, AL035696, AC005003, AB001523, AL022326, AL049844,                           AC004033, AL031666, AP000493, AC007263, AC005231, AC004263,                           AL133448, AC002463, AL035587, AF015416, AL031591, AC005180,                           AC004912, AL049757, AC006449, AC004913, AC005696, AF205588,                           AC005746, AP001053, Z83826, AC004837, AC005225, AC008044,                           AL080243, AL133246, AP000500, AC004832, AC004821, AC005519,                           AC005539, AC007308, AC004841, AC006121, AL034429, AP000354,                           AC002470, AC004079, L44140, Z93023, AC007934, Z93020, Z95116,                           AC005057, AL033527, Z93017, AL121769, AC004887, AP000692,                           AC005624, AC004668, AC004765, AF196969, AC005520, AFI21781,                           AC005102, AL121653, AF107885, AL035086, AC007023, Z83844,                           AC002040, AC005859, AC004602, AC005940, AL031295, AC007225,                           AC003007, AL031291, AL049760, AC002310, U73630, AL020993,                           AL109952, AC005291, Z94056, AC010209, AJ003147, AP000114,                           AP000046, AC006236, AL034423, AC004000, AC002511, AC004687,                           AC002107, AC005725, AC004491, AL020997, AL133245, AC006241,                           AC007666, AL049843, AP000359, AC002350, U96629, AC007421,                           AC009516, AC006064, U52111, AC004970, AC005800, AC006001,                           AL035659, AL021154, AC004894, AC008069, AC002553, AC006111,                           AC002306, AC005944, AJ239318, AL109963, Z85996, AC005514,                           AL109759, AC000134, AC006071, AC002565, AC005531, AC007766,                           Z97054, AF050154, AC005895, AC004257, AL049694, AC002477,                           AC007358, AL117258, AC007052, AC004150, AC004859, AC004929,                           AC005071, and AL109627.       HFKGC14   53   573785   1-245   15-259       HFKGD10   54   968172   1-452   15-466   AA774921.       HFKGD48   55   954952   1-384   15-398       HFKHB46   56   965767   1-406   15-420   N40788, N94129, AL035405, AB015329, and AB028949.       HFKHB67   57   965847   1-622   15-636   AI363493, AW071799, AI828530, AI858641, AI565804, AW005098,                           AI826054, AI499730, AI949049, AI373508, AW243539, AI589687,                           AI859191, AI885149, AI869624, AI933285, AW026755, AI950294,                           AA548687, AA550893, AI480068, and AJ236623.       HFKHB84   58   854902   1-202   15-216       HFKHD35   59   854887   1-596   15-610   AI401095.       HFKHD38   60   854861   1-491   15-505   AA917529, and AI290232.       HFKHE67   61   881093   1-399   15-413   AL041748, AA282295, H83772, AA262182, AW206483, W37970,                           AI660249, AW365844, AA442059, AL121242, AA455718, AA534588,                           AL040142, and AL117662.       HFKHF54   62   855118   1-513   15-527       HFKHG06   63   965906   1-339   15-353   AA631941, AA436930, AI424442, AW161498, AW250779, AW163044,                           AA041408, AA056752, AA044406, AA454563, R48332, AA258235,                           AI129362, H45477, AI694307, AA905034, AA429473, AI421826,                           AI377349, AW156992, AI087169, AI193858, AW025506, AI355265,                           AI682330, AI193077, W81387, AA978265, AA369310, AA628812,                           AI826085, AA127040, AA917602, AA913533, AI568969, AW157076,                           AI310416, AA769689, AA913096, AI929761, AI741886, AA369311,                           AA496016, AA640738, AA635317, AA542886, AW190530, AI149098,                           AA972224, AI338612, AI480213, AW058014, AW328289, AW204399,                           AI685684, F31697, AW328288, AI468074, R48441, W79715, F32457,                           AA610691, AA196235, AW405036, F18177, F36944, F36941, AI721278,                           R09319, AA610446, AW246920, AA310193, F31667, AA041506, F34442,                           AA456455, F37799, AA125762, AA058430, AW450353, and AC004643.       HFKHH68   64   961433   1-531   15-545   AA374854, AW135564, AI271848, AI762632, and Z82195.       HFKHR74   65   953800   1-514   15-528   AW299437, AI640149, AA348101, AW135484, Z42797, R35430,                           AI636408, AW269210, AI271987, AA922757, AI765884, and AL008733.       HFKHZ39   66   928269   1-708   15-722   AA416704, and AA416608.       HFKID43   67   854988   1-527   15-541       HFKID48   68   879771   1-402   15-416   AI269245, AW451368, and AI424466.       HFKIF01   69   914971   1-389   15-403       HFKIF60   70   914948   1-418   15-432       HFKIH06   71   934051   1-546   15-560   Z43354, H84549, F05371, AA852957, AW161586, R82800, and AL021878.       HFKII05   72   930948   1-400   15-414       HFKII11   73   965846   1-430   15-444       HFKIP07   74   924825   1-337   15-351       HFKIP11   75   965072   1-434   15-448   W88721, R11591, T08135, AA736429, and AI479791.       HFKIR40   76   883093   1-498   15-512   AA022743, H46779, H46081, W07846, AI751420, AA334026, N46299,                           N77316, AA384525, N35279, AW378996, and AF009750.       HFKIS93   77   854862   1-208   15-222   AL050318.       HFKIV55   78   922739   1-408   15-422       HFKIW31   79   918243   1-412   15-426   AB022696, AB033108, AJ007627, AF109143, and AB022697.       HFKIX76   80   854993   1-159   15-173       HFKJE03   81   959898   1-445   15-459       HFKJK90   82   926511   1-598   15-612       HFKJL17   83   854829   1-231   15-245       HFKJL36   84   930422   1-400   15-414   AL046409, AA469451, AW069227, AW301350, AW303196, AW274349,                           AI634187, AW328331, AW089016, AI350211, AI457313, AW167330,                           AI926033, AW193265, AI431303, AW151247, AL041706, AI687343,                           AW157005, AW193432, AI281881, AA341865, AI341548, AW438643,                           AI281561, AW340905, AI375710, AI189932, AA992126, AI754257,                           AI028510, AL041381, AI679045, AA524616, AW265385, AW276827,                           AA477503, AW407632, AW407578, AI688846, AI244157, AA551503,                           AA169245, AI619997, AI312309, AA225273, AL042420, AI457397,                           AI583466, T06828, AI251576, AA297666, AI824562, AW327624,                           AI669589, AL047553, AW380335, AI744995, AA523843, AW023111,                           AI374809, AA350859, AI798489, AA904211, AI341664, AA857812,                           AI306232, AA501614, AW268322, AI830390, AA666295, AW168846,                           AA219098, AA578832, AA618035, AA177061, AW238341, W60522,                           AI801600, AW301771, F33121, AI598003, T74524, AA129746, AL079869,                           AI054418, AI866908, AI733856, AI598060, AI471455, AI282661,                           AW026305, AI421950, AI419337, AA130647, AA548610, AA701131,                           AI859438, AL138265, AI791659, H73550, AI922224, AI282310,                           AW162288, AI989408, AI624024, AL031588, AL117328, AC004895,                           AP000099, AL049569, AP000036, AC005071, AL023284, AL049776,                           AL049869, AF207550, AL133245, AC005015, AL034420, AC000025,                           AC005952, AC005527, AC007406, AL049780, AC005081, AL031258,                           AC007055, AC005529, U18394, AC006530, AL033504, X53550, U18391,                           X55925, AL133163, Z95114, AC002312, Z93241, AC006480, AC005488,                           Z84469, U18392, AL096791, AC016025, AL035659, U18393, U57009,                           AL096768, U18398, U18395, I51997, AL133246, X55448, U18387,                           AC004812, AP000493, AC006236, U18399, U57006, AL117330,                           AC006088, AP000557, AC002310, AC007199, AC006115, AL030996,                           AP000152, AC005562, AL008631, AL050341, Z94802, AC005726,                           AC005231, AC004638, U78027, AC005921, X55931, AL022316, Z95152,                           AL022345, AC005911, AL121603, AC006305, AC007216, AC002404,                           AC007686, AL031680, AL109847, AC005821, X55926, X54175,                           AL031577, AC009516, AC004134, X55924, Z49918, AC007065,                           AC006139, L44140, AC005102, U57008, AC004985, AC006277, U18396,                           U95742, AC005332, AC005086, AL049540, I34294, U18390, AC002477,                           AC006312, AF196779, AF030453, AC002369, X54179, AC005484,                           AP000555, AC005722, AL031666, U47924, X54178, AL031584, AF024533,                           AC005274, AL034549, AF001548, AC005300, AF088219, AC004832,                           AF045555, AC007298, X54181, AL121655, AC009509, AP000514,                           AC005089, AL109801, AL109839, AC003665, AL096701, AC005004,                           Z81364, AF015147, AL033392, Z68869, X55932, AC006449, AC004859,                           AC004878, U67801, AC006211, AC009247, AC007880, AC005180,                           AC006511, U95739, AL035695, AL049759, AC007845, AC006241,                           AL031681, AC005765, D87675, AL035422, AL035086, AC005088,                           AL133448, AC004890, AC005412, AL024507, AC002072, AL020997,                           AC002400, U82828, X55923, AC016026, AC003080, AC002546,                           AC004263, Z83840, AC005183, U62317, AC008044, AC004707,                           AL009051, AC002301, AC006996, Z99128, AL023575, AL023807,                           AC007899, AC005695, AL049709, AP000116, AP000049, AP000113,                           AP000045, AC007371, U95740, AC004408, AC005531, AP000501,                           AC005602, AC005996, AC004019, AC006057, AC006062, U80017,                           AL078593, AL033527, AC004884, AC006077, L24093, AC002470,                           AL031277, AC006578, Z98742, AF109907, X55927, AC004000,                           AC004084, AC007785, AB014079, AP000311, AF129756, AC006130,                           AC003684, AF130343, AF205588, AL050318, AL033521, AC000052,                           AL024498, AC005200, U62293, AC003663, AC007688, AC004230,                           AC005924, AP000313, AL135744, AC005288, Z84480, and AC006019.       HFKJP08   85   918312   1-303   15-317       HFKJW29   86   932310   1-337   15-351       HFKKG09   87   854888   1-626   15-640       HFKKM02   88   918260   1-124   15-138       HFKKM61   89   855082   1-520   15-534       HFKKQ02   90   918270   1-345   15-359   AI972194, and AL137434       HFKKR11   91   965858   1-428   15-442       HFKKS48   92   854927   1-529   15-543       HFKKU68   93   854913   1-521   15-535   AA579342, AA578995, AA846923, AI493583, AA441810, AA502207,                           AI251576, AI279417, AA904275, AA225273, AI306232, AW302017,                           AA584484, AW274191, AA831903, AA721998, AA856815, W23546,                           N86471, AI051037, AA358409, AA489856, AA846046, AA368155,                           AW302048, C14698, AI640411, AA536040, T06598, AI445883, AA501614,                           AA493808, AI278972, AI027056, AI742168, AA642053, AA070614,                           AA847508, AA570588, AI354333, H71678, AA612727, AW161016,                           AA713769, M78021, AA481887, AA613761, R56485, AA845804,                           AA598605, AA847427, AA457685, AI891070, AI796594, H28709,                           AL037910, AI280535, AW073510, T84117, AI560191, AA302661,                           AA350644, AA436140, AA548692, AI049924, AI761120, AI798041,                           AI004591, AL041375, AA570441, AI801540, AA429942, AA610433,                           AW274078, AI356440, AW150209, AI732807, AI744306, AI453155,                           AA857381, AI433104, AA303054, AA018588, AA584654, AA552989,                           AA708305, AI962030, AW089625, AA342238, AA215470, AI537020,                           AI053518, AI689019, AA486896, AA651639, AL047349, AI754653,                           AA632765, AL031311, Z99128, AL132987, AC016830, AJ010770,                           AC004491, AC002381, AC005291, AC005756, L78810, Z83844, AP000557,                           AL133382, AJ003147, U47924, AP000692, AC005921, AL022316,                           AC008101, AC006023, AL035249, AL096791, AC004796, AL121652,                           AC007312, AC016027, AC002312, AC009516, AL109758, AC007227,                           AC005057, AC007283, AC007919, U95742, AF108083, AC005527,                           AC004859, AP000967, AP000065, AL033392, AF053356, AC006312,                           AC005747, AC007934, AC005874, AF134471, AP000552, AL031282,                           AC002365, AC004013, AC007041, AC004967, AC005280, AD000092,                           AC005914, AL050318, AP000030, AC005212, AB022785, AF196969,                           AC005529, AC006511, AC004253, AL049759, AL020997, AC005288,                           AC006449, AC007314, AC006262, AC005531, AC006130, AL035072,                           AC007216, AL022163, AL121658, AC005399, AL109984, Z85986,                           AF217403, AL031589, AC004821, AC005480, AL121754, AL031289,                           AL133448, AL024498, AL022476, AC004408, AC005839, AC005015,                           AL031255, AC004382, AL031584, AC002351, AC006277, AP000502,                           AC005486, AC002115, AC006530, AC008372, AL109798, AC007541,                           AC004526, AC007686, AC005730, AC002477, AC005837, AC006271,                           AD000812, AF196779, AP000512, AC005971, AL117344, AC003957,                           AC004883, AL121769, AC005081, AL139054, AC005821, AF111169,                           Z98304, AC003085, AC006160, AL031729, AC005244, AC004106,                           AF003626, AF134726, AC004520, AP000503, AC005011, AL117258,                           AC004637, AL008627, AC006064, AC005684, AL031591, AL121603,                           AF200465, AC002301, AL031120, AC007486, AL021918, AC004701,                           AC003684, AC004228, AL022336, AC005261, AC006965, AL049830,                           AC004150, AC005300, AC005800, AC004812, AL035458, AC005066,                           AL034420, AC004973, AC002316, AC002126, AC003950, AC007546,                           AC004848, AC004815, AC012384, AC005940, AL031733, AL049776,                           Z84487, AC006057, AL031673, AC005512, AC007051, AL035683,                           AP000049, AC006211, Z95152, AL023575, AL109827, U07562, AC006430,                           AC006317, Z84466, Y10196, AP000355, Z98941, AC005520, AC004079,                           AC005484, U80017, U91318, U85195, Z97629, AC005225, AL133245,                           AC003007, AP000113, AC005620, AC005231, AP000350, AC004552,                           AL050348, AP000311, AP000208, AP000130, AP000031, AP000558,                           AL021546, AP000509, AC005325, AC004020, AL031346, AC002400,                           AL035659, AC007371, AC002430, AC007384, AC005736, AF038458,                           AF109907, AF124523, AP000555, AL031281, AC004217, AC005358,                           AC008018, AL121653, AL049869, AC000159, AC004638, AB029343,                           AC005086, AC009247, AC005411, L78833, AL133163, AL031848,                           AC016025, AC003665, U52112, AC005920, AE000658, AP000517,                           AL031284, AL035587, AC008044, AC004854, AL049872, and AC005523.       HFKLD11   94   965830   1-693   15-707   H19388, H12126, D58283, D80024, C14389, D59275, D80043, D80195,                           D50979, D80227, D59502, D80164, D59467, D59859, D80022, D80166,                           D81030, D51423, D59619, D80210, D51799, D80391, C15076, D80240,                           D80253, D59787, C14331, D80269, D80038, D80188, D80212, D80193,                           D80196, D80219, D57483, D59927, D80378, D80366, D59889, D50995,                           D51060, AA305409, D59610, D80045, C14429, D80241, AA305578,                           T03269, C14014, AW178893, C75259, D52291, D51022, AW179328,                           AW177440, D81026, AW378532, D80134, AW178775, AA514188,                           D80248, D51250, AW369651, D80268, F13647, D80251, D80522,                           AW178762, D59695, AI910186, AW177501, AW177511, AW352158,                           AA514186, D80133, AW360811, D58253, D80168, D81111, C14227,                           C05695, AI905856, AW375405, C14298, AW352117, AW377671, C14407,                           D80064, AW176467, Z21582, D80132, D80247, AW366296, AW360844,                           AW360817, AW375406, AW378534, AW179332, AW377672, AW179023,                           AW178905, D80302, AW378540, AW360834, AW352171, D80439,                           AW377676, AW178906, AW352170, AW177731, AW178907, AW179019,                           AW179024, D59373, AW177505, AW179020, AW360841, AW178909,                           AW177456, AW179329, AW178980, AW177733, AW378528, AA285331,                           AW178908, AW178754, AW179018, AW352174, D51103, D51097,                           T11417, AI557751, AW179004, AW179012, AW178914, AW378525,                           AW367967, D80157, AW177722, AW177728, D51759, AW179220,                           AW179009, AW178774, AW178911, AW378543, AW352163, D58246,                           D59503, AW178983, AW352120, C06015, AW178781, T48593, D59627,                           D58101, AI535850, D80014, AW177508, AW177723, D59653, D80258,                           AA809122, D45260, C14975, AW378533, AI525923, AI557774,                           AW367950, AW177497, D59317, H67854, C03092, H67866, D51213,                           D59474, AW177734, AW178986, T03116, D45273, AI535686, AI525917,                           T02974, C14973, C14344, AI525227, D51221, D59551, C14957, D60010,                           AI525920, AA514184, D60214, AI525912, C14046, T03048, AI525222,                           AI525242, AI535961, AI525235, AI525925, AW378542, D31458, N66429,                           AW378539, AI525215, C16955, C05763, Z33452, AI525237, Z30160,                           AB002349, AJ132110, A84916, A62300, AR018138, A62298, AB028859,                           X67155, Y17188, D26022, A25909, AF058696, A67220, D89785, A78862,                           D34614, AR008278, D88547, I82448, X82626, AR025207, Y12724,                           A82595, AR016808, AB002449, AR060385, A94995, AB012117,                           AR008443, X68127, A85396, AR066482, I50133, A44171, I50126, I50132,                           I50128, A85477, I19525, A86792, U87250, AR066488, X93549, AR016514,                           AR060138, A45456, A26615, AR052274, Y09669, A43192, A43190,                           AR038669, AR066490, AR066487, I14842, A30438, I18367, D88507,                           AR054175, D50010, Y17187, A63261, AR008408, AR008277, AR008281,                           AR062872, A70867, AF135125, I79511, AR016691, AR016690, U46128,                           D13509, A64136, A68321, AR060133, AB033111, U87247, Z82022,                           U79457, AF123263, AR064240, AR032065, A63887, AR060382, and                           AR008382.       HFKLD58   95   918235   1-348   15-362   AI751333, AA324706, R16682, and T69796.       HFKLJ15   96   918247   1-488   15-502       HFKLL08   97   958065   1-417   15-431   AA081810.       HFKLR52   98   879749   1-496   15-510   H17284, H83139, AW247248, AW135333, T19309, AA427497, R78686,                           AA372220, T08998, T30713, C04405, M78822, H19555, R78660, H26455,                           AA134463, AC005943, and AF072247.       HFKLX38   99   880220   1-295   15-309       HFKLY01   100   914907   1-473   15-487   R91200, and AI076204.       HFKM101   101   914876   1-400   15-414       HKDAE56   102   733549   1-317   15-331   AW183074, AA746339, AA487204, AA486844, R86202, R73197,                           AA652204, W48671, and AL137485.       HKDAF34   103   703405   1-440   15-454   AA664604, AA593471, F32893, AI820673, AA904275, AA558298,                           AI471418, AI732251, R82388, AI540840, AA601986, AI287921,                           AA679872, AA808998, AA574442, AA807583, AA226584, AA448838,                           AI754291, AA077776, AA130647, T03412, AI168205, AA669102,                           AI446474, AW238016, AA649682, AI457597, AA377730, AI357976,                           AW383952, AI357823, N23260, AA828047, AW069227, AA086318,                           AA488620, H71250, H55894, F23327, AA354821, AI355246, AA551798,                           AA809186, AA828867, AI569510, AA708678, AF034176, T65812,                           AI471691, AA599495, AI473701, AI279759, T47739, F27015, AW261996,                           AI627581, AI241705, F25301, AA610509, AI609223, AA557982, F33566,                           AI634187, AI284108, AW268190, AA652868, R93233, AA367788,                           AI457313, AL043721, AI290388, AI783911, H79849, AA226270, N23097,                           AL119838, H64278, AI797901, AI797892, AW189353, AI915293,                           AA461308, AA365307, AA828860, AA100672, AI358089, AI687962,                           AA599352, AA745524, AI709174, AA714073, AA775049, AA581914,                           AA483606, AA526724, AW440633, T86119, H79915, AA350886,                           AI251111, H72688, AP000049, AP000116, AP000311, AC005158,                           AC005887, AC000059, AF097738, AF196969, AP000011, AP000152,                           AP000269, AP000103, AC005856, AC006511, AL133243, AC002477,                           AC007535, AP001059, AP001058, AP000557, AC005295, AL034379,                           AP000504, AL132777, AL034349, AC004477, M87914, AC007161,                           AC007397, AL031230, AC006512, AF129756, AP000032, AL021578,                           AL031228, AL035703, AC004087, Z75747, AC004825, AC002367,                           AC002041, AF157065, AC003037, AC004859, AP000150, AC000085,                           AC002429, AC005701, AL031058, AC005755, AL096712, AC006111,                           AJ250915, AC003101, AP000251, AL034555, AP000030, AC004841,                           AP000009, AC006241, AC009501, AL035448, AC005358, AL023494,                           AC002457, AL079305, AC004979, AL132985, U80017, AC006539,                           AL109799, AC002039, AC005484, AC005696, AC005913, AC006132,                           AC004881, AC007546, AC005908, AL031770, AL121825, AC004814,                           AL034402, AL033517, AC002073, AC000118, AL008710, Z98036,                           AL022165, AC004761, AC003041, AL034420, AC004975, AC004522,                           AC005919, AC003962, AC005971, AC007298, AC006077, AL050321,                           AC004821, AL022302, AL031985, Z69890, AF134726, AC005399,                           AL121653, AC007363, AL022578, AC007917, AF019563, Z83840,                           AP000509, U02068, AF037222, AD000833, AL035450, AP000347,                           AL022400, AP000263, AC002536, AC005486, AC010582, AL117339,                           AC005567, AL031276, AC007308, AC006257, AP000497, AC004106,                           U50871, Z93016, AL096773, X87344, AL096791, U29874, AL035072,                           AP000133, AP000211, AP000100, AC005498, AC002105, AC016027,                           AL035587, AC005529, AL050332, AC005057, AF084941, U63630,                           D84394, AB014077, AC004209, AC006139, AC006009, AP000514,                           AC006356, AC006050, AC005037, AC005291, AC006261, U33208,                           Y10196, AC004234, AP000036, AC004854, AC004895, AP000272,                           AC004185, AF061032, AP000104, AC005368, AL020997, AC004263,                           AP000045, AC002377, AC005081, AC007312, Z99943, AC003002,                           AC007277, AC005274, AC003043, I34294, AL034421, AC005479,                           AC009542, AL022326, AC002045, AL121655, AC004231, AL049757,                           AL021918, AJ011930, AC004663, AL109946, AC009330, AC007388,                           AF178081, AC004152, AC000075, AC016473, AC009363, AC006966,                           AC005664, AL137191, AC006547, AC005899, AC002542, AL109628,                           AC005839, AP000350, AC004189, Z94044, AL031390, AC006088,                           AC005520, Z75744, U24498, AL096774, AC003667, AL117258,                           AC006368, AC005746, AC005257, AD000092, AF047825, AC004596,                           AL133448, AC005207, AP000502, AL034548, AL008735, Z70280,                           AC005277, AC009241, AL022311, D83402, AL022476, AF195658,                           AC000004, AL121852, AL049780, AC006530, AF205588, and AC004383.       HKDAF84   104   781937   1-386   15-400   AA716460, AA938390, AA828592, AA719523, H40478, AI078409,                           AW237905, AA077637, AA722138, AA846923, AA709110, AI280266,                           AI858889, F27108, AI537368, AI521525, AA339923, AA604843,                           AA878140, AI653465, AI190648, AI244157, AA634991, AA298788,                           AA614864, AI300818, AI310992, AI860414, AA491743, AA182577,                           AA586646, AA947369, AW020150, AI926102, AI865375, AI703335,                           AI280500, AA297666, AA642809, AA381762, AA535216, AA654874,                           R62150, AI290405, AA074086, AI421783, AI491765, AW301712,                           AW246558, AR036572, U91328, AC006039, AC005993, AL035563,                           AC003049, AC007376, AC005592, AC005482, AC002302, AL034402,                           AC007425, AC008928, AC004585, AC004216, AC010206, AC005102,                           Z98200, AF001549, AC004791, AC002978, AC005207, AC004616,                           AC005011, AC005999, AC007655, AL035420, AC004125, AC006480,                           AC007263, AC004409, I34294, AL096776, AC007308, AL133355,                           AP000517, AC002390, AC007276, AC008012, AC002470, AC004106,                           AC005291, AC005215, AC002375, AC002492, AC000119, AF002993,                           Z98744, AC005057, AC005082, AC007284, AC003037, AC003043,                           Z99716, U62293, AC004859, AF109907, AL050308, AL035252, AC007240,                           AC004785, AP000689, AC009399, AC005911, U91321, AC005477,                           AC002094, AP000247, AL008726, AP000114, AP000216, Z98950,                           AC005295, AL022477, AC002128, AC005821, Z83826, AC002553,                           AC005261, AC004605, AC002554, AF196970, AL096701, AL050332,                           AC006293, AL078593, AF064861, AC006241, AC005839, AC006088,                           AC004707, AC008064, AL078602, AC002394, AC005971, AC005887,                           AP001053, AP000140, AC005780, AC006065, AC002384, U02052,                           AC009498, AC003982, AC009946, AL049712, AF111168, AC005412,                           AC004887, U91318, AL117258, AC004598, AL009181, AC003098,                           AP000088, AC005071, U52112, AF134726, AP000556, AC007685,                           AC007687, AC004856, AC004985, AL024498, AC005874, AF134471,                           AC005081, AC006285, AC007536, AL109758, AC005480, U91326,                           AC005697, AL139054, AC004702, AC011456, Z93241, AC004408,                           AL022327, U66059, AC008055, Z93930, Z84814, AC004687, AC003035,                           AC006115, AF121781, AL049795, AC006059, AL022323, AC004858,                           AC004797, AF051976, AC000026, AP000503, Z97055, AL031767,                           AC007546, AC004796, AL035405, AC004921, AC002538, AF047825,                           AC005484, AC005089, AF196969, AC002544, AP000512, AC007114,                           AL109956, AF111169, AC004542, AC005231, AC009501, AL049692, and                           AC002059.       HKDBC65   105   572866   1-58   15-72       HKDBI41   106   537508   1-321   15-335   AL119324, AL119457, AL042544, AL119399, AL119443, AW392670,                           Z99396, AL119355, U46351, U46347, AL119319, AL119497, AL134902,                           U46349, AL134538, AW372827, AL119483, AL119464, AW384394,                           AW363220, AL119444, AL037205, AL119484, AL119363, AL119391,                           U46350, AL119418, U46341, AL119341, AL043019, AL042984,                           AL119439, AL119522, AL119396, U46346, AL119335, AL043033,                           AL119401, AL134531, AL134533, AL134528, AL119496, AL134525,                           AL134536, U46345, AL042433, AL042450, AL134542, AL042614,                           AL043029, AI142132, AL043011, AL042542, AL043003, AL042965,                           AL042975, AL042551, AL078614, AC004527, AB026436, AR060234,                           AR066494, AR054110, A81671, and AR069079.       HKDBL02   107   920498   1-524   15-538       HKIBB08   108   960371   1-289   15-303       HKIBB81   109   525592   1-357   15-371   AP000011, and AP000152.       HKIMC34   110   573424   1-147   15-161       HKIXA02   111   920413   1-251   15-265   AI223167.       HKIXA37   112   735445   1-336   15-350   H49186, AL039679, N36307, AI940110, AW173245, T66334, AA157923,                           N42794, F12064, H58569, and AF091083.       HKIXB03   113   924636   1-667   15-681   AA534863, AA746476, AI807346, AI807337, AA814725, AI342011,                           AA860170, AA862556, AI167626, AI565166, N90805, AA425316,                           AA063596, AA721653, AA927981, N50990, AI830609, AI700334,                           AI924447, AA928627, AA047076, AA844403, R41759, AI651907, H44039,                           H15256, F07545, F06839, R55583, AI952216, AI952225, W19518,                           AI658871, AA877252, AL133582, and AF169802.       HKIXB53   114   727457   1-361   15-375       HKIXB79   115   770139   1-398   15-412   AA445925, and AA310604.       HKIXD42   116   683533   1-416   15-430   AF222684.       HKIXG58   117   464241   1-239   15-253   AW020280, AA737317, AI962169, AA516381, and AI650724.       HKIXH32   118   920217   1-365   15-379       HKIXI82   119   779905   1-431   15-445       HKIXM09   120   920219   1-84   15-98       HKIXM81   121   961026   1-331   15-345   H92687, R51268, AW444753, R61794, AI094594, AI356668, AI361265,                           AI359113, R42776, AA634158, H11261, AI371482, AI423166, AA127468,                           T16365, T31025, T78304, AI627405, AL038445, AI567582, AL036673,                           AI863382, AA807088, AI335426, AI348777, AW161202, AL039086,                           AL038605, AW243886, AW020419, AW161156, AI468872, AI355779,                           AI364788, AL047655, AI567993, AI473799, AI537677, AI582912,                           AA641818, AA464646, AI923989, AI469775, AA715307, AI961589,                           AA809974, AI766348, AI345347, AW274192, AA748353, AI862144,                           AL045500, AI433157, AI648567, AI554821, AI866465, AW151136,                           AW151979, AI539771, AA738216, AI623736, AI590043, AW088903,                           AI494201, AW071417, AI500659, AI207510, AI815232, AI801325,                           AI500523, AI538850, AI866608, AI887775, AI582932, AI284517,                           AI872423, AI224027, AI500706, AI500061, AI445237, AI491776,                           AI611728, AW151138, AI889189, AI521560, AI500662, AL041150,                           AI539800, AW172723, AI284509, AL036631, AI440263, AI538885,                           AI889168, AI866573, AI633493, AI434256, AI289310, AI273179,                           AI866469, AI805769, AI434242, AI888661, AI500714, AI284513,                           AI888118, AI269862, AI859991, AI436429, AI889147, AI581033,                           AI371228, AI491710, AI440252, AL047422, R81679, AI866786, N29277,                           AI860003, AI610557, AI242736, AA761557, AI828574, AI887499,                           AA287231, AI539781, AW080402, AI539707, AI919593, AW089557,                           AI559957, AW167918, AI521571, AI307557, AI491852, AI371251,                           AW302924, AW020693, AW162194, AI537244, AL048644, AL041772,                           AL120254, AW051088, AI345335, AI620284, AI345688, AI557104,                           AW021717, AW150457, AI885949, AI345416, AI345612, AL120300,                           AI433037, AL046618, AL037454, AI799183, AI345415, AI671642,                           AI933992, AI698401, AI305745, AI889133, AI866820, AA743354,                           AI570966, AL038564, AI624963, AI251485, AW198112, AW274355,                           AL119791, AI890907, AI690946, AI610645, AW161402, AW020397,                           AW082113, AW058233, AI432644, AL036980, AL045672, AW268122,                           AI873704, F37471, AI538008, AI349598, AA572758, AL040241,                           AW089006, AW269097, AL119836, AW105459, AI310571, AI624279,                           AW268220, AI312428, AI252414, AW022682, AW191003, AW129264,                           AI866510, AI345180, AL045421, AI340603, AI285419, AI580674,                           AI348897, AW083804, AW071362, AI282355, AL039276, AW269098,                           AL135024, AI349256, AW268251, AI890507, R36271, AI312152,                           AI866461, AI923046, AI343091, AI247193, AL040694, AW075084,                           AL045620, AI310925, AI309443, AI242248, AL048375, AI307736,                           AW051453, AA420722, AL080011, AI312399, AI349937, AI307543,                           AI334884, AW268768, AI345251, AW071412, AL110306, AL036274,                           AI307708, AI922315, AI312325, AW071395, AI274759, AI340659,                           AF078851, U78525, E02221, AF090900, AL049283, AF176651, AF113690,                           A03736, A08916, AL050172, I89947, AL133075, AL122049, I48978,                           AL080126, X84990, AL117457, AL137533, AF061943, AF067790,                           AL122050, AF111851, AL137459, M27260, Z72491, E06743, AF113694,                           A77033, A77035, AF026124, X06146, AB007812, AL110280, AL137656,                           AR034821, A08913, X81464, S61953, AL050277, AR038854, M86826,                           I66342, AL117435, AL137548, AL080124, A08912, A08910, AF118094,                           Y11587, I89931, A08909, AJ003118, AJ005690, I00734, AL050393,                           AL122110, I49625, AL117460, AF017152, E00617, E00717, E00778,                           AF146568, A08908, AL133072, S78214, AF057300, AF057299, AF113689,                           AR038969, A18777, AL023657, AL137547, X72889, AR011880,                           AR068751, I89934, AL050024, AL110196, X62580, AF031147, AF159615,                           AL080234, I80064, AL137537, AB019565, AL117648, Y16645, AF118070,                           AF118090, AL049314, AL080158, AF081197, AF081195, AF113699,                           I03321, AL122098, AL137529, AF177401, U42766, AL137479, AL110218,                           AF113677, AL133558, AL133080, X70685, AL133081, AL110197, X52128,                           AF090886, AL133077, AL110225, AF106657, AL049465, X98834,                           AF026816, AL137538, S76508, E03348, AF090934, X79812, AF065135,                           AR029490, AL117583, AL110221, AL137550, AL096744, AF061573,                           AL122121, AF113013, I68732, A58524, A58523, AL137539, AF078844,                           S83456, AJ000937, AL080159, I33392, AL049382, U90884, AF153205,                           U00763, AL117649, AL122093, AL133113, AL137294, X65873, AF102578,                           AL080163, AF008439, AL122123, AL133104, AF017437, AF090943,                           X87582, AJ238278, AF094480, E01314, D16301, AL133665, E01614,                           E13364, AL137480, AF100781, AF114170, I89944, AF097996, AF069506,                           I48979, U68233, I92592, AL050149, AL050116, AF090901, AL050092,                           AL110222, AJ006417, A15345, AL137283, AL080074, AL049452,                           AF000301, S68736, AL050155, AL133619, E15569, E07361, AF100931,                           AL049300, AR013797, A65341, Y11254, AR000496, U39656, A08907,                           AL122111, Z82022, X92070, Y09972, AF058921, I09499, U96683,                           AL133568, AL133565, AF079765, S77771, Y10655, S75997, AR020905,                           AB016226, AF126247, S36676, AF067728, AF087943, AL117416, I17544,                           I30339, I30334, AF090903, AL133016, AL080140, AF158248, AL137527,                           AL133010, AL137641, X93495, X63574, AB029065, X53587, D83032,                           AC002467, X63410, AF091084, AL137478, AF079763, E15324, AL133557,                           Z37987, AF162270, AF205861, AF125948, U35846, AF106862, X96540,                           AF113691, AL080060, and AL137429.       HKIXP16   122   881511   1-1160   15-1174   AW205069, AA189103, AA582811, AA326944, AW207340, R83516,                           R83501, AI823332, AA191201, AA984461, AA058749, and AA017452.       HKIXQ25   123   681855   1-478   15-492   AI798901, AW148631, and AI700179.       HKIXX58   124   666516   1-210   15-224   AA062779, AW080899, and AW366555.       HKIXY04   125   736085   1-320   15-334   AI057150, H49739, AI984831, AI884976, AI421871, AW071893,                           AI457802, AI799691, AI094736, AI417318, H46204, AI458974, AA063092,                           AI421296, H18874, AI366673, AI076029, and L08074.       HKIYF45   126   970756   1-385   15-399   AA299177, AI279417, N63249, AA533762, H72530, AA507822,                           AA644090, AA747977, R72148, AW275719, AW265735, AI912401,                           AL079734, AA565232, AA535216, AI821918, AI457389, AA559241,                           AW301809, AI186438, AL118612, AA630854, AA077737, AI039539,                           AW340905, AI560085, T57774, AA452887, AA581247, AI207465,                           AA994578, AA084609, AA527209, AI471691, AI311647, AI587349,                           F08248, Z82243, AC005783, AC004910, AF205588, AC006552, AL031595,                           AL117337, Z15025, AC003007, AC006947, AC005088, AF030453,                           AL035587, AC002350, AC005722, Z99716, AL109847, AC004929,                           AL022313, AC005919, AP000505, AC005632, AC004491, AC007845,                           Z84466, AC007371, AC003101, AC002468, AC005037, AC005800,                           AL049780, AF129756, Y14768, AL031681, AP000193, AF121781,                           AC005071, AC004985, AC005067, AP000050, U82668, AL121603,                           Z97353, AL021918, AC006254, AL022721, AL031311, AC007055,                           AC002369, Z82189, AP000117, AC006071, AL078638, AL009181,                           AC004905, U96629, AC005015, Z83844, AC005295, AL034420,                           AC004955, AC005081, AP000688, AL133243, AC007461, Z82198,                           AC002310, AC006077, U91322, AC006026, AF111169, AC005399,                           AC006449, AC000026, AC002544, AC004836, AC005940, AP000066,                           AC002113, AC002477, AC002565, AC003010, Z85986, AC007011,                           AC016025, AC004975, Z95331, AL031680, AC007934, AP001067,                           AL035422, AF207550, AL133245, AL133244, AF134726, AL022326,                           AF043945, AC006597, D87009, AC006023, AC006123, AL022324,                           Z83840, AC005527, AF088219, AC016026, Z96074, AC004813, AC005844,                           AC002425, AF047825, AC005280, AC005014, AC002559, AL109952,                           Z95152, AC005207, AL034549, AP000305, AC004966, Z86090, AC005245,                           AC007666, AC005619, AC005525, AP000501, Z93017, AC005899,                           AB023049, AC006006, AC005697, AC004859, AC004472, AC004525,                           AC005233, AC004134, AC007066, AL117328, AC004125, AC005095,                           Z97054, AC005553, AL008710, AC004263, AL009031, AP000047, Z82195,                           AC006479, AC004973, AL109627, AL035405, AC004383, Z93930,                           AL022476, AL050307, AC005529, AC003982, AC008249, AC006241,                           AC007041, AL133448, AL133353, AC004476, AC005531, AF038458,                           AC004972, AL031848, AC004797, AC007386, AL049839, AC009248,                           AL031281, AL022163, AL021155, AJ246003, Z94056, AC004104,                           AC003689, AP000115, AC012627, AC008012, Z84480, AC009247,                           AC005695, AC005274, AC004470, AC006512, Z83822, AC007201,                           AC005736, AC005837, AC007687, AL035659, AL021397, AC005755,                           AL022332, AC005318, AC005209, AB003151, AC005225, AP000511,                           AL009174, AC004408, AC005900, AL022165, AC002306, AL024474,                           AC005702, AC004522, AC007458, AC005664, AC005548, AL023280,                           AL031003, AL034429, AP000215, AC005972, AL139054, AC006328,                           AC004835, AC004019, AL121658, AJ011930, AC006021, AL049540,                           AC005519, AC000025, AC003108, AL096801, AC004707, AC004895, and                           Z99495.       HKIYJ26   127   927503   1-155   15-169       HKIYJ63   128   703320   1-351   15-365   AI813822, M86178, and D56993.       HKIYK78   129   699311   1-75   15-89   AA632824.       HKIYQ89   130   625636   1-226   15-240   AI791534, AI277912, AI291379, AI733045, and AF079765.       HKMAA07   131   954358   1-368   15-382   AI284640, AA327323, H81283, AI281697, AL079843, AA829223,                           AW440976, AA649642, AI824562, AI282336, AW236342, AI801591,                           AI053672, AI674873, AA649484, AA199616, AA649542, T06828,                           AL137954, AW270382, AA077817, AA559290, AI334443, N25296,                           AA513293, AI801701, AA977743, AA603156, AA649722, AI249997,                           AA649705, R38154, AA825357, AA099612, AA831599, T94866,                           AL041733, T71030, AA368936, AA747480, N54902, AA664535, T41124,                           AA552885, AA768097, AA558060, AA605274, AA579727, AI312149,                           R97934, AI688846, H50727, AA810370, AA650450, W47183, AI270117,                           H81733, AA100372, AA515435, AA504638, AA824654, AA552945,                           AA629874, AI002820, AI830390, AA664015, W79504, AA804379, T69435,                           AA441788, R88888, AA862173, AA350859, AA927092, AA317170,                           T47739, AA771811, AA331025, H64778, AW088058, AI888008,                           AW276435, AA521399, AA533036, AI291124, AA916371, F23274,                           AA167673, F34826, AI291268, AI339440, AI358571, AI537030,                           AA461233, AA526779, AA167659, F36273, AI264743, H81785, AI963095,                           AA012982, AI471481, R91994, T67515, AA745410, T05101, AA599920,                           H23455, AW276827, AI358501, F23250, AA513972, AW406659,                           AA632624, N29933, AL046409, AA601499, AI709365, AA643962,                           AL040948, H56729, AI002834, AA568778, H02631, AI246796, AW406447,                           AI446464, AA650271, AL120269, AI281903, AA557879, AI061296,                           F18974, AA662998, AA401657, AF150152, T07451, AI469172, AA020850,                           AI144330, T93015, AI268812, AW190760, AA604869, AA662992,                           AW193265, H69640, F34511, AA858197, AA779040, AA587256,                           AA728873, D57369, AI371070, AA525876, AA688036, AI379719, H94870,                           AA244357, AA678443, AI623898, AA934680, AW338086, AA229785,                           AA578391, AA947547, W16581, AA610783, AW193432, AA503473,                           AI281881, AW072587, AA824655, H02251, AW261871, AI928790,                           AA564859, F35673, AI431303, AA774184, R93061, AA127435, F25203,                           AA177063, AA364429, H92548, AA521323, AA483731, AA521277,                           AA702293, AA846935, T41155, AC004227, U07000, AL049776,                           AC004531, AC002433, Z95152, AP000555, AL132712, AC002531, Z93930,                           AC016831, AC005251, AL096707, Z30983, AC004477, AC006572,                           AC005037, AP000952, AL021579, AL049589, AC007050, AC007041,                           AC005090, AL049829, AL049745, AL023494, AC007066, AC004447,                           AC006064, AC006515, AC005881, AL078621, AJ010770, AL133245,                           AC005288, AP000567, AL022326, Z95114, AC000111, AP000553,                           AC007386, AF117829, AC004738, AC006137, AF178030, AL034349,                           AF053356, AL024474, AP000343, AL049552, AC004066, AC004125,                           AP001053, AC000379, AC004988, AC005244, AC009178, AL133500,                           AL078638, AC009802, M87917, AC008064, AC008372, AC004884,                           M87916, AC005768, U62317, AC005175, AL035697, AC004167,                           AC002312, AC006121, AC004455, AP000556, AP000557, AP000552,                           AC009516, AL035699, AL022160, M87918, AC005246, AC006518,                           AL132777, AL035684, AL009173, AC010170, AC004526, AF111169,                           AC005699, AC005562, AC006144, AC005924, AL109618, AL035425,                           AC004917, AL078634, X75335, S70707, AC008173, Z97206, Z49155,                           AC007695, AL008728, AP000080, AP000018, AC002551, AC006205,                           AL031177, AF106564, AC007214, AL031664, AC006480, AC005531,                           AL008720, AC005516, X54179, AC000159, AC005779, U02058,                           AC007216, Y10196, AL109654, AC007285, AC005837, AC004859,                           AC004916, AC005084, AL034420, AL110122, AC007324, X55932,                           AP000359, AF017104, AC008101, AC002073, AC007390, AC006151,                           AP000657, AC007676, AL035405, AC003024, AC002426, U13056,                           AL080114, AC007075, AC001163, AC008079, AL049766, AC006130,                           AC003010, Z94865, Z82976, U61375, AC004475, AL023575, Z99756,                           AC006525, AF165175, AC006486, AC004879, AC004542, AL021808,                           AC005701, AL022329, AC006305, U02048, AC004972, AC002449,                           Z93783, Z84469, AP001068, AC004675, AL096710, AC009181, AC007429,                           AL035423, U92032, Z84489, AC006063, AC005703, AL031311, U91326,                           AC006450, U18394, X55925, U18393, X54176, U57005, AC004687,                           I51997, X55928, AC005792, U18390, Z93021, Z83001, AC003665,                           AL008629, AL022476, M87919, U57006, S70697, AC002402, AC005281,                           U63721, AJ223364, X52851, AF175325, AL022311, AL133289, U14689,                           U72787, AF094481, Z85989, AC005763, AC002077, AC004152, Z75746,                           L34079, Z49236, AC004221, AC005625, AC002056, AC005688, AP001043,                           AC004699, AL109621, AC005003, AL008709, AF017732, AL035494,                           AL022575, Z94801, AL049859, AF121781, AL035681, AC002564,                           AL132776, AC000118, AL050348, AL121655, AC004217, and AC003087.       HKMAD31   132   825566   1-342   15-356       HKMAD43   133   842064   1-203   15-217       HKMBA17   134   534523   1-128   15-142   AC005293.       HKMBD44   135   715761   1-157   15-171   AC005293.       HKMLD48   136   575873   1-379   15-393   AW025715, and AI460301.       HKMLJ39   137   705467   1-411   15-425   H72622, R89288, and H47983.       HKMLM38   138   951020   1-333   15-347   AW026332.       HKMLN96   139   881479   1-423   15-437       HKMLS46   140   575879   1-331   15-345       HKMMB01   141   851712   1-69   15-83   F31737, C05097, AW292351, AA293615, AA232172, F32267, W39303,                           AA219693, AA062553, AA489273, AA629322, AI954937, AI004409,                           AA069747, AA193645, AA406524, N56499, N90393, AW105577,                           AA447848, AA535460, AA021181, AA009649, AW149464, AA975649,                           AA974657, AA310963, AA378894, AA436530, H15979, W07688,                           AA187461, and H08985.       HKMMF21   142   969002   1-845   15-859   AL043121, AA774273, AI281498, AI494568, H26563, and AI971558.       HKMMG47   143   720379   1-319   15-333   AA393293, AA776793, AA621738, AA398634, and AI015507.       HKMMJ67   144   575750   1-339   15-353   R11510, AA653291, AW007980, AA804334, T93227, AA666205,                           AI336398, AA015948, AI915270, H48768, AA070462, AA598627,                           AA935827, AA230155, H90688, AA665475, AI567391, AA329535,                           H87756, AI096738, AI298597, AL118912, F31575, AA564925, AA559166,                           AA653955, AA565911, AA984920, W23432, AL118925, AA604515,                           AI275982, AA523695, AA583579, AI749306, AI469468, AA226770,                           R20234, AI627917, AA074252, AI791145, N76251, AA846969, AA507526,                           AI694178, AA583568, AA838162, AA706845, AA548221, AI187148,                           F02188, AA745183, AA351808, AA056569, AA077886, AI299192,                           AA834769, AI349130, AL138252, AI310670, AA564642, AL048291,                           T05684, W31062, F09188, AA454504, AA304858, AA932787, AI270177,                           U46402, N54179, AI888261, R93026, F07564, AP000152, AC004856,                           AL022316, L47234, AC005736, AC005562, AC002565, AL034420,                           AC007226, AC002492, AC005666, Z85986, AC005081, AC003663,                           AC005484, AL121852, AC006064, AP000501, AC002347, AC007051,                           AC007919, AL023553, AC004262, U63630, AL034554, AP000689,                           AC008171, AC005914, AC007225, AC004813, AC004797, AL096791,                           AL109827, AC006262, Y14768, AP000505, AC004019, AF196779, Z95115,                           AL133353, AC000052, AC006441, AC007057, AC004655, AC005899,                           AL031677, AC005049, AL034429, AF109907, AL021939, AP000305,                           AC005971, AC006251, AC004143, AC007314, AP000512, AL008635,                           AC010205, AL022721, AP000556, AP000032, AC005215, M63543,                           AP000047, AL008725, AL078596, AL021579, AC005409, AL031846,                           AC002365, AC003070, AC004447, AL122020, AC004462, Z83846,                           AF207550, AC002389, AC006449, M63544, AL049766, AC005089,                           AC007096, AL031295, AC004067, AP000115, AC004967, AL035462,                           AC005844, AC007263, AC000026, AC011456, Z98752, AC005730,                           AC006480, AC004890, AC003689, AL049834, AC005237, AC007308,                           AC003982, AC006011, AP000499, AP000547, AC002470, AC004938,                           AF124523, AC004232, AC006530, AL035681, AC009516, AL049795,                           AL035410, AC005920, U91326, L77570, AL035420, AL109963,                           AC005088, AL031003, AF045555, AP000558, AF184110, AF117829,                           AP000050, AC003098, AC005782, AC004686, AP000031, AC005763,                           AC004905, AC004802, AC004629, AL022069, AF190465, Z92542,                           AL031291, AC004073, L39891, AP000557, AF053356, AP000117,                           AL008712, AC005288, AC004832, AC005725, AP000466, Z98044,                           AC005229, AC000003, AC005231, AL022313, AC004383, AC002985,                           AC006388, AJ246003, AP001058, AC006071, AL109952, AB026898,                           AC004531, AF118808, AC003003, AL049761, AC004878, AC007151,                           AL031668, X04981, AL031589, AC005684, AC004859, AL022323,                           AL079342, AL121652, AL020995, AL121658, AC004601, AC005598,                           AC007551, AC004084, AL049830, AC007637, AC004675, AC005600,                           AL109753, AC004020, AC002115, AC003043, AC002990, AL133245,                           AC007450, AC003041, AL049696, AL022322, AC006121, AC006059,                           AC004941, AC005565, AC004230, Z98036, AL049780, AC005803,                           AP000688, AL049699, AL049839, AC005932, AC006538, AL022162,                           AC006559, AP000112, AP000044, AC002477, AL022327, AL135960, and                           AJ131016.       HKQAF25   145   529197   1-438   15-452       HRAAC11   146   966861   1-366   15-380       HRAAS14   147   658067   1-294   15-308       HRABC50   148   720370   1-261   15-275       HRABQ95   149   961330   1-453   15-467   A90834.       HRABT03   150   923842   1-546   15-560       HRABY74   151   666239   1-360   15-374   AA747489.       HRACE09   152   625425   1-128   15-142   AI524975, and AL049742.       HRACF86   153   867212   1-362   15-376       HRACK33   154   701937   1-310   15-324       HRACL64   155   674012   1-350   15-364   D63222, AL049780, and AC007055.       HRACM94   156   785191   1-381   15-395       HRACW03   157   923428   1-485   15-499       HRACW27   158   682578   1-519   15-533       HRACW36   159   708201   1-544   15-558   AC005746.       HRACW69   160   708769   1-524   15-538   Z59283.       HRACY16   161   659733   1-443   15-457       HRADF21   162   670398   1-326   15-340   T89839.       HRADJ92   163   756539   1-450   15-464       HRADN24   164   877323   1-463   15-477   AA320117, AI005063, AW182019, and AI419865.       HRADP10   165   963784   1-503   15-517   AI699927.       HRADP39   166   732757   1-491   15-505       HRAEC03   167   923401   1-461   15-475       HRKAB10   168   968272   1-329   15-343   AL117354.       HRKAB42   169   575562   1-489   15-503       HRKAE11   170   967519   1-423   15-437       HRKAF31   171   698347   1-360   15-374   H78377, and AA521207.       HRKAE24   172   677443   1-458   15-472   T60013, T59943, and AC005730.       HRKAC62   173   742429   1-282   15-296   H85425.       HRKAB80   174   930473   1-342   15-356   C16308.       HRKAA82   175   880783   1-464   15-478   AI283411, and AA658041.       HRAEF05   176   931998   1-720   15-734   AA664000, T79318, and AC004751.       HRAED30   177   867176   1-399   15-413   Z45488, F06844, and F06845.       HRAEB43   178   714842   1-374   15-388   N54560, AP000240, and AP000096.       HRAEB29   179   690179   1-360   15-374   AI268324, AA059045, AA902370, and AA058983.       HRADZ48   180   883281   1-553   15-567       HRADZ34   181   703680   1-198   15-212   H67464.       HRADZ26   182   681117   1-448   15-462   AI493184, AA045538, AA043428, AA043429, AA456045, AA056933, and                           AA455405.       HRADR43   183   714857   1-308   15-322   H39785, and AA449864.       HRADR21   184   830039   1-138   15-152   AA262832, and AC007386.       HRADO13   185   656380   1-434   15-448   H25660.       HRADM45   186   717358   1-468   15-482   AA418916, AA426580, AJ271722, AP000260, AP000036, AF055919,                           AP000099, and AP000098.       HRADK79   187   774597   1-427   15-441   R74368, N91304, AA355100, AA341453, and AL133019.       HRADE49   188   722595   1-454   15-468   H59422.       HRADC18   189   665268   1-436   15-450   R25089, T80075, T74125, R17491, F12383, T80363, and Z42149.       HRADA93   190   792001   1-381   15-395   H80804, and AA018791.       HRADA17   191   867198   1-685   15-699   AA573432, AI580135, AA505816, AA854201, AA767090, T06331, and                           H85075.       HRACX37   192   711466   1-422   15-436   H70301, H90332, AI188509, W16618, AI907810, N40106, AA306845,                           AA459427, R73372, R27210, R27220, R69145, AA229423, AA126690,                           AA976946, N42379, H91785, AA188772, AA126582, AI885640, R23074,                           AI206563, AI139889, AA654555, AI052590, AA230120 AI347291,                           AW192757, AA132427, W05104, AI471542, AA135777, AI986230,                           H91108, AA707153, AW262764, W48771, AC005041, AC006544,                           AF100753, AF100754, AF100746, and U41736.       HRACV73   193   764141   1-145   15-159   AA057691.       HRACV26   194   793997   1-640   15-654   AA651639, AI469599, AA574442, AI345681, AI345675, AW419262,                           AA610509, H53168, AW270258, N70143, AW341903, AI144055,                           AI587583, AI587565, AI581486, AA657835, AW407578, AI133083,                           AW157005, AI338426, AL042635, AA584489, AI610920, AI564185,                           AI915293, AW304584, AI028510, AA992126, AI926102, AI753113,                           AA720732, AC005736, AC002352, AC002073, AL035461, U95090,                           AC006211, AC007546, AC006285, AC016025, AL008718, AC004859,                           AC003043, AL022165, AC005071, AL109758, AC005081, AC004531,                           AC005837, AL096791, AC007201, AC006468, AL031055, AC006071,                           AC005619, AC005037, AL022237, AP000555, AC006581, AL109827,                           Z85987, AF111167, AC005971, AL023575, AC006121, AC005015,                           AC004815, AL049872, AC004491, AE000658, L78833, AL035683,                           AC004963, AC007308, AC002288, AC004019, AL022336, AC000353,                           AL049766, L78810, AC000052, AC004659, AC006449, AC005399,                           AC005209, AL034548, U85195, AC004991, AL024498, AC005632,                           AC007227, AL035458, AL008726, AL021546, AC005921, AC004134,                           AL049745, AC005841, AC007666, U47924, AC002994, AP000045,                           AC006480, AL135744, AC004882, AC007285, AL022476, AD000092,                           AF030876, AL049761, AC004596, AC004000, AC007686, AJ003147,                           AP000513, AC004217, AC005261, AL121769, AL021154, AB023048,                           AC002312, AC007114, AC002301, AC004834, AL135960, AJ131016,                           AC005520, AC005004, AC003108, AF111168, U82828, AC005089,                           AC004686, AL121603, AC008372, AC006966, AP000212, AP000134,                           AC002996, AP000117, AC005899, AC007676, AL109865, AL050318,                           AL121653, AP000349, U91321, AC010582, Y07848, AL021917,                           AC005822, AC005102, AC005288, Z84466, AL031431, AL096701,                           AC004263, AL049540, AC005911, AC005839, AL022316, AC005049,                           AL031662, AC005529, U91323, AC007386, AC002527, AC006965,                           AC006064, AL049636, AL024507, AL133163, AC007193, AC009247,                           AF001549, U80017, AC007688, AL049869, AC004216, AL109613,                           AP000505, AC005484, AP000557, AL020993, AP000152, AC004797,                           AF139813, AC007537, AC005823, AF001552, AL080242, AC005920,                           AC005486, AL031774, Z84469, AC004230, AC004858, AC006277,                           AF196779, AP000248, AC005088, AC003070, AF196969, AC002395,                           AP000065, AL008582, AC005043, AC022517, AF111169, Z95152,                           AL049776, AC007057, AC002470, AC005988, AP000501, AC007216,                           AL033527, AC004967, AC005377, AC006057, AL050307, AL031427,                           AF109907, AC004408, AC006512, AC006251, AC006948, AC018633,                           AC005231, U95739, Z98941, Z95113, Z85986, AL031311, U95742,                           AL034549, AC004821, AL022238, AL022318, AL133371, AC005207,                           AC005480, AL139054, AC006088, AC006538, AC004913, AF205588,                           AC004605, AC007226, AC005291, AC005740, AL009181, AL109984,                           AC002091, Z99716, Z98036, AC004887, AC006430, AC007774, and                           AC006146.       HRACT91   195   789974   1-1105   15-1119   AI761584, AI452446, AI564993, AA428692, AA429277, D60307,                           AI204130, AW206702, D60210, AI049636, D60211, AW051267,                           AA402443, D60308, H64707, AA912390, R12661, D81473, Z45744,                           AA293842, AW369660, AW369633, AW369689, and AA156894.       HRACR57   196   745443   1-552   15-566   AA877534, AI934510, AA055383, W07505, W69338, and W88492.       HRACR49   197   722524   1-213   15-227       HRACM83   198   780394   1-522   15-536   N62132, N45978, and AC005162.       HRACH20   199   669556   1-639   15-653   N21499, R20462, R13242, and R20071.       HRACF04   200   615036   1-428   15-442   N53719.       HRACD65   201   918345   1-458   15-472   T88854, AA255775, W26641, N41302, AA410811, AL031297, and                           AL117233.       HRACC06   202   867214   1-358   15-372   AA528258, R07857, T50622, AC006347, AL049710, AC004765, and                           U51010.       HRACA82   203   778964   1-377   15-391   AA287885, AA233147, AI057520, AI452790, AI034327, AI042330,                           AW300416, AA504817, AA282203, and AW292179.       HRACA19   204   668528   1-590   15-604   T94250.       HRABZ94   205   793278   1-883   15-897   AA203682, R11958, and AL023913.       HRABZ67   206   751496   1-455   15-469   AW082208, AI130971, AJ689477, AI384096, AI127759, AI393165,                           AI986215, AI129980, AW263339, H04472, AI300059, R01272, F00396,                           N52203, F00413, N57809, and AC004542.       HRABR30   207   691157   1-462   15-476   T92597.       HRABO60   208   871380   1-512   15-526   AA548533.       HRABO08   209   959104   1-537   15-551   AI927074, AI927063, AW207590, and AI288011.       HRABM45   210   875735   1-613   15-627   R56681, H64690, H86726, AW204431, H65184, AA133944, AW135934,                           AC003663, and AL050339.       HRABD15   211   867228   1-471   15-485   AI767564, AI478603, and AI478594.       HRABC08   212   959124   1-474   15-488   H98167, N20650, N22462, AA554457, and AL133427.       HRABA59   213   867239   1-516   15-530   AI082362.       HRABA25   214   847318   1-305   15-319   AA101076, AI862736, AA709152, AA830942, AA766567, AA708948,                           AA976015, AA179314, AI696090, AW058602, AA236485, AI470182,                           AI636141, AI740927, AA441789, AA483384, AA806410, AW450175,                           AI990817, H01020, R63373, AA482750, R63424, and AB020636.       HRAAW62   215   742631   1-321   15-335   AI867370, AA045092, and AI687863.       HRAAO95   216   582177   1-650   15-664   W69604.       HRAAM31   217   945071   1-1232   15-1246   AC006230.       HRAAJ29   218   867255   1-614   15-628   AI624968, AI624948, AA837331, AI624973, AA526412, AI624957,                           AC004040, AL031276, Z84814, AC005480, and AF129756.       HRAAI91   219   790090   1-638   15-652   H78468, and R08726.       HRAAH86   220   785398   1-517   15-531   AI023753, AA001229, and AA001641.       HRAAD24   221   676567   1-545   15-559   AA421924, AI831586, AI809492, AI459208, AI004779, AW016677,                           AA284915, AA723667, AW192116, AA223870, AW242807, AW072338,                           T54449, T54509, AI636686, AA642433, AA805919, AA828462, AA825472,                           AW418510, AA480341, AI250716, AI250588, AI334750, AI284803,                           AI250328, AI340813, AI307038, AI311955, AI223588, AI223723,                           AI250596, AI270886, AI224332, AI223516, AC006208, and AL117428.       HRAAD13   222   657088   1-512   15-526   R91223, and AC002379.       HKTAB66   223   525582   1-341   15-355   AI792876, AW271346, AI671738, AI935429, AI632015, AI650906,                           AI913380, AI822004, AI627643, AI522001, AI670856, AI498352,                           AI493102, and AI261726.       HKTAA13   224   971677   1-350   15-364   AA214502, and AA215293.       HKPMB95   225   795060   1-415   15-429   N39433, N39449, AW236570, AI989655, AL031650, and AC012627.       HKPBA75   226   767550   1-293   15-307   R63681, AC004815, and AC020663.       HKPBA63   227   525587   1-374   15-388       HKPBA51   228   518897   1-57   15-71       HKMSA84   229   783091   1-616   15-630   H72903, Z69715, and AL031681.       HKMSA12   230   970839   1-484   15-498   AA748780, AI288540, and AW303631.       HKMNC21   231   575816   1-438   15-452   AL035070.       HKMMY63   232   745145   1-386   15-400   R48693, and AL031985.       HKMMX31   233   731638   1-281   15-295   AA778266, AI332820, T57965, AA761034, AA765224, AW001999,                           AW027403, AI589147, AA781723, AI055817, AI042046, AI285392,                           AA573478, AW304220, F21355, AW440771, AA832326, AW304290,                           AA922723, AI417388, AI222795, AW103932, AA032231, AA861295,                           AA197294, AW249478, AW362135, AI348613, AI318391, AI423193,                           AI204082, AA838032, AI992201, AI762824, AI034448, AI346512,                           AI459979, N78868, AI300015, AI568758, AI346024, N95534, AA424509,                           T87621, AA403210, AA079692, AA683132, T82693, AA525375, F36972,                           AI589253, AI362276, F32550, W24223, AA953774, AI355822, AA764943,                           F23590, AA617633, AA296723, F36426, AA285289, T57883, and                           AB028972.       HKMMU45   234   871759   1-684   15-698   W31265, AI475110, AA436263, H52387, R96206, AR060643, and                           AJ010605.       HKMMR58   235   736099   1-300   15-314   T39187.       HKMMJ41   236   920910   1-505   15-519   R93764, R83166, W04900, AA206565, and R71112.       HKMMB27   237   575799   1-392   15-406   AC007899.       HKMMB10   238   964728   1-376   15-390   AL049835, AC003014, AB020868, AL136504, AC002395, AL050307,                           AL049636, AC006971, AC006581, AL035451, AL022319, AL034377,                           AP000510, AL035089, AL133353, AC005225, AC004386, Z92844,                           AC005483, AC004678, Z99128, Z85986, AC004542, AC005049,                           AC002425, AL050318, AL121653, AC005746, AC006362, AC005971,                           AC002418, AL031427, AC007686, AC006511, AL049779, AL023807,                           AL049540, AL109758, AL133249, AL022336, U80017, AC006040,                           AL022165, AC006539, AC005081, AC002420, AL121823, AC007055,                           AC005736, AC005755, AC005482, AC004814, AL024498, AL009181, and                           AC006328.       HKMLY45   239   575805   1-414   15-428       HKMLO33   240   859903   1-329   15-343   AA825808, AA825795, AA825804, and AW008231.       HKMLM54   241   825104   1-392   15-406   AA150384, Z43101, AA368774, AA401857, T32633, AA204673,                           AA470948, T34471, AI557055, AA259160, AW176688, AW408251,                           D63478, and AJ243670.       HKMLK76   242   840137   1-552   15-566   H94820.       HKMLF28   243   705533   1-403   15-417   N31007, and AA769578.       HKMLD21   244   671010   1-424   15-438   N47213.       HKMLC74   245   765669   1-452   15-466   AA081681.       HKMLC56   246   733473   1-278   15-292   N51179, and AC005037.       HKMBD80   247   522402   1-74   15-88   W95976, AI697463, AW014466, AA601222, AC005827, Z93021, L44140,                           AC005180, AL035551, AC000120, AL050379, AC007324, and AC005391.       HKMBD57   248   522406   1-335   15-349   AA555280, R40497, AA340630, AC003012, AC003686, AC000379, and                           AC002312.       HKMBC21   249   670144   1-425   15-439   W92845.       HKMBA94   250   793011   1-314   15-328   H44491, AI820761, AI820823, R73029, AI668574, AA740672, and                           AC007556.       HKIYT69   251   843327   1-392   15-406   AI525572, AL031228, AL121654, AF001905, and AC005303.       HKIYS82   252   779904   1-438   15-452   N30552, N30560, AW069273, AA136771, AA730795, AA425283,                           AA601376, AA218874, AA666295, AA846944, AI446618, AL048060,                           F17549, AL048090, AA584360, AW089260, AW151247, AA708490,                           AA665411, AA483735, AA262079, AW057760, AA513582, AA528490,                           AA417701, AA533066, AI369977, AI003044, AA320106, M77888,                           AA772493, AA015948, F27846, AA505108, AI039257, AA078084,                           AI028148, AA676592, AI932902, AW270329, AI886434, AC005701,                           L47229, AL035425, AL034430, AL121603, Z97987, AL109628, M94579,                           AL022726, Z93020, AP000558, L47227, AL078612, AC007363, AC007546,                           AC005779, AL079342, AC005827, AP000694, AL139054, AC007919,                           AC006251, AC006511, AC009516, AC004000, AC005529, AC005666,                           AL033527, AC002036, AC006312, AC005393, AC004686, Z98743,                           AC003013, AL080243, AL033381, AC005325, AC005822, AC012627,                           AC007051, AL121595, AC003665, AL031121, AC006241, AC004231,                           Z98050, AL022324, AL035587, AC006968, AC005730, AL049694,                           AL049795, AL031680, AC004167, X69907, AC006166, AC007066,                           AC005160, AC005039, AL035445, AC007637, AJ003147, AC004859,                           Z98742, Z97181, AB023051, AC005755, Z73417, AC007688, Z84466,                           AC003029, AC004953, Z47066, AP001068, AL049843, AC005399,                           AC005722, AC006130, AL031294, AC002091, AL022336, U73630,                           AL133246, AC004472, AL117258, AC005479, AF001549, AC006582,                           AC004150, AP000512, AC002350, AC002314, AB003151, Z95116,                           AL022156, AC005015, AD000671, AC004263, Z93017, AC002470,                           AL031133, AL023879, AL132642, U07563, U85195, AL022318, AF165926,                           AL035086, AE000658, AC006468, AC005332, AB018315, AL050333,                           AC006581, AD000833, AC005913, AC005031, AL096707, AP000689,                           AL022345, AC007055, AC007899, AC006561, AC004856, U78027,                           AC005358, Z97056, AC006006, AB004907, AP000692, U07000,                           AC005004, U80017, AC005837, AC007227, AP000702, AP000703,                           AL035457, AC005726, AL109613, AC005234, I38891, AC004253,                           AP000280, AC005288, AC005387, AC004131, AC009247, AC005881,                           AL133448, AL031427, AC000353, AC006274, AB011399, AL049636,                           AC004185, Z97053, AL009181, AC005207, AC005326, AP000039,                           AP000107, AC006398, Z95114, AC004031, AL022721, AC003074,                           AC007421, AC004743, AC008372, AC007021, AL035659, AL050341,                           AC002097, AC000039, AL049869, AC004938, AL096701, Z95327,                           AC006101, AL008582, AL031311, AC006121, AL034402, AC006449,                           AC004893, AC005856, U50871, AC005844, AL049757, AC004998,                           AL035422, AF015416, AC007151, AC002366, AL031589, AC004497,                           AF072711, AC006369, AC005914, AP000556, AC005618, AF217403,                           U62317, AL135783, AC005229, AP000302, AC005391, and AC011456.       HKIYN76   253   770080   1-158   15-172   AA233994, AI457263, H56018, and AI743796.       HKIYM14   254   658464   1-443   15-457   R50790, AW027856, AW023560, AB007880, and AC007011.       HKIYL69   255   757602   1-374   15-388   R44551, AI763301, AI298955, AA770581, AI832042, AI692426, T16755,                           Z41400, and F02737.       HKIYF03   256   924241   1-638   15-652   W84674, AW151108, AW190029, AI588945, H16736, AA701270, R53539,                           H11918, R53968, Z40891, AA599662, F08905, R37016, AA658995,                           F04952, AC005384, and AB011106.       HKIYC59   257   868263   1-793   15-807   W92350, R59008, Z45806, R25845, and R24549.       HKIYC29   258   725699   1-450   15-464   AA047649, AI125839, AI872037, AA078734, N31414, AI888750,                           AW173398, AA291569, AW151816, AI341552, AI147369, AI862320,                           AI460209, H44641, AI890791, AI288302, AI214768, H27098, AI680219,                           H24850, AI569963, AI803398, AA863240, AI587333, AI094729,                           AW275815, AI569966, AI207907, AA025245, AI055872, AI683892,                           AI815179, T55123, AA935404, AA935951, AI760992, AA181579,                           AI095094, AI376224, AI446239, AI521568, AA573591, AI510822, D53868,                           AI936953, AI050810, AI923788, AI754186, AA532835, AI366038,                           AI086308, AA731469, AA026039, AI200772, AA971210, AI124087,                           T94904, W87621, N68630, AA351862, AA506007, AA293586, AI538601,                           AI023071, AI949442, AW418675, AA219074, AW132055, T31872,                           AA065311, AA725853, AA996363, T94859, AA401943, AA164940,                           AI142377, AA128692, AA515058, AA987687, W87540, AI453287,                           H48222, AA774750, AI708636, AA977606, AA598580, H73586, M78415,                           AA219073, AA040892, AA749251, AA903880, AA875848, T24684,                           H10339, AA223894, N80052, AW073120, AA631389, AA643905,                           AA205285, AA731952, AI061149, H00634, AA047663, AI380002,                           AI972718, AW263374, D19661, AA554760, AI422650, R09485, AA016101,                           AA665703, H24851, AW188764, AI718445, AI749700, AB027196, D87451,                           and AB026621.       HKIXT41   259   881507   1-429   15-443   H08815.       HKIXQ80   260   775405   1-436   15-450       HKIXQ47   261   720373   1-461   15-475   AI816841, AW303567, AA234572, AA232836, AW197490, AI700925,                           AA931539, AA508888, AI806376, AA234632, AA837317, AI796862,                           AI745150, AW149610, AW001856, and AW299388.       HKIXB15   262   660458   1-134   15-148   N63346.       HKISB59   263   739423   1-430   15-444   AW016452, AI091148, H06383, AI424991, AA598689, AI693507,                           AI863108, AA599060, R39887, AA813482, AA620528, AI364268,                           AI241940, AW089149, AW090733, R41807, AW088875, Z38240,                           AA676754, and AA121202.       HKISA86   264   785613   1-479   15-493   R59058, R56277, F09135, AI688639, AW297044, AL031290, and                           AB006627.       HKIMG64   265   857190   1-404   15-418   AA493955.       HKIMG03   266   924745   1-569   15-583   AA443730, AI299674, AA043886, AI299675, AI685891, AI928142,                           AW381568, AI718755, AW024319, AI337229, AI760661, AI056045,                           AI982597, and AL021978.       HKIBB62   267   742526   1-562   15-576   H00797, R79425, AI863313, and AC009509.       HKDBF75   268   881308   1-575   15-589   AI928004, AI494057, AW205409, AI478645, AW300209, AI636105,                           AI822029, AW195364, AI365231, AW194974, AI373880, AI244760,                           AI792838, AI800298, AA962549, AI271782, AI792223, AI015994,                           AI733514, AI431716, AW242559, AI636287, AI927024, AI628447,                           AI927179, AW237692, AI474905, and AW242942.       HFKLK34   269   907556   1-651   15-665   AA203368.       HFKLC10   270   963164   1-412   15-426   AI927912, AI969307, D51799, AA305409, D80227, C15076, D59859,                           D80166, D80269, D81030, D51423, D59619, D80210, D80240, D80253,                           D50979, D80195, D58283, C14331, D80212, D80164, D80022, D80188,                           D59467, D80219, C14389, D80378, D80391, D59275, D57483, D59610,                           D80043, D59787, D59502, D80366, D59889, D59927, D80196, D80038,                           D50995, D80024, D80193, D80241, C14429, C75259, D51060, D80045,                           T03269, AW178893, C14014, D51022, D80134, AW179328, AW177440,                           AW378532, D81026, AA305578, AW178775, AW369651, AA514188,                           D51079, F13647, D51250, D80251, D80522, D80248, D58253, D80949,                           AA514186, D59695, D81111, AW352158, AW178762, D80168, C14298,                           C14227, D80064, D80133, AW177501, AI910186, AW177511, AW360811,                           C14407, Z21582, C05695, AI905856, D80268, AW352117, AW176467,                           AW375405, AW378540, D80132, AW377671, AW366296, AW360844,                           AW360817, AW375406, AW378534, D80302, AW179332, AW377672,                           AW179023, AW178905, D80439, D59373, AW360834, AA285331,                           AW352171, AW377676, AW178906, AW352170, AW177731, AW178907,                           D51097, AW179019, AW179024, D80247, AW177505, AW179020,                           AW360841, AI557751, AW352174, AW178909, AW177456, AW179329,                           AW178980, AW177733, AW378528, AW178908, AW178754, AW179018,                           T11417, AW179220, D51103, AW179004, D80157, AW179012,                           AW178914, AW367967, AW378525, D51759, AW177722, D58246,                           AW177728, AW179009, D58101, AW178774, AW178911, AW378543,                           AW352163, D80014, AW178983, D59503, AW352120, AW178781,                           T48593, D59627, C06015, D80258, D59653, AI525920, AW177723,                           D45260, C14975, T03116, AW177508, AI535850, AI557774, AW378533,                           AW378539, H67854, D80228, AW367950, D51213, AW177497, C03092,                           H67866, T02974, AA809122, D59317, AW178986, AI525923, AI525917,                           D45273, D51221, AW177734, D59474, D50981, C14344, C14973,                           AA514184, C14957, D60010, AI525925, AI535686, D59551, AI525235,                           AI525928, D60214, T03048, AI525912, AI525227, C14046, AI525215,                           AI535961, AI525242, AW378542, AI525222, C16955, Z33452, C05763,                           A62298, A62300, A84916, AJ132110, AR018138, X67155, Y17188,                           D26022, A25909, A67220, D89785, A78862, D34614, AF058696,                           AR008278, AB028859, D88547, X82626, AR025207, Y12724, AB012117,                           AR060385, A82595, X68127, A94995, AB002449, A85396, AR066482,                           I50128, AR008443, A44171, I50133, A85477, U87250, I19525, A86792,                           X93549, I50126, I50132, AR066488, AR016514, AR060138, A45456,                           A26615, AR052274, AR066490, Y09669, A43192, A43190, AR038669,                           AR066487, I18367, A30438, AR054175, D88507, I14842, D50010, Y17187,                           X64588, AF135125, AR008277, AR008281, A63261, AR008408,                           AR062872, A70867, AR016691, AR016690, U46128, D13509, A64136,                           A68321, AR060133, I79511, AB033111, U87247, AR064240, AB023656,                           U79457, AF123263, AR032065, X93535, and AR008382.       HFKJP91   271   836476   1-525   15-539   AA081997, and AA285241.       HFKGB24   272   677402   1-401   15-415   AA156760.       HFKFI85   273   589991   1-1175   15-1189       HFKFI46   274   586801   1-405   15-419       HFKEM62   275   917769   1-423   15-437   AA463278, AW131567, AW170150, AW166143, AI332804, AW243538,                           W23206, AI936822, H73017, AI377689, AI219849, AI805901, AI217314,                           AA317712, AI421619, AA429791, H11862, AA984550, AA361590,                           AA600084, AA382978, AI674528, R31389, W03369, AA234327, AI095810,                           H83544, Z25103, N42433, AA355008, T69216, and AC005837.       HFKDH49   276   826803   1-378   15-392       HFKDF03   277   960977   1-495   15-509   AA594916, and AA341585.       HFKDE75   278   766436   1-380   15-394   T92523, AA341577, T91760, AP000056, AP000124, AP000171, and                           AP000330.       HFKCO51   279   725968   1-459   15-473   AA179210, AA341233, and AC004889.       HFKCO02   280   917279   1-535   15-549   AA341205, C14014, H67854, AW367950, D51423, D58283, D80038,                           D80022, C14331, D59275, C14389, D80247, D80043, AA305578, D80439,                           D51022, D59859, D80195, D80253, D80166, D80522, D59467, D59619,                           D80210, D51799, D80391, D80164, D80240, D59787, D80227, D59502,                           AA305409, D81030, D80366, D81026, D80269, D80212, D80268, D80196,                           D80188, D80248, D50979, D80219, D59610, D50995, D59927, D57483,                           C15076, D51060, D59889, C14429, D80024, D80193, D80133, D80045,                           AA514186, AA514188, D80157, D51103, AW360811, H67866, D80378,                           D80241, AW177440, D80302, D51759, D80251, AW178893, T03269,                           AW377671, AW375405, D45260, C75259, AW178906, AW179019,                           AW366296, C06015, AW360844, T48593, AW179328, AW360817,                           AW352170, AW375406, AA809122, AW378534, AW177731, AW179332,                           C05695, AW377672, AW179023, AW178905, AW177505, D59373,                           D59653, AW378528, AW178762, AW378532, AW179020, AW177501,                           AW177511, AW352171, AW377676, AW176467, AW178908, C03092,                           AW178907, AW179024, D51250, AW360834, AW360841, T11417,                           AW352120, AW178775, AW179004, AW178909, AW177456, D80014,                           AW179329, AW178980, AW178914, AW178774, AW177733, AW178754,                           AW179018, AW352158, AW352117, C14344, AW178986, AI525235,                           AI525923, F13647, D80258, C14973, AI525917, H67858, AW179009,                           AW178911, AW179012, C14077, T03116, AW378543, AW378525,                           AW378540, AW177722, AW352163, D80168, D58246, D81111, D59317,                           D51079, D60214, C14227, D59503, D51213, D80064, AW177728, D60010,                           AW378533, D59627, D51221, C14407, D59474, AI525920, AI557774,                           AW178781, AA514184, AI535686, AW177734, C14046, D58101,                           AI910186, D59551, C14957, AI905856, C14298, AI525227, AI557751,                           T02974, AW177723, AI525215, C16955, AI525242, Z33452 AI525912,                           AA285331, AW378542, AI525925, AW378539, D45273, AI525222,                           AI525237, C05763, Z21582, Z30160, AW360855, T03048, C04682,                           AI525228, T02868, D51053, AW369651, AI525928, C13958, D80314,                           T11191, D88547, A62300, AR018138, A84916, AR060385, AF058696,                           AR008278, AR016514, A62298, AB028859, A82595, AJ132110,                           AB002449, I50126, I50132, I50128, I50133, A26615, AR052274,                           AR060138, A45456, D50010, A43192, X67155, A43190, AR066488,                           Y17188, A94995, D26022, Y12724, A25909, A67220, D89785, A78862,                           D34614, AR008443, AR038669, Y09669, AR054175, AR066487, A30438,                           I14842, Y17187, D13509, X82626, A63261, AR008277, AR008281, I82448,                           AR062872, AR008408, A70867, X64588, AR016691, AR016690, I79511,                           U46128, AR025207, AR060133, A64136, A68321, AR032065, X68127,                           AF123263, and AR008382.       HFKCJ69   281   753680   1-336   15-350   AA341194, N49338, N36753, AI148212, and AI250776.       HFKCJ52   282   725974   1-503   15-517   AA486842, R68537, AA341183, T97103, AA487202, AA723375, D80566,                           and R68243.       HFKCG41   283   712718   1-555   15-569   AI732737, AI741369, AA341070, AA428957, and AI734133.       HFKCC73   284   742991   1-318   15-332   AI689230, AA340797, AI468638, R39889, AI652406, R39287, F10762,                           AA971179, AW075374, AI654978, AI866259, AI919420, W22264, and                           AI904302.       HFKBC11   285   967999   1-813   15-827   W06923, AA340596, F02342, AC004520, AF191069, AF096876,                           AC005971, AL050307, Z93244, AC003006, AL049553, AC005702,                           AL035106, AP000271, AP000104, AP000032, AC006486, AC005019,                           AL121603, AC007262, AC004925, AC002470, and AC006208.       HFKBC08   286   960526   1-720   15-734   AI792777, AI733133, AA340456, AA918869, and AW295960.       HCKAA51   287   534949   1-71   15-85   AL022325, and AL031588.       HBAMD83   288   573369   1-327   15-341       HBAMD81   289   778176   1-400   15-414       HBAMD79   290   573373   1-189   15-203       HBAMD74   291   573372   1-382   15-396       HBAMD69   292   573371   1-398   15-412       HBAMD66   293   750532   1-362   15-376   AI793233, AC001228, AC006600, L14561, AC004801, and AC008042.       HBAMD57   294   573370   1-361   15-375   AL133224.       HBAMD50   295   864379   1-332   15-346       HBAMD41   296   573374   1-354   15-368   AC008085.       HBAMD36   297   573367   1-388   15-402       HBAMD35   298   571354   1-319   15-333       HBAMD33   299   573365   1-297   15-311       HBAMD32   300   573362   1-363   15-377       HBAMD31   301   698280   1-243   15-257   AL117354, and AC005519.       HBAMD14   302   573378   1-268   15-282       HBAMC66   303   575218   1-347   15-361   AL134524, AL134110, AL045327, AL045328, AL038838, AI547295,                           AL037343, AL038983, AL037436, AL037335, AI142134, AL037323,                           AL044125, AL047163, AL037295, AL037443, AL037727, AL038532,                           AL042898, AL038761, AL043941, AL038822, AL037435, AL041347,                           AL040193, AL047012, AL048677, AL043923, AL043814, AL041238,                           AL044162, AL044186, AL040617, AL040472, AL038651, AL040576,                           AL040463, D29033, AL043845, AL047170, AL043496, AL044037,                           AI318479, AL041635, AL040294, AL043538, AL040621, AL044064,                           AL047219, AL041459, AL041577, AL040625, AL045684, AL041752,                           AL045753, AL040464, AL046850, AL040768, AL040510, AL043467,                           AL040052, AL045671, AL040444, AL046994, AL043677, AL040839,                           AL047183, AL043492, AL041602, AL046914, AL044074, AL041730,                           AL041523, AL043627, AL041374, AL041324, AL043848, AL043570,                           AL041955, AL039360, AL042135, AL046442, AL038745, AL041133,                           AL041098, AL040322, AL039316, AL039643, AL046392, AL040119,                           AL041096, AL044272, AL044258, AL041163, AL041168, AL042096,                           AL049018, AL041159, AL041296, AL047057, AL045920, AL038878,                           AL040148, AL045817, AL041086, AL041358, AL040458, AL044187,                           AL039432, AL041292, AL041346, U46344, AL045990, AL041142,                           AL040332, AL040571, AL079852, AL037341, AL040529, AL039338,                           AL079878, AL041197, AL046330, AL040745, AL040370, AL044274,                           AL040128, AL048714, AL038024, AL047036, AL048657, AL135012,                           AL045494, AL042523, AL037279, AL038040, AW363350, AL038041,                           AL042420, AL042468, AL042741, AL042655, AR066494, AJ238010,                           AR064707, A93923, D17247, A93916, A93931, A85203, AR023813, and                           AL133053.       HBAMC65   304   750405   1-371   15-385       HBAMC63   305   572936   1-400   15-414   AL121823.       HBAMC62   306   572927   1-375   15-389   Z80901, AC000044, and AC000034.       HBAMC52   307   572935   1-403   15-417   R92238, U82672, AC005969, AC006249, AL133249, Z83827, and                           AL079334.       HBAMC51   308   572929   1-256   15-270       HBAMC42   309   572938   1-151   15-165       HBAMC35   310   571360   1-347   15-361       HBAMC34   311   572926   1-336   15-350       HBAMC23   312   572946   1-461   15-475       HBAMC05   313   932234   1-305   15-319   AL045327, AL134524, AL038878, AL134110, AL045328, U46344,                           AI318479, AL047163, AL042898, AL037295, AL037436, AL038838,                           AL037343, AI547295, AL038983, AI142134, D29033, AL037335,                           AL037323, AL048677, AL038651, AL038761, AL037727, AL037443,                           AL038532, AL135012, AL038822, AL048657, AI547297, AL037435,                           AL045494, AL038745, AL042523, AL040472, AL043941, AL039432,                           AL047037, AL045817, AL043923, AL043814, AL045753, AL044125,                           AL038024, AI547292, AW363350, AL047012, AL042135, AL041238,                           AL044186, AL040617, AL041347, AL043845, AL038040, AL047183,                           AL040193, AL044162, AL037341, AL040464, AL040463, AL047219,                           AL047170, AL040625, AL044037, AL045684, AL041752, AL041635,                           AL040294, AL044064, AL041459, AL041577, AL046850, AL040768,                           AL045671, AL046994, AL046914, AL042420, AL042468, AL043496,                           AL043538, AL040621, AL040510, AL043467, AL043677, AL046442,                           AL040839, AL043492, AL041602, AL044074, AL041730, AL041523,                           AL043627, AL041374, AL043848, AL043570, AL045891, AL040052,                           AL038041, AI547258, AL046273, AL079852, AL045990, AL046392,                           AL042741, AL042655, AL039643, AI547279, AL043089, AL043321,                           AR066494, D17247, A93923, A93916, A93931, A85203, AL133053,                           AL122101, AR023813, AL133074, and AL133049.       HBAGW31   314   960146   1-1038   15-1052   AI536637, N57401, AW451874, AA186627, AA155619, AA630132,                           AA157375, AA157874, T87885, AA157981, H75748, T78968, T87975,                           H75882, AA155657, T78915, and AC005632.       HBAGR76   315   864389   1-459   15-473   W85958.       HBAGH38   316   487933   1-449   15-463   R24932, AA808824, AL050181, and AB011090.       HBAFV7I   317   932783   1-488   15-502   AA421030, AI770016, AI693177, AI918036, AI338497, AA805525,                           AA749368, AW104323, AI932332, AI536849, N69071, AI475851,                           AI910707, AI628055, AI272788, R12698, AW339028, AA487625,                           AA101186, H41527, T23854, AW162414, AW161923, T10224, AA912188,                           H18616, R53452, Z39946, AA610763, AW086187, F03171, H19985,                           AI205478, AI638791, H92276, H41634, F02580, F01551, F02581,                           AW003446, H19984, H18615, AW207551, AA988910, AA932333,                           AI086160, AI094725, AW439925, AA365932, AW169022, AB010441, and                           AF106624.       HBAFU01   318   916248   1-460   15-474   AA459874.       HBAFP29   319   690521   1-435   15-449   H30825, AA284220, AA405396, and AA610768.       HBAFI04   320   615078   1-275   15-289   R48069, AI766113, AA829235, and AI912666.       HBAFF55   321   753801   1-453   15-467   AA063554, AA922507, AW451853, AI961015, AI660496, AA811829,                           AW295582, AW139627, AW449697, AA805067, AI742099, AW028304,                           AI421698, AI890848, AI498772, AI524750, AA302949, AA521445,                           AI142614, AI383910, R65847, AW105651, AW438961, AI497884, T90217,                           AA811312, AA039322, AI699283, AA936584, N80792, AA535950,                           AI950605, AI688529, AW205828, and R26106.       HBAFF09   322   926667   1-1100   15-1114   AI222323, AW104230, AW274395, and AA917623.       HBAFC04   323   615472   1-473   15-487   AA234412, and AA233482.       HAKAD91   324   509854   1-333   15-347   AI148006, AA312407, and AA312378.       HAKAD72   325   509855   1-446   15-460   AA312192, and AA312203.                  
 
       [0107]                                       TABLE 4                       Code   Description   Tissue   Organ   Cell Line   Disease   Vector                  AR022   a_Heart   a_Heart                       AR023   a_Liver   a_Liver       AR024   a_mammary gland   a_mammary gland       AR025   a_Prostate   a_Prostate       AR026   a_small intestine   a_small intestine       AR027   a_Stomach   a_Stomach       AR028   Blood B cells   Blood B cells       AR029   Blood B cells activated   Blood B cells               activated       AR030   Blood B cells resting   Blood B cells               resting       AR031   Blood T cells activated   Blood T cells               activated       AR032   Blood T cells resting   Blood T cells               resting       AR033   brain   brain       AR034   breast   breast       AR035   breast cancer   breast cancer       AR036   Cell Line CAOV3   Cell Line CAOV3       AR037   cell line PA-1   cell line PA-1       AR038   cell line transformed   cell line               transformed       AR039   colon   colon       AR040   colon (9808co65R)   colon (9808co65R)       AR041   colon (9809co15)   colon (9809co15)       AR042   colon cancer   colon cancer       AR043   colon cancer   colon cancer           (9808co64R)   (9808co64R)       AR044   colon cancer 9809co14   colon cancer               9809co14       AR045   corn clone 5   corn clone 5       AR046   corn clone 6   corn clone 6       AR047   corn clone 2   corn clone 2       AR048   corn clone 3   corn clone 3       AR049   Corn Clone 4   Corn Clone 4       AR050   Donor II B Cells 24 hrs   Donor II B Cells               24 hrs       AR051   Donor II B Cells 72 hrs   Donor II B Cells               72 hrs       AR052   Donor II B-Cells 24 hrs.   Donor II B-Cells               24 hrs.       AR053   Donor II B-Cells 72 hrs   Donor II B-Cells               72 hrs       AR054   Donor II Resting B Cells   Donor II Resting B               Cells       AR055   Heart   Heart       AR056   Human Lung (clonetech)   Human Lung               (clonetech)       AR057   Human Mammary   Human Mammary           (clontech)   (clontech)       AR058   Human Thymus   Human Thymus           (clonetech)   (clonetech)       AR059   Jurkat (unstimulated)   Jurkat               (unstimulated)       AR060   Kidney   Kidney       AR061   Liver   Liver       AR062   Liver (Clontech)   Liver (Clontech)       AR063   Lymphocytes chronic   Lymphocytes           lymphocytic leukaemia   chronic               lymphocytic               leukaemia       AR064   Lymphocytes diffuse   Lymphocytes           large B cell lymphoma   diffuse large B cell               lymphoma       AR065   Lymphocytes follicular   Lymphocytes           lymphoma   follicular               lymphoma       AR066   normal breast   normal breast       AR067   Normal Ovarian   Normal Ovarian           (4004901)   (4004901)       AR068   Normal Ovary   Normal Ovary           9508G045   9508G045       AR069   Normal Ovary   Normal Ovary           9701G208   9701G208       AR070   Normal Ovary   Normal Ovary           9806G005   9806G005       AR071   Ovarian Cancer   Ovarian Cancer       AR072   Ovarian Cancer   Ovarian Cancer           (9702G001)   (9702G001)       AR073   Ovarian Cancer   Ovarian Cancer           (9707G029)   (9707G029)       AR074   Ovarian Cancer   Ovarian Cancer           (9804G011)   (9804G011)       AR075   Ovarian Cancer   Ovarian Cancer           (9806G019)   (9806G019)       AR076   Ovarian Cancer   Ovarian Cancer           (9807G017)   (9807G017)       AR077   Ovarian Cancer   Ovarian Cancer           (9809G001)   (9809G001)       AR078   ovarian cancer 15799   ovarian cancer               15799       AR079   Ovarian Cancer   Ovarian Cancer           17717AID   17717AID       AR080   Ovarian Cancer   Ovarian Cancer           4004664B1   4004664B1       AR081   Ovarian Cancer   Ovarian Cancer           4005315A1   4005315A1       AR082   ovarian cancer   ovarian cancer           94127303   94127303       AR083   Ovarian Cancer   Ovarian Cancer           96069304   96069304       AR084   Ovarian Cancer   Ovarian Cancer           9707G029   9707G029       AR085   Ovarian Cancer   Ovarian Cancer           9807G045   9807G045       AR086   ovarian cancer   ovarian cancer           9809G001   9809G001       AR087   Ovarian Cancer   Ovarian Cancer           9905C032RC   9905C032RC       AR088   Ovarian cancer   Ovarian cancer           9907C00 3rd   9907 C00 3rd       AR089   Prostate   Prostate       AR090   Prostate (clonetech)   Prostate               (clonetech)       AR091   prostate cancer   prostate cancer       AR092   prostate cancer #15176   prostate cancer               #15176       AR093   prostate cancer #15509   prostate cancer               #15509       AR094   prostate cancer #15673   prostate cancer               #15673       AR095   Small Intestine   Small Intestine           (Clontech)   (Clontech)       AR096   Spleen   Spleen       AR097   Thymus T cells activated   Thymus T cells               activated       AR098   Thymus T cells resting   Thymus T cells               resting       AR099   Tonsil   Tonsil       AR100   Tonsil geminal center   Tonsil geminal           centroblast   center centroblast       AR101   Tonsil germinal center B   Tonsil germinal           cell   center B cell       AR102   Tonsil lymph node   Tonsil lymph node       AR103   Tonsil memory B cell   Tonsil memory B               cell       AR104   Whole Brain   Whole Brain       AR105   Xenograft ES-2   Xenograft ES-2       AR106   Xenograft SW626   Xenograft SW626       H0011   Human Fetal Kidney   Human Fetal   Kidney           Uni-ZAP               Kidney               XR       H0012   Human Fetal Kidney   Human Fetal   Kidney           Uni-ZAP               Kidney               XR       H0053   Human Adult Kidney   Human Adult   Kidney           Uni-ZAP               Kidney               XR       H0119   Human Pediatric Kidney   Human Pediatric   Kidney           Uni-ZAP               Kidney               XR       H0239   Human Kidney Tumor   Human Kidney   Kidney       disease   Uni-ZAP               Tumor               XR       H0334   Kidney cancer   Kidney Cancer   Kidney       disease   Uni-ZAP                               XR       H0356   Human Kidney   Human Kidney   Kidney           pCMVSport1       H0361   Human rejected kidney   Human Rejected           disease   pBluescript               Kidney       H0399   Human Kidney Cortex,   Human Kidney               Lambda           re-rescue   Cortex               ZAP II       H0408   Human kidney Cortex,   Human Kidney               pBluescript           subtracted   Cortex       H0410   H. Male bladder, adult   H Male Bladder,   Bladder           pSport1               Adult       H0411   H Female Bladder,   Human Female   Bladder           pSport1           Adult   Adult Bladder       H0431   H. Kidney Medulla, re-   Kidney medulla   Kidney           pBluescript           excision       H0441   H. Kidney Cortex,   Kidney cortex   Kidney           pBluescript           subtracted       H0453   H. Kidney Pyramid,   Kidney pyramids   Kidney           pBluescript           subtracted       H0461   H. Kidney Medulla,   Kidney medulla   Kidney           pBluescript           subtracted       H0555   Rejected Kidney, lib 4   Human Rejected   Kidney       disease   pCMVSport               Kidney               3.0       H0620   Human Fetal Kidney;   Human Fetal   Kidney           Uni-ZAP           Reexcision   Kidney               XR       S0015   Kidney medulla   Kidney medulla   Kidney           Uni-ZAP                               XR       S0023   Human Kidney Cortex -   Human Kidney           unamplified   Cortex       S0024   Human Kidney Medulla -   Human Kidney           unamplified   Medulla       S0025   Human Kidney   Human Kidney           Pyramids - unamplified   Pyramids       S0288   7TMCTK (Kidney)   7TMCTK   Brain           PCRII               (Kidney)       L0005   Clontech human aorta           polyA + mRNA (#6572)       L0163   Human heart cDNA       heart           (YNakamura)       L0366   Stratagene schizo brain   schizophrenic               Bluescript           S11   brain S-11 frontal               SK-               lobe       L0369   NCI_CGAP_AA1   adrenal adenoma   adrenal           Bluescript                   gland           SK-       L0373   NCI_CGAP_Co11   tumor   colon           Bluescript                               SK-       L0435   Infant brain, LLNL array                   lafmid BA           of Dr M Soares 1NIB       L0438   normalized infant brain   total brain   brain           lafmid BA           cDNA       L0439   Soares infant brain 1NIB       whole brain           Lafmid BA       L0471   Human fetal heart,                   Lambda           Lambda ZAP Express                   ZAP                               Express       L0475   KG1-a Lambda Zap           KG1-a       Lambda Zap           Express cDNA library                   Express                               (Stratagene)       L0485   STRATAGENE Human   skeletal muscle   leg muscle           Lambda           skeletal muscle cDNA                   ZAPII           library, cat. #936215       L0517   NCI_CGAP_Pr1                   pAMP10       L0518   NCI_CGAP_Pr2                   pAMP10       L0519   NCI_CGAP_Pr3                   pAMP10       L0520   NCI_CGAP_Alv1   alveolar               pAMP10               rhabdomyosarcoma       L0521   NCI_CGAP_Ew1   Ewing&#39;s sarcoma               pAMP10       L0527   NCI_CGAP_Ov2   ovary               pAMP10       L0529   NCI_CGAP_Pr6   prostate               pAMP10       L0532   NCI_CGAP_Thy1   thyroid               pAMP10       L0536   NCI_CGAP_Br4   normal ductal   breast           pAMP10               tissue       L0542   NCI_CGAP_Pr11   normal prostatic   prostate           pAMP10               epithelial cells       L0565   Normal Human   Bone   Hip           pBluescript           Trabecular Bone Cells       L0591   Stratagene HeLa cell s3                   pBluescript           937216                   SK-       L0592   Stratagene hNT neuron                   pBluescript           (#937233)                   SK-       L0594   Stratagene                   pBluescript           neuroepithelium                   SK-           NT2RAMI 937234       L0595   Stratagene NT2 neuronal   neuroepithelial   brain           pBluescript           precursor 937230   cells               SK-       L0596   Stratagene colon       colon           pBluescript           (#937204)                   SK-       L0597   Stratagene corneal       cornea           pBluescript           stroma (#937222)                   SK-       L0598   Morton Fetal Cochlea   cochlea   ear           pBluescript                               SK-       L0599   Stratagene lung       lung           pBluescript           (#937210)                   SK-       L0600   Weizmann Olfactory   olfactory   nose           pBluescript           Epithelium   epithelium               SK-       L0601   Stratagene pancreas       pancreas           pBluescript           (#937208)                   SK-       L0603   Stratagene placenta       placenta           pBluescript           (#937225)                   SK-       L0605   Stratagene fetal spleen   fetal spleen   spleen           pBluescript           (#937205)                   SK-       L0643   NCI_CGAP_Co19   moderately   colon           pCMV-               differentiated               SPORT6               adenocarcinoma       L0651   NCI_CGAP_Kid8   renal cell tumor   kidney           pCMV-                               SPORT6       L0662   NCI_CGAP_Gas4   poorly   stomach           pCMV-               differentiated               SPORT6               adenocarcinoma               with signet r       L0666   NCI_CGAP_Ut1   well-differentiated   uterus           pCMV-               endometrial               SPORT6               adenocarcinoma, 7       L0717   Gessler Wilms tumor                   pSPORT1       L0731   Soares_pregnant_uterus —         uterus           pT7T3-Pac           NbHPU       L0740   Soares melanocyte   melanocyte               pT7T3D           2NbHM                   (Pharmacia)                               with a                               modified                               polylinker       L0742   Soares adult brain       brain           pT7T3D           N2b5HB55Y                   (Pharmacia)                               with a                               modified                               polylinker       L0743   Soares breast 2NbHBst       breast           pT7T3D                               (Pharmacia)                               with a                               modified                               polylinker       L0744   Soares breast 3NbHBst       breast           pT7T3D                               (Pharmacia)                               with a                               modified                               polylinker       L0745   Soares retina N2b4HR   retina   eye           pT7T3D                               (Pharmacia)                               with a                               modified                               polylinker       L0746   Soares retina N2b5HR   retina   eye           pT7T3D                               (Pharmacia)                               with a                               modified                               polylinker       L0747   Soares_fetal_heart_NbH       heart           pT7T3D           H19W                   (Pharmacia)                               with a                               modified                               polylinker       L0748   Soares fetal liver spleen       Liver and           pT7T3D           1NFLS       Spleen           (Pharmacia)                               with a                               modified                               polylinker       L0749   Soares_fetal_liver_spleen —         Liver and           pT7T3D           1NFLS_S1       Spleen           (Pharmacia)                               with a                               modified                               polylinker       L0750   Soares_fetal_lung_NbH       lung           pT7T3D           L19W                   (Pharmacia)                               with a                               modified                               polylinker       L0751   Soares ovary tumor   ovarian tumor   ovary           pT7T3D           NbHOT                   (Pharmacia)                               with a                               modified                               polylinker       L0752   Soares_parathyroid_tumor —     parathyroid tumor   parathyroid           pT7T3D           NbHPA       gland           (Pharmacia)                               with a                               modified                               polylinker       L0753   Soares_pineal_gland_N3       pineal           pT7T3D           HPG       gland           (Pharmacia)                               with a                               modified                               polylinker       L0754   Soares placenta Nb2HP       placenta           pT7T3D                               (Pharmacia)                               with a                               modified                               polylinker       L0755   Soares_placenta_8to9weeks —         placenta           pT7T3D           2NbHP8to9W                   (Pharmacia)                               with a                               modified                               polylinker       L0756   Soares_multiple_sclerosis —     multiple sclerosis               pT7T3D           2NbHMSP   lesions               (Pharmacia)                               with a                               modified                               polylinker                               V_TYPE       L0758   Soares_testis_NHT                   pT7T3D-Pac                               (Pharmacia)                               with a                               modified                               polylinker       L0759   Soares_total_fetus_Nb2                   pT7T3D-Pac           HF8_9w                   (Pharmacia)                               with a                               modified                               polylinker       L0761   NCI_CGAP_CLL1   B-cell, chronic               pT7T3D-Pac               lymphotic               (Pharmacia)               leukemia               with a                               modified                               polylinker       L0763   NCI_CGAP_Br2   breast               pT7T3D-Pac                               (Pharmacia)                               with a                               modified                               polylinker       L0764   NCI_CGAP_Co3   colon               pT7T3D-Pac                               (Pharmacia)                               with a                               modified                               polylinker       L0766   NCI_CGAP_GCB1   germinal center B               pT7T3D-Pac               cell               (Pharmacia)                               with a                               modified                               polylinker       L0768   NCI_CGAP_GC4   pooled germ cell               pT7T3D-Pac               tumors               (Pharmacia)                               with a                               modified                               polylinker       L0769   NCI_CGAP_Brn25   anaplastic   brain           pT7T3D-Pac               oligodendroglioma               (Pharmacia)                               with a                               modified                               polylinker       L0770   NCI_CGAP_Brn23   glioblastoma   brain           pT7T3D-Pac               (pooled)               (Pharmacia)                               with a                               modified                               polylinker       L0774   NCI_CGAP_Kid3       kidney           pT7T3D-Pac                               (Pharmacia)                               with a                               modified                               polylinker       L0775   NCI_CGAP_Kid5   2 pooled tumors   kidney           pT7T3D-Pac               (clear cell type)               (Pharmacia)                               with a                               modified                               polylinker       L0776   NCI_CGAP_Lu5   carcinoid   lung           pT7T3D-Pac                               (Pharmacia)                               with a                               modified                               polylinker       L0777   Soares_NhHMPu_S1   Pooled human   mixed (see           pT7T3D-Pac               melanocyte, fetal   below)           (Pharmacia)               heart, and pregnant               with a                               modified                               polylinker       L0779   Soares_NFL_T_GBC_S1       pooled           pT7T3D-Pac                               (Pharmacia)                               with a                               modified                               polylinker       L0783   NCI_CGAP_Pr22   normal prostate   prostate           pT7T3D-Pac                               (Pharmacia)                               with a                               modified                               polylinker       L0789   NCI_CGAP_Sub3                   pT7T3D-Pac                               (Pharmacia)                               with a                               modified                               polylinker       L0794   NCI_CGAP_GC6   pooled germ cell               pT7T3D-Pac               tumors               (Pharmacia)                               with a                               modified                               polylinker       L0803   NCI_CGAP_Kid11       kidney           pT7T3D-Pac                               (Pharmacia)                               with a                               modified                               polylinker       L0805   NCI_CGAP_Lu24   carcinoid   lung           pT7T3D-Pac                               (Pharmacia)                               with a                               modified                               polylinker       L0806   NCI_CGAP_Lu19   squamous cell   lung           pT7T3D-Pac               carcinoma, poorly               (Pharmacia)               differentiated (4               with a                               modified                               polylinker       L0809   NCI_CGAP_Pr28       prostate           pT7T3D-Pac                               (Pharmacia)                               with a                               modified                               polylinker                    
       [0108]                   TABLE 5                       OMIM           Reference   Description                  107777   Diabetes insipidus, nephrogenic, autosomal recessive, 222000       108725   Atherosclerosis, susceptibility to       120700   C3 deficiency       123940   White sponge nevus, 193900       133171   [Erythrocytosis, familial], 133100       136836   Fucosyltransferase-6 deficiency       139350   Epidermolytic hyperkeratosis, 113800       139350   Keratoderma, palmoplantar, nonepidermolytic       145981   Hypocalciuric hypercalcemia, type II       147141   Leukemia, acute lymphoblastic       148040   Epidermolysis bullosa simplex, Koebner, Dowling-Meara, and           Weber-Cockayne types, 131900, 131760, 131800       148041   Pachyonychia congenita,           Jadassohn-Lewandowsky type, 167200       148043   Meesmann corneal dystrophy, 122100       148070   Liver disease, susceptibility to, from hepatotoxins or viruses       164953   Liposarcoma       177070   Spherocytosis, hereditary, Japanese type       177070   Hermansky-Pudlak syndrome, 203300       182500   Cataract, congenital       188070   Bleeding disorder due to defective thromboxane A2 receptor       203800   Alstrom syndrome       218000   Andermann syndrome       227220   [Eye color, brown]       229600   Fructose intolerance       231550   Achalasia-addisonianism-alacrimia syndrome       243500   Isovalericacidemia       264300   Pseudohermaphroditism, male, with gynecomastia       600194   Ichthyosis bullosa of Siemens, 146800       600231   Palmoplantar keratoderma, Bothnia type       600536   Myopathy, congenital       600542   Chondrosarcoma, extraskeletal myxoid       600808   Enuresis, nocturnal, 2       600839   Bartter syndrome, 241200       600956   Persistent Mullerian duct syndrome, type II, 261550       600957   Persistent Mullerian duct syndrome, type I, 261550       601238   Cerebellar ataxia, Cayman type       601284   Hereditary hemorrhagic telangiectasia-2, 600376       601769   Osteoporosis, involutional       601769   Rickets, vitamin D-resistant, 277440       601800   [Hair color, brown]       601846   Muscular dystrophy with rimmed vacuoles       601928   Monilethrix, 158000       602014   Hypomagnesemia with secondary hypocalcemia       602088   Nephronophthisis, infantile       602116   Glioma       602153   Monilethrix, 158000       602216   Peutz-Jeghers syndrome, 175200       602404   Parkinson disease, type 3       602477   Febrile convulsions, familial, 2                    
       [0109] Polynucleotide and Polypeptide Variants  
       [0110] The present invention is also directed to variants of the excretory system associated polynucleotide sequence disclosed in SEQ ID NO: X or the complementary strand thereto, nucleotide sequences encoding the polypeptide of SEQ ID NO: Y, the nucleotide sequence of SEQ ID NO: X encoding the polypeptide sequence as defined in column 6 of Table 1A, nucleotide sequences encoding the polypeptide as defined in column 6 of Table 1A, the nucleotide sequence as defined in columns 8 and 9 of Table 2, nucleotide sequences encoding the polypeptide encoded by the nucleotide sequence as defined in columns 8 and 9 of Table 2, the nucleotide sequence as defined in column 6 of Table 1B, nucleotide sequences encoding the polypeptide encoded by the nucleotide sequence as defined in column 6 of Table 1B, the cDNA sequence contained in Clone ID NO: Z, and/or nucleotide sequences encoding a polypeptide encoded by the cDNA sequence contained in Clone ID NO: Z.  
       [0111] The present invention also encompasses variants of the polypeptide sequence disclosed in SEQ ID NO: Y, a polypeptide sequence as defined in column 6 of Table 1A, a polypeptide sequence encoded by the polynucleotide sequence in SEQ ID NO: X, a polypeptide sequence encoded by the nucleotide sequence as defined in columns 8 and 9 of Table 2, a polypeptide sequence encoded by the nucleotide sequence as defined in column 6 of Table 1B, a polypeptide sequence encoded by the complement of the polynucleotide sequence in SEQ ID NO: X, and/or a polypeptide sequence encoded by the cDNA sequence contained in Clone ID NO: Z.  
       [0112] “Variant” refers to a polynucleotide or polypeptide differing from the polynucleotide or polypeptide of the present invention, but retaining essential properties thereof. Generally, variants are overall closely similar, and, in many regions, identical to the polynucleotide or polypeptide of the present invention.  
       [0113] Thus, one aspect of the invention provides an isolated nucleic acid molecule comprising, or alternatively consisting of, a polynucleotide having a nucleotide sequence selected from the group consisting of: (a) a nucleotide sequence described in SEQ ID NO: X or contained in the cDNA sequence of Clone ID NO: Z; (b) a nucleotide sequence in SEQ ID NO: X or the cDNA in Clone ID NO: Z which encodes a mature excretory system associated polypeptide; (c) a nucleotide sequence in SEQ ID NO: X or the cDNA sequence of Clone ID NO: Z, which encodes a biologically active fragment of an excretory system associated polypeptide; (d) a nucleotide sequence in SEQ ID NO: X or the cDNA sequence of Clone ID NO: Z, which encodes an antigenic fragment of an excretory system associated polypeptide; (e) a nucleotide sequence encoding an excretory system associated polypeptide having the complete amino acid sequence of SEQ ID NO: Y or the complete amino acid sequence encoded by the cDNA in Clone ID NO: Z; (f) a nucleotide sequence encoding a mature excretory system associated polypeptide of the amino acid sequence of SEQ ID NO: Y or the amino acid sequence encoded by the cDNA in Clone ID NO: Z; (g) a nucleotide sequence encoding a biologically active fragment of an excretory system associated polypeptide having the complete amino acid sequence of SEQ ID NO: Y or the complete amino acid sequence encoded by the cDNA in Clone ID NO: Z; (h) a nucleotide sequence encoding an antigenic fragment of an excretory system associated polypeptide having the complete amino acid sequence of SEQ ID NO: Y or the complete amino acid sequence encoded by the cDNA in Clone ID NO: Z; and (i) a nucleotide sequence complementary to any of the nucleotide sequences in (a), (b), (c), (d), (e), (f), (g), or (h), above.  
       [0114] The present invention is also directed to nucleic acid molecules which comprise, or alternatively consist of, a nucleotide sequence which is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%, identical to, for example, any of the nucleotide sequences in (a), (b), (c), (d), (e), (f), (g), (h), or (i) above, the nucleotide coding sequence in SEQ ID NO: X or the complementary strand thereto, the nucleotide coding sequence of the cDNA contained in Clone ID NO: Z or the complementary strand thereto, a nucleotide sequence encoding the polypeptide of SEQ ID NO: Y, a nucleotide sequence encoding a polypeptide sequence encoded by the nucleotide sequence in SEQ ID NO: X, a polypeptide sequence encoded by the complement of the polynucleotide sequence in SEQ ID NO: X, a nucleotide sequence encoding the polypeptide encoded by the cDNA contained in Clone ID NO: Z, the nucleotide coding sequence in SEQ ID NO: X as defined in columns 8 and 9 of Table 2 or the complementary strand thereto, a nucleotide sequence encoding the polypeptide encoded by the nucleotide sequence in SEQ ID NO: X as defined in columns 8 and 9 of Table 2 or the complementary strand thereto, the nucleotide coding sequence in SEQ ID NO: B as defined in column 6 of Table 1B or the complementary strand thereto, a nucleotide sequence encoding the polypeptide encoded by the nucleotide sequence in SEQ ID NO: B as defined in column 6 of Table 1B or the complementary strand thereto, the nucleotide sequence in SEQ ID NO: X encoding the polypeptide sequence as defined in column 6 of Table 1A or the complementary strand thereto, nucleotide sequences encoding a polypeptide as defined in column 6 of Table 1A or the complementary strand thereto, and/or polynucleotide fragments of any of these nucleic acid molecules (e.g., those fragments described herein). Polynucleotides which hybridize to the complement of these nucleic acid molecules under stringent hybridization conditions or alternatively, under lower stringency conditions, are also encompassed by the invention, as are polypeptides encoded by these polynucleotides and nucleic acids.  
       [0115] In a preferred embodiment, the invention encompasses nucleic acid molecules which comprise, or alternatively, consist of a polynucleotide which hybridizes under stringent hybridization conditions, or alternatively, under lower stringency conditions, to a polynucleotide in (a), (b), (c), (d), (e), (f), (g), (h), or (i) above, as are polypeptides encoded by these polynucleotides. In another preferred embodiment, polynucleotides which hybridize to the complement of these nucleic acid molecules under stringent hybridization conditions or alternatively, under lower stringency conditions, are also encompassed by the invention, as are polypeptides encoded by these polynucleotides.  
       [0116] In another embodiment, the invention provides a purified protein comprising, or alternatively consisting of, a polypeptide having an amino acid sequence selected from the group consisting of: (a) the complete amino acid sequence of SEQ ID NO: Y or the complete amino acid sequence encoded by the cDNA in Clone ID NO: Z; (b) the amino acid sequence of a mature excretory system associated polypeptide having the amino acid sequence of SEQ ID NO: Y or the amino acid sequence encoded by the cDNA in Clone ID NO: Z; (c) the amino acid sequence of a biologically active fragment of an excretory system associated polypeptide having the complete amino acid sequence of SEQ ID NO: Y or the complete amino acid sequence encoded by the cDNA in Clone ID NO: Z; and (d) the amino acid sequence of an antigenic fragment of an excretory system associated polypeptide having the complete amino acid sequence of SEQ ID NO: Y or the complete amino acid sequence encoded by the cDNA in Clone ID NO: Z.  
       [0117] The present invention is also directed to proteins which comprise, or alternatively consist of, an amino acid sequence which is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%, identical to, for example, any of the amino acid sequences in (a), (b), (c), or (d), above, the amino acid sequence shown in SEQ ID NO: Y, the amino acid sequence encoded by the cDNA contained in Clone ID NO: Z, the amino acid sequence of the polypeptide encoded by the nucleotide sequence in SEQ ID NO: X as defined in columns 8 and 9 of Table 2, the amino acid sequence of the polypeptide encoded by the nucleotide sequence in SEQ ID NO: B as defined in column 6 of Table 1B, the amino acid sequence as defined in column 6 of Table 1A, an amino acid sequence encoded by the nucleotide sequence in SEQ ID NO: X, and an amino acid sequence encoded by the complement of the polynucleotide sequence in SEQ ID NO: X. Fragments of these polypeptides are also provided (e.g., those fragments described herein). Further proteins encoded by polynucleotides which hybridize to the complement of the nucleic acid molecules encoding these amino acid sequences under stringent hybridization conditions or alternatively, under lower stringency conditions, are also encompassed by the invention, as are the polynucleotides encoding these proteins.  
       [0118] By a nucleic acid having a nucleotide sequence at least, for example, 95% “identical” to a reference nucleotide sequence of the present invention, it is intended that the nucleotide sequence of the nucleic acid is identical to the reference sequence except that the nucleotide sequence may include up to five point mutations per each 100 nucleotides of the reference nucleotide sequence encoding the polypeptide. In other words, to obtain a nucleic acid having a nucleotide sequence at least 95% identical to a reference nucleotide sequence, up to 5% of the nucleotides in the reference sequence may be deleted or substituted with another nucleotide, or a number of nucleotides up to 5% of the total nucleotides in the reference sequence may be inserted into the reference sequence. The query sequence may be an entire sequence referred to in Table 1A or 2 as the ORF (open reading frame), or any fragment specified, as described herein.  
       [0119] As a practical matter, whether any particular nucleic acid molecule or polypeptide is at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to a nucleotide sequence of the present invention can be determined conventionally using known computer programs. A preferred method for determining the best overall match between a query sequence (a sequence of the present invention) and a subject sequence, also referred to as a global sequence alignment, can be determined using the FASTDB computer program based on the algorithm of Brutlag et al. (Comp. App. Biosci. 6:237-245 (1990)). In a sequence alignment the query and subject sequences are both DNA sequences. An RNA sequence can be compared by converting U&#39;s to T&#39;s. The result of said global sequence alignment is expressed as percent identity. Preferred parameters used in a FASTDB alignment of DNA sequences to calculate percent identity are: Matrix=Unitary, k-tuple=4, Mismatch Penalty=1, Joining Penalty=30, Randomization Group Length=0, Cutoff Score=1, Gap Penalty=5, Gap Size Penalty 0.05, Window Size=500 or the length of the subject nucleotide sequence, whichever is shorter.  
       [0120] If the subject sequence is shorter than the query sequence because of 5′ or 3′ deletions, not because of internal deletions, a manual correction must be made to the results. This is because the FASTDB program does not account for 5′ and 3′ truncations of the subject sequence when calculating percent identity. For subject sequences truncated at the 5′ or 3′ ends, relative to the query sequence, the percent identity is corrected by calculating the number of bases of the query sequence that are 5′ and 3′ of the subject sequence, which are not matched/aligned, as a percent of the total bases of the query sequence. Whether a nucleotide is matched/aligned is determined by results of the FASTDB sequence alignment. This percentage is then subtracted from the percent identity, calculated by the above FASTDB program using the specified parameters, to arrive at a final percent identity score. This corrected score is what is used for the purposes of the present invention. Only bases outside the 5′ and 3′ bases of the subject sequence, as displayed by the FASTDB alignment, which are not matched/aligned with the query sequence, are calculated for the purposes of manually adjusting the percent identity score.  
       [0121] For example, a 90 base subject sequence is aligned to a 100 base query sequence to determine percent identity. The deletions occur at the 5′ end of the subject sequence and therefore, the FASTDB alignment does not show a matched/alignment of the first 10 bases at 5′ end. The 10 unpaired bases represent 10% of the sequence (number of bases at the 5′ and 3′ ends not matched/total number of bases in the query sequence) so 10% is subtracted from the percent identity score calculated by the FASTDB program. If the remaining 90 bases were perfectly matched the final percent identity would be 90%. In another example, a 90 base subject sequence is compared with a 100 base query sequence. This time the deletions are internal deletions so that there are no bases on the 5′ or 3′ of the subject sequence which are not matched/aligned with the query. In this case the percent identity calculated by FASTDB is not manually corrected. Once again, only bases 5′ and 3′ of the subject sequence which are not matched/aligned with the query sequence are manually corrected for. No other manual corrections are to made for the purposes of the present invention.  
       [0122] By a polypeptide having an amino acid sequence at least, for example, 95% “identical” to a query amino acid sequence of the present invention, it is intended that the amino acid sequence of the subject polypeptide is identical to the query sequence except that the subject polypeptide sequence may include up to five amino acid alterations per each 100 amino acids of the query amino acid sequence. In other words, to obtain a polypeptide having an amino acid sequence at least 95% identical to a query amino acid sequence, up to 5% of the amino acid residues in the subject sequence may be inserted, deleted, (indels) or substituted with another amino acid. These alterations of the reference sequence may occur at the amino or carboxy terminal positions of the reference amino acid sequence or anywhere between those terminal positions, interspersed either individually among residues in the reference sequence or in one or more contiguous groups within the reference sequence.  
       [0123] As a practical matter, whether any particular polypeptide is at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to, for instance, the amino acid sequence of a polypeptide referred to in Table 1A (e.g., an amino acid sequence identified in columns 5 or 6) or Table 2 (e.g., the amino acid sequence of the polypeptide encoded by the polynucleotide sequence defined in columns 8 and 9 of Table 2) or a fragment thereof, the amino acid sequence of the polypeptide encoded by the polynucleotide sequence in SEQ ID NO: B as defined in column 6 of Table 1B or a fragment thereof, the amino acid sequence of the polypeptide encoded by the nucleotide sequence in SEQ ID NO: X or a fragment thereof, or an amino acid sequence of the polypeptide encoded by cDNA contained in Clone ID NO: Z, or a fragment thereof, can be determined conventionally using known computer programs. A preferred method for determining the best overall match between a query sequence (a sequence of the present invention) and a subject sequence, also referred to as a global sequence alignment, can be determined using the FASTDB computer program based on the algorithm of Brutlag et al. (Comp. App. Biosci.6:237-245 (1990)). In a sequence alignment the query and subject sequences are either both nucleotide sequences or both amino acid sequences. The result of said global sequence alignment is expressed as percent identity. Preferred parameters used in a FASTDB amino acid alignment are: Matrix=PAM 0, k-tuple=2, Mismatch Penalty=1, Joining Penalty=20, Randomization Group Length=0, Cutoff Score=1, Window Size=sequence length, Gap Penalty=5, Gap Size Penalty=0.05, Window Size=500 or the length of the subject amino acid sequence, whichever is shorter.  
       [0124] If the subject sequence is shorter than the query sequence due to N- or C-terminal deletions, not because of internal deletions, a manual correction must be made o the results. This is because the FASTDB program does not account for N- and C-terminal truncations of the subject sequence when calculating global percent identity. For subject sequences truncated at the N- and C-termini, relative to the query sequence, the percent identity is corrected by calculating the number of residues of the query sequence that are N- and C-terminal of the subject sequence, which are not matched/aligned with a corresponding subject residue, as a percent of the total bases of the query sequence. Whether a residue is matched/aligned is determined by results of the FASTDB sequence alignment. This percentage is then subtracted from the percent identity, calculated by the above FASTDB program using the specified parameters, to arrive at a final percent identity score. This final percent identity score is what is used for the purposes of the present invention. Only residues to the N- and C-termini of the subject sequence, which are not matched/aligned with the query sequence, are considered for the purposes of manually adjusting the percent identity score. That is, only query residue positions outside the farthest N- and C-terminal residues of the subject sequence.  
       [0125] For example, a 90 amino acid residue subject sequence is aligned with a 100 residue query sequence to determine percent identity. The deletion occurs at the N-terminus of the subject sequence and therefore, the FASTDB alignment does not show a matching/alignment of the first 10 residues at the N-terminus. The 10 unpaired residues represent 10% of the sequence (number of residues at the N- and C-termini not matched/total number of residues in the query sequence) so 10% is subtracted from the percent identity score calculated by the FASTDB program. If the remaining 90 residues were perfectly matched the final percent identity would be 90%. In another example, a 90 residue subject sequence is compared with a 100 residue query sequence. This time the deletions are internal deletions so there are no residues at the N- or C-termini of the subject sequence which are not matched/aligned with the query. In this case the percent identity calculated by FASTDB is not manually corrected. Once again, only residue positions outside the N- and C-terminal ends of the subject sequence, as displayed in the FASTDB alignment, which are not matched/aligned with the query sequence are manually corrected for. No other manual corrections are to made for the purposes of the present invention.  
       [0126] The polynucleotide variants of the invention may contain alterations in the coding regions, non-coding regions, or both. Especially preferred are polynucleotide variants containing alterations, which produce silent substitutions, additions, or deletions, but do not alter the properties or activities of the encoded polypeptide. Nucleotide variants produced by silent substitutions due to the degeneracy of the genetic code are preferred. Moreover, polypeptide variants in which less than 50, less than 40, less than 30, less than 20, less than 10, or 5-50, 5-25, 5-10, 1-5, or 1-2 amino acids are substituted, deleted, or added in any combination are also preferred. Polynucleotide variants can be produced for a variety of reasons, e.g., to optimize codon expression for a particular host (change codons in the human mRNA to those preferred by a bacterial host such as  E. coli ).  
       [0127] Naturally occurring variants are called “allelic variants,” and refer to one of several alternate forms of a gene occupying a given locus on a chromosome of an organism. (Genes II, Lewin, B., ed., John Wiley &amp; Sons, New York (1985).) These allelic variants can vary at either the polynucleotide and/or polypeptide level and are included in the present invention. Alternatively, non-naturally occurring variants may be produced by mutagenesis techniques or by direct synthesis.  
       [0128] Using known methods of protein engineering and recombinant DNA technology, variants may be generated to improve or alter the characteristics of the polypeptides of the present invention. For instance, one or more amino acids can be deleted from the N-terminus or C-terminus of the polypeptides of the present invention without substantial loss of biological function. As an example, the authors of Ron et al., J. Biol. Chem. 268:2984-2988 (1993), reported variant KGF proteins having heparin binding activity even after deleting 3, 8, or 27 amino-terminal amino acid residues. Similarly, Interferon gamma exhibited up to ten times higher activity after deleting 8-10 amino acid residues from the carboxy terminus of this protein. (Dobeli et al., J. Biotechnology 7:199-216 (1988).)  
       [0129] Moreover, ample evidence demonstrates that variants often retain a biological activity similar to that of the naturally occurring protein. For example, Gayle and coworkers (J. Biol. Chem. 268:22105-22111 (1993)) conducted extensive mutational analysis of human cytokine IL-1a. They used random mutagenesis to generate over 3,500 individual IL-1a mutants that averaged 2.5 amino acid changes per variant over the entire length of the molecule. Multiple mutations were examined at every possible amino acid position. The investigators found that “[m]ost of the molecule could be altered with little effect on either [binding or biological activity].” In fact, only 23 unique amino acid sequences, out of more than 3,500 nucleotide sequences examined, produced a protein that significantly differed in activity from wild-type.  
       [0130] Furthermore, even if deleting one or more amino acids from the N-terminus or C-terminus of a polypeptide results in modification or loss of one or more biological functions, other biological activities may still be retained. For example, the ability of a deletion variant to induce and/or to bind antibodies, which recognize the secreted form will likely be retained when less than the majority of the residues of the secreted form are removed from the N-terminus or C-terminus. Whether a particular polypeptide lacking N- or C-terminal residues of a protein retains such immunogenic activities can readily be determined by routine methods described herein and otherwise known in the art.  
       [0131] Thus, the invention further includes polypeptide variants which show a functional activity (e.g., biological activity) of the polypeptides of the invention. Such variants include deletions, insertions, inversions, repeats, and substitutions selected according to general rules known in the art so as have little effect on activity.  
       [0132] The present application is directed to nucleic acid molecules at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleic acid sequences disclosed herein, (e.g., encoding a polypeptide having the amino acid sequence of an N and/or C terminal deletion), irrespective of whether they encode a polypeptide having functional activity. This is because even where a particular nucleic acid molecule does not encode a polypeptide having functional activity, one of skill in the art would still know how to use the nucleic acid molecule, for instance, as a hybridization probe or a polymerase chain reaction (PCR) primer. Uses of the nucleic acid molecules of the present invention that do not encode a polypeptide having functional activity include, inter alia, (1) isolating a gene or allelic or splice variants thereof in a cDNA library; (2) in situ hybridization (e.g., “FISH”) to metaphase chromosomal spreads to provide precise chromosomal location of the gene, as described in Verma et al., Human Chromosomes: A Manual of Basic Techniques, Pergamon Press, New York (1988); (3) Northern Blot analysis for detecting mRNA expression in specific tissues (e.g., normal excretory system or diseased excretory system tissues); and (4) in situ hybridization (e.g., histochemistry) for detecting mRNA expression in specific tissues (e.g., normal excretory system or diseased excretory system tissues).  
       [0133] Preferred, however, are nucleic acid molecules having sequences at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleic acid sequences disclosed herein, which do, in fact, encode a polypeptide having functional activity. By a polypeptide having “functional activity” is meant, a polypeptide capable of displaying one or more known functional activities associated with a full-length (complete) protein of the invention. Such functional activities include, but are not limited to, biological activity, antigenicity [ability to bind (or compete with a polypeptide of the invention for binding) to an anti-polypeptide of the invention antibody], immunogenicity (ability to generate antibody which binds to a specific polypeptide of the invention), ability to form multimers with polypeptides of the invention, and ability to bind to a receptor or ligand for a polypeptide of the invention.  
       [0134] The functional activity of the polypeptides, and fragments, variants and derivatives of the invention, can be assayed by various methods.  
       [0135] For example, in one embodiment where one is assaying for the ability to bind or compete with full-length polypeptide of the present invention for binding to an anti-polypeptide of the invention antibody, various immunoassays known in the art can be used, including but not limited to, competitive and non-competitive assay systems using techniques such as radioimmunoassays, ELISA (enzyme linked immunosorbent assay), “sandwich” immunoassays, immunoradiometric assays, gel diffusion precipitation reactions, immunodiffusion assays, in situ immunoassays (using colloidal gold, enzyme or radioisotope labels, for example), western blots, precipitation reactions, agglutination assays (e.g., gel agglutination assays, hemagglutination assays), complement fixation assays, immunofluorescence assays, protein A assays, and immunoelectrophoresis assays, etc. In one embodiment, antibody binding is detected by detecting a label on the primary antibody. In another embodiment, the primary antibody is detected by detecting binding of a secondary antibody or reagent to the primary antibody. In a further embodiment, the secondary antibody is labeled. Many means are known in the art for detecting binding in an immunoassay and are within the scope of the present invention.  
       [0136] In another embodiment, where a ligand is identified, or the ability of a polypeptide fragment, variant or derivative of the invention to multimerize is being evaluated, binding can be assayed, e.g., by means well-known in the art, such as, for example, reducing and non-reducing gel chromatography, protein affinity chromatography, and affinity blotting. See generally, Phizicky et al., Microbiol. Rev. 59:94-123 (1995). In another embodiment, the ability of physiological correlates of a polypeptide of the present invention to bind to a substrate(s) of the polypeptide of the invention can be routinely assayed using techniques known in the art.  
       [0137] In addition, assays described herein (see Examples) and otherwise known in the art may routinely be applied to measure the ability of polypeptides of the present invention and fragments, variants and derivatives thereof to elicit polypeptide related biological activity (either in vitro or in vivo). Other methods will be known to the skilled artisan and are within the scope of the invention.  
       [0138] Of course, due to the degeneracy of the genetic code, one of ordinary skill in the art will immediately recognize that a large number of the nucleic acid molecules having a sequence at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to, for example, the nucleic acid sequence of the cDNA contained in Clone ID NO: Z, a nucleic acid sequence referred to in Table 1A (e.g., SEQ ID NO: X), a nucleic acid sequence disclosed in Table 2 (e.g., the nucleic acid sequence delineated in columns 8 and 9) or fragments thereof, will encode polypeptides “having functional activity.” In fact, since degenerate variants of any of these nucleotide sequences all encode the same polypeptide, in many instances, this will be clear to the skilled artisan even without performing the above described comparison assay. It will be further recognized in the art that, for such nucleic acid molecules that are not degenerate variants, a reasonable number will also encode a polypeptide having functional activity. This is because the skilled artisan is fully aware of amino acid substitutions that are either less likely or not likely to significantly effect protein function (e.g., replacing one aliphatic amino acid with a second aliphatic amino acid), as further described below.  
       [0139] For example, guidance concerning how to make phenotypically silent amino acid substitutions is provided in Bowie et al., “Deciphering the Message in Protein Sequences: Tolerance to Amino Acid Substitutions,” Science 247:1306-1310 (1990), wherein the authors indicate that there are two main strategies for studying the tolerance of an amino acid sequence to change.  
       [0140] The first strategy exploits the tolerance of amino acid substitutions by natural selection during the process of evolution. By comparing amino acid sequences in different species, conserved amino acids can be identified. These conserved amino acids are likely important for protein function. In contrast, the amino acid positions where substitutions have been tolerated by natural selection indicates that these positions are not critical for protein function. Thus, positions tolerating amino acid substitution could be modified while still maintaining biological activity of the protein.  
       [0141] The second strategy uses genetic engineering to introduce amino acid changes at specific positions of a cloned gene to identify regions critical for protein function. For example, site directed mutagenesis or alanine-scanning mutagenesis (introduction of single alanine mutations at every residue in the molecule) can be used. See Cunningham et al., Science 244:1081-1085 (1989). The resulting mutant molecules can then be tested for biological activity.  
       [0142] As the authors state, these two strategies have revealed that proteins are surprisingly tolerant of amino acid substitutions. The authors further indicate which amino acid changes are likely to be permissive at certain amino acid positions in the protein. For example, most buried (within the tertiary structure of the protein) amino acid residues require nonpolar side chains, whereas few features of surface side chains are generally conserved. Moreover, tolerated conservative amino acid substitutions involve replacement of the aliphatic or hydrophobic amino acids Ala, Val, Leu and Ile; replacement of the hydroxyl residues Ser and Thr; replacement of the acidic residues Asp and Glu; replacement of the amide residues Asn and Gln, replacement of the basic residues Lys, Arg, and His; replacement of the aromatic residues Phe, Tyr, and Trp, and replacement of the small-sized amino acids Ala, Ser, Thr, Met, and Gly. Besides conservative amino acid substitutions, variants of the present invention include (i) substitutions with one or more of the non-conserved amino acid residues, where the substituted amino acid residues may or may not be one encoded by the genetic code, or (ii) substitutions with one or more of the amino acid residues having a substituent group, or (iii) fusion of the mature polypeptide with another compound, such as a compound to increase the stability and/or solubility of the polypeptide (for example, polyethylene glycol), or (iv) fusion of the polypeptide with additional amino acids, such as, for example, an IgG Fc fusion region peptide, serum albumin (preferably human serum albumin) or a fragment or variant thereof, or leader or secretory sequence, or a sequence facilitating purification. Such variant polypeptides are deemed to be within the scope of those skilled in the art from the teachings herein.  
       [0143] For example, polypeptide variants containing amino acid substitutions of charged amino acids with other charged or neutral amino acids may produce proteins with improved characteristics, such as less aggregation. Aggregation of pharmaceutical formulations both reduces activity and increases clearance due to the aggregate&#39;s immunogenic activity. See Pinckard et al., Clin. Exp. Immunol. 2:331-340 (1967); Robbins et al., Diabetes 36:838-845 (1987); Cleland et al., Crit. Rev. Therapeutic Drug Carrier Systems 10:307-377 (1993).  
       [0144] A further embodiment of the invention relates to polypeptides which comprise the amino acid sequence of a polypeptide having an amino acid sequence which contains at least one amino acid substitution, but not more than 50 amino acid substitutions, even more preferably, not more than 40 amino acid substitutions, still more preferably, not more than 30 amino acid substitutions, and still even more preferably, not more than 20 amino acid substitutions from a polypeptide sequence disclosed herein. Of course it is highly preferable for a polypeptide to have an amino acid sequence which comprises the amino acid sequence of a polypeptide of SEQ ID NO: Y, an amino acid sequence encoded by SEQ ID NO: X, an amino acid sequence encoded by the portion of SEQ ID NO: X as defined in columns 8 and 9 of Table 2, an amino acid sequence encoded by the complement of SEQ ID NO: X, and/or the amino acid sequence encoded by cDNA contained in Clone ID NO: Z which contains, in order of ever-increasing preference, at least one, but not more than 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid substitutions.  
       [0145] In specific embodiments, the polypeptides of the invention comprise, or alternatively, consist of, fragments or variants of a reference amino acid sequence selected from: (a) the amino acid sequence of SEQ ID NO: Y or fragments thereof (e.g., the mature form and/or other fragments described herein); (b) the amino acid sequence encoded by SEQ ID NO: X or fragments thereof, (c) the amino acid sequence encoded by the complement of SEQ ID NO: X or fragments thereof, (d) the amino acid sequence encoded by the portion of SEQ ID NO: X as defined in columns 8 and 9 of Table 2 or fragments thereof, and (e) the amino acid sequence encoded by cDNA contained in Clone ID NO: Z or fragments thereof, wherein the fragments or variants have 1-5, 5-10, 5-25, 5-50, 10-50 or 50-150, amino acid residue additions, substitutions, and/or deletions when compared to the reference amino acid sequence. In preferred embodiments, the amino acid substitutions are conservative. Polynucleotides encoding these polypeptides are also encompassed by the invention.  
       [0146] Polynucleotide and Polypeptide Fragments  
       [0147] The present invention is also directed to polynucleotide fragments of the polynucleotides (nucleic acids) of the invention. In the present invention, a “polynucleotide fragment” refers to a polynucleotide having a nucleic acid sequence which, for example: is a portion of the cDNA contained in Clone ID NO: Z or the complementary strand thereto; is a portion of the polynucleotide sequence encoding the polypeptide encoded by the cDNA contained in Clone ID NO: Z or the complementary strand thereto; is a portion of a polynucleotide sequence encoding the amino acid sequence encoded by the region of SEQ ID NO: X as defined in columns 8 and 9 of Table 2 or the complementary strand thereto; is a portion of the polynucleotide sequence of SEQ ID NO: X as defined in columns 8 and 9 of Table 2 or the complementary strand thereto; is a portion of the polynucleotide sequence in SEQ ID NO: X or the complementary strand thereto; is a polynucleotide sequence encoding a portion of the polypeptide of SEQ ID NO: Y; is a polynucleotide sequence encoding a portion of a polypeptide encoded by SEQ ID NO: X; is a polynucleotide sequence encoding a portion of a polypeptide encoded by the complement of the polynucleotide sequence in SEQ ID NO: X; is a portion of a polynucleotide sequence encoding the amino acid sequence encoded by the region of SEQ ID NO: B as defined in column 6 of Table 1B or the complementary strand thereto; or is a portion of the polynucleotide sequence of SEQ ID NO: B as defined in column 6 of Table 1B or the complementary strand thereto.  
       [0148] The polynucleotide fragments of the invention are preferably at least about 15 nt, and more preferably at least about 20 nt, still more preferably at least about 30 nt, and even more preferably, at least about 40 nt, at least about 50 nt, at least about 75 nt, or at least about 150 nt in length. A fragment “at least 20 nt in length,” for example, is intended to include 20 or more contiguous bases from the cDNA sequence contained in Clone ID NO: Z, or the nucleotide sequence shown in SEQ ID NO: X or the complementary stand thereto. In this context “about” includes the particularly recited value or a value larger or smaller by several (5, 4, 3, 2, or 1) nucleotides, at either terminus or at both termini. These nucleotide fragments have uses that include, but are not limited to, as diagnostic probes and primers as discussed herein. Of course, larger fragments (e.g., at least 160, 170, 180, 190, 200, 250, 500, 600, 1000, or 2000 nucleotides in length) are also encompassed by the invention.  
       [0149] Moreover, representative examples of polynucleotide fragments of the invention, comprise, or alternatively consist of, a sequence from about nucleotide number 1-50, 51-100, 101-150, 151-200, 201-250, 251-300, 301-350, 351-400, 401-450, 451-500, 501-550, 551-600, 651-700, 701-750, 751-800, 800-850, 851-900, 901-950, 951-1000, 1001-1050, 1051-1100, 1101-1150, 1151-1200, 1201-1250, 1251-1300, 1301-1350, 1351-1400, 1401-1450, 1451-1500, 1501-1550, 1551-1600, 1601-1650, 1651-1700, 1701-1750, 1751-1800, 1801-1850, 1851-1900, 1901-1950, 1951-2000, 2001-2050, 2051-2100, 2101-2150, 2151-2200, 2201-2250, 2251-2300, 2301-2350, 2351-2400, 2401-2450, 2451-2500, 2501-2550, 2551-2600, 2601-2650, 2651-2700, 2701-2750, 2751-2800, 2801-2850, 2851-2900, 2901-2950, 2951-3000, 3001-3050, 3051-3100, 3101-3150, 3151-3200, 3201-3250, 3251-3300, 3301-3350, 3351-3400, 3401-3450, 3451-3500, 3501-3550, 3551-3600, 3601-3650, 3651-3700, 3701-3750, 3751-3800, 3801-3850, 3851-3900, 3901-3950, 3951-4000, 4001-4050, 4051-4100, 4101-4150, 4151-4200, 4201-4250, 4251-4300, 4301-4350, 4351-4400, 4401-4450, 4451-4500, 4501-4550, 4551-4600, 4601-4650, 4651-4700, 4701-4750, 4751-4800, 4801-4850, 4851-4900, 4901-4950, 4951-5000, 5001-5050, 5051-5100, 5101-5150, 5151-5200, 5201-5250, 5251-5300, 5301-5350, 5351-5400, 5401-5450, 5451-5500, 5501-5550, 5551-5600, 5601-5650, 5651-5700, 5701-5750, 5751-5800, 5801-5850, 5851-5900, 5901-5950, 5951-6000, 6001-6050, 6051-6100, 6101-6150, 6151-6200, 6201-6250, 6251-6300, 6301-6350, 6351-6400, 6401-6450, 6451-6500, 6501-6550, 6551-6600, 6601-6650, 6651-6700, 6701-6750, 6751-6800, 6801-6850, 6851-6900, 6901-6950, 6951-7000, 7001-7050, 7051-7100, 7101-7150, 7151-7200, 7201-7250, 7251-7300 or 7301 to the end of SEQ ID NO: X, or the complementary strand thereto. In this context “about” includes the particularly recited range or a range larger or smaller by several (5, 4, 3, 2, or 1) nucleotides, at either terminus or at both termini. Preferably, these fragments encode a polypeptide, which has a functional activity (e.g., biological activity). More preferably, these polynucleotides can be used as probes or primers as discussed herein. Polynucleotides which hybridize to one or more of these polynucleotides under stringent hybridization conditions or alternatively, under lower stringency conditions are also encompassed by the invention, as are polypeptides encoded by these polynucleotides.  
       [0150] Further representative examples of polynucleotide fragments of the invention, comprise, or alternatively consist of, a sequence from about nucleotide number 1-50, 51-100, 101-150, 151-200, 201-250, 251-300, 301-350, 351-400, 401-450, 451-500, 501-550, 551-600, 651-700, 701-750, 751-800, 800-850, 851-900, 901-950, 951-1000, 1001-1050, 1051-1100, 1101-1150, 1151-1200, 1201-1250, 1251-1300, 1301-1350, 1351-1400, 1401-1450, 1451-1500, 1501-1550, 1551-1600, 1601-1650, 1651-1700, 1701-1750, 1751-1800, 1801-1850, 1851-1900, 1901-1950, 1951-2000, 2001-2050, 2051-2100, 2101-2150, 2151-2200, 2201-2250, 2251-2300, 2301-2350, 2351-2400, 2401-2450, 2451-2500, 2501-2550, 2551-2600, 2601-2650, 2651-2700, 2701-2750, 2751-2800, 2801-2850, 2851-2900, 2901-2950, 2951-3000, 3001-3050, 3051-3100, 3101-3150, 3151-3200, 3201-3250, 3251-3300, 3301-3350, 3351-3400, 3401-3450, 3451-3500, 3501-3550, 3551-3600, 3601-3650, 3651-3700, 3701-3750, 3751-3800, 3801-3850, 3851-3900, 3901-3950, 3951-4000, 4001-4050, 4051-4100, 4101-4150, 4151-4200, 4201-4250, 4251-4300, 4301-4350, 4351-4400, 4401-4450, 4451-4500, 4501-4550, 4551-4600, 4601-4650, 4651-4700, 4701-4750, 4751-4800, 4801-4850, 4851-4900, 4901-4950, 4951-5000, 5001-5050, 5051-5100, 5101-5150, 5151-5200, 5201-5250, 5251-5300, 5301-5350, 5351-5400, 5401-5450, 5451-5500, 5501-5550, 5551-5600, 5601-5650, 5651-5700, 5701-5750, 5751-5800, 5801-5850, 5851-5900, 5901-5950, 5951-6000, 6001-6050, 6051-6100, 6101-6150, 6151-6200, 6201-6250, 6251-6300, 6301-6350, 6351-6400, 6401-6450, 6451-6500, 6501-6550, 6551-6600, 6601-6650, 6651-6700, 6701-6750, 6751-6800, 6801-6850, 6851-6900, 6901-6950, 6951-7000, 7001-7050, 7051-7100, 7101-7150, 7151-7200, 7201-7250, 7251-7300 or 7301 to the end of the cDNA sequence contained in Clone ID NO: Z, or the complementary strand thereto. In this context “about” includes the particularly recited range or a range larger or smaller by several (5, 4, 3, 2, or 1) nucleotides, at either terminus or at both termini. Preferably, these fragments encode a polypeptide which has a functional activity (e.g., biological activity). More preferably, these polynucleotides can be used as probes or primers as discussed herein. Polynucleotides which hybridize to one or more of these polynucleotides under stringent hybridization conditions or alternatively, under tower stringency conditions are also encompassed by the invention, as are polypeptides encoded by these polynucleotides.  
       [0151] Moreover, representative examples of polynucleotide fragments of the invention comprise, or alternatively consist of, a nucleic acid sequence comprising one, two, three, four, five, six, seven, eight, nine, ten, or more of the above described polynucleotide fragments of the invention in combination with a polynucleotide sequence delineated in Table 1B column 6. Additional, representative examples of polynucleotide fragments of the invention comprise, or alternatively consist of, a nucleic acid sequence comprising one, two, three, four, five, six, seven, eight, nine, ten, or more of the above described polynucleotide fragments of the invention in combination with a polynucleotide sequence that is the complementary strand of a sequence delineated in column 6 of Table 1B. In further embodiments, the above-described polynucleotide fragments of the invention comprise, or alternatively consist of, sequences delineated in Table 1B, column 6, and have a nucleic acid sequence which is different from that of the BAC fragment having the sequence disclosed in SEQ ID NO: B (see Table 1B, column 5). In additional embodiments, the above-described polynucleotide fragments of the invention comprise, or alternatively consist of, sequences delineated in Table 1B, column 6, and have a nucleic acid sequence which is different from that published for the BAC clone identified as BAC ID NO: A (see Table 1B, column 4). In additional embodiments, the above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated Table 1B, column 6, and have a nucleic acid sequence which is different from that contained in the BAC clone identified as BAC ID NO: A (see Table 1B, column 4). Polypeptides encoded by these polynucleotides, other polynucleotides that encode these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides and polypeptides are also encompassed by the invention.  
       [0152] In additional specific embodiments, polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more fragments of the sequences delineated in column 6 of Table 1B, and the polynucleotide sequence of SEQ ID NO: X (e.g., as defined in Table 1B, column 2) or fragments or variants thereof. Polypeptides encoded by these polynucleotides, other polynucleotides that encode these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention.  
       [0153] In additional specific embodiments, polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more fragments of the sequences delineated in column 6 of Table 1B which correspond to the same Clone ID NO: Z (see Table 1B, column 1), and the polynucleotide sequence of SEQ ID NO: X (e.g., as defined in Table 1A or 1B) or fragments or variants thereof. Polypeptides encoded by these polynucleotides, other polynucleotides that encode these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention.  
       [0154] In further specific embodiments, polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more fragments of the sequences delineated in the same row of column 6 of Table 1B, and the polynucleotide sequence of SEQ ID NO: X (e.g., as defined in Table 1A or 1B) or fragments or variants thereof. Polypeptides encoded by these polynucleotides, other polynucleotides that encode these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention.  
       [0155] In additional specific embodiments, polynucleotides of the invention comprise, or alternatively consist of a polynucleotide sequence in which the 3′ 10 polynucleotides of one of the sequences delineated in column 6 of Table 1B and the 5′ 10 polynucleotides of the sequence of SEQ ID NO: X are directly contiguous. Nucleic acids which hybridize to the complement of these 20 contiguous polynucleotides under stringent hybridization conditions or alternatively, under lower stringency conditions, are also encompassed by the invention. Polypeptides encoded by these polynucleotides and/or nucleic acids, other polynucleotides and/or nucleic acids that encode these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides, nucleic acids, and polypeptides are also encompassed by the invention.  
       [0156] In additional specific embodiments, polynucleotides of the invention comprise, or alternatively consist of a polynucleotide sequence in which the 3′ 10 polynucleotides of one of the sequences delineated in column 6 of Table 1B and the 5′ 10 polynucleotides of a fragment or variant of the sequence of SEQ ID NO: X (e.g., as described herein) are directly contiguous Nucleic acids which hybridize to the complement of these 20 contiguous polynucleotides under stringent hybridization conditions or alternatively, under lower stringency conditions, are also encompassed by the invention. Polypeptides encoded by these polynucleotides and/or nucleic acids, other polynucleotides and/or nucleic acids encoding these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides, nucleic acids, and polypeptides are also encompassed by the invention.  
       [0157] In further specific embodiments, polynucleotides of the invention comprise, or alternatively consist of a polynucleotide sequence in which the 3′ 10 polynucleotides of a fragment or variant of the sequence of SEQ ID NO: X and the 5′ 10 polynucleotides of the sequence of one of the sequences delineated in column 6 of Table 1 B are directly contiguous. Nucleic acids which hybridize to the complement of these 20 contiguous polynucleotides under stringent hybridization conditions or alternatively, under lower stringency conditions, are also encompassed by the invention. Polypeptides encoded by these polynucleotides and/or nucleic acids, other polynucleotides and/or nucleic acids encoding these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides, nucleic acids, and polypeptides are also encompassed by the invention.  
       [0158] In specific embodiments, polynucleotides of the invention comprise, or alternatively consist of a polynucleotide sequence in which the 3′ 10 polynucleotides of one of the sequences delineated in column 6 of Table 1B and the 5′ 10 polynucleotides of another sequence in column 6 are directly contiguous. In preferred embodiments, the 3′ 10 polynucleotides of one of the sequences delineated in column 6 of Table 1B is directly contiguous with the 5′ 10 polynucleotides of the next sequential exon delineated in Table 1B, column 6. Nucleic acids which hybridize to the complement of these 20 contiguous polynucleotides under stringent hybridization conditions or alternatively, under lower stringency conditions, are also encompassed by the invention. Polypeptides encoded by these polynucleotides and/or nucleic acids, other polynucleotides and/or nucleic acids encoding these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides, nucleic acids, and polypeptides are also encompassed by the invention.  
       [0159] In the present invention, a “polypeptide fragment” refers to an amino acid sequence which is a portion of that contained in SEQ ID NO: Y, a portion of an amino acid sequence encoded by the portion of SEQ ID NO: X as defined in columns 8 and 9 of Table 2, a portion of an amino acid sequence encoded by the polynucleotide sequence of SEQ ID NO: X, a portion of an amino acid sequence encoded by the complement of the polynucleotide sequence in SEQ ID NO: X, and/or a portion of an amino acid sequence encoded by the cDNA contained in Clone ID NO: Z. Protein (polypeptide) fragments may be “free-standing,” or comprised within a larger polypeptide of which the fragment forms a part or region, most preferably as a single continuous region. Representative examples of polypeptide fragments of the invention, include, for example, fragments comprising, or alternatively consisting of, from about amino acid number 1-20, 21-40, 41-60, 61-80, 81-100, 102-120, 121-140, 141-160, 161-180, 181-200, 201-220, 221-240, 241-260, 261-280, 281-300, 301-320, 321-340, 341-360, 361-380, 381-400, 401-420, 421-440, 441-460, 461-480, 481-500, 501-520, 521-540, 541-560, 561-580, 581-600, 601-620, 621-640, 641-660, 661-680, 681-700, 701-720, 721-740, 741-760, 761-780, 781-800, 801-820, 821-840, 841-860, 861-880, 881-900, 901-920, 921-940, 941-960, 961-980, 981-1000, 1001-1020, 1021-1040, 1041-1060, 1061-1080, 1081-1100, 1101-1120, 1121-1140, 1141-1160, 1161-1180, 1181-1200, 1201-1220, 1221-1240, 1241-1260, 1261-1280, 1281-1300, 1301-1320, 1321-1340, 1341-1360, 1361-1380, 1381-1400, 1401-1420, 1421-1440, or 1441 to the end of the coding region. In a preferred embodiment, polypeptide fragments of the invention include, for example, fragments comprising, or alternatively consisting of, from about amino acid number 1-20, 21-40, 41-60, 61-80, 81-100, 102-120, 121-140, 141-160, 161-180, 181-200, 201-220, 221-240, 241-260, 261-280, 281-300, 301-320, 321-340, 341-360, 361-380, 381-400, 401-420, 421-440, 441-460, 461-480, 481-500, 501-520, 521-540, 541-560, 561-580, 581-600, 601-620, 621-640, 641-660, 661-680, 681-700, 701-720, 721-740, 741-760, 761-780, 781-800, 801-820, 821-840, 841-860, 861-880, 881-900, 901-920, 921-940, 941-960, 961-980, 981-1000, 1001-1020, 1021-1040, 1041-1060, 1061-1080, 1081-1100, 1101-1120, 1121-1140, 1141-1160, 1161-1180, 1181-1200, 1201-1220, 1221-1240, 1241-1260, 1261-1280, 1281-1300, 1301-1320, 1321-1340, 1341-1360, 1361-1380, 1381-1400, 1401-1420, 1421-1440, or 1441 to the end of the coding region of SEQ ID NO: Y. Moreover, polypeptide fragments of the invention may be at least about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 100, 110, 120, 130, 140, or 150 amino acids in length. In this context “about” includes the particularly recited ranges or values, or ranges or values larger or smaller by several (5, 4, 3, 2, or 1) amino acids, at either extreme or at both extremes. Polynucleotides encoding these polypeptide fragments are also encompassed by the invention.  
       [0160] Even if deletion of one or more amino acids from the N-terminus of a protein results in modification of loss of one or more biological functions of the protein, other functional activities (e.g., biological activities, ability to multimerize, ability to bind a ligand) may still be retained. For example, the ability of shortened muteins to induce and/or bind to antibodies which recognize the complete or mature forms of the polypeptides generally will be retained when less than the majority of the residues of the complete or mature polypeptide are removed from the N-terminus. Whether a particular polypeptide lacking N-terminal residues of a complete polypeptide retains such immunologic activities can readily be determined by routine methods described herein and otherwise known in the art. It is not unlikely that a mutein with a large number of deleted N-terminal amino acid residues may retain some biological or immunogenic activities. In fact, peptides composed of as few as six amino acid residues may often evoke an immune response.  
       [0161] Accordingly, polypeptide fragments include the secreted protein as well as the mature form. Further preferred polypeptide fragments include the secreted protein or the mature form having a continuous series of deleted residues from the amino or the carboxy terminus, or both. For example, any number of amino acids, ranging from 1-60, can be deleted from the amino terminus of either the secreted polypeptide or the mature form. Similarly, any number of amino acids, ranging from 1-30, can be deleted from the carboxy terminus of the secreted protein or mature form. Furthermore, any combination of the above amino and carboxy terminus deletions are preferred. Similarly, polynucleotides encoding these polypeptide fragments are also preferred.  
       [0162] The present invention further provides polypeptides having one or more residues deleted from the amino terminus of the amino acid sequence of a polypeptide disclosed herein (e.g., a polypeptide of SEQ ID NO: Y, a polypeptide encoded by the polynucleotide sequence contained in SEQ ID NO: X or the complement thereof, a polypeptide encoded by the portion of SEQ ID NO: X as defined in columns 8 and 9 of Table 2, a polypeptide encoded by the portion of SEQ ID NO: B as defined in column 6 of Table 1B, and/or a polypeptide encoded by the cDNA contained in Clone ID NO: Z). In particular, N-terminal deletions may be described by the general formula m−q, where q is a whole integer representing the total number of amino acid residues in a polypeptide of the invention (e.g., the polypeptide disclosed in SEQ ID NO: Y, or the polypeptide encoded by the portion of SEQ ID NO: X as defined in columns 8 and 9 of Table 2), and m is defined as any integer ranging from 2 to q−6. Polynucleotides encoding these polypeptides are also encompassed by the invention.  
       [0163] The present invention further provides polypeptides having one or more residues from the carboxy terminus of the amino acid sequence of a polypeptide disclosed herein (e.g., a polypeptide of SEQ ID NO: Y, a polypeptide encoded by the polynucleotide sequence contained in SEQ ID NO: X, a polypeptide encoded by the portion of SEQ ID NO: X as defined in columns 8 and 9 of, Table 2, and/or a polypeptide encoded by the cDNA contained in Clone ID NO: Z). In particular, C-terminal deletions may be described by the general formula 1−n, where n is any whole integer ranging from 6 to q−1, and where n corresponds to the position of amino acid residue in a polypeptide of the invention. Polynucleotides encoding these polypeptides are also encompassed by the invention.  
       [0164] In addition, any of the above described N- or C-terminal deletions can be combined to produce a N- and C-terminal deleted polypeptide. The invention also provides polypeptides having one or more amino acids deleted from both the amino and the carboxyl termini, which may be described generally as having residues m−n of a polypeptide encoded by SEQ ID NO: X (e.g., including, but not limited to, the preferred polypeptide disclosed as SEQ ID NO: Y and the polypeptide encoded by the portion of SEQ ID NO: X as defined in columns 8 and 9 of Table 2), the cDNA contained in Clone ID NO: Z, and/or the complement thereof, where n and m are integers as described above. Polynucleotides encoding these polypeptides are also encompassed by the invention.  
       [0165] Also as mentioned above, even if deletion of one or more amino acids from the C-terminus of a protein results in modification of loss of one or more biological functions of the protein, other functional activities (e.g., biological activities, ability to multimerize, ability to bind a ligand) may still be retained. For example the ability of the shortened mutein to induce and/or bind to antibodies which recognize the complete or mature forms of the polypeptide generally will be retained when less than the majority of the residues of the complete or mature polypeptide are removed from the C-terminus. Whether a particular polypeptide lacking C-terminal residues of a complete polypeptide retains such immunologic activities can readily be determined by routine methods described herein and otherwise known in the art. It is not unlikely that a mutein with a large number of deleted C-terminal amino acid residues may retain some biological or immunogenic activities. In fact, peptides composed of as few as six amino acid residues may often evoke an immune response.  
       [0166] The present application is also directed to proteins containing polypeptides at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to a polypeptide sequence set forth herein. In preferred embodiments, the application is directed to proteins containing polypeptides at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to polypeptides having the amino acid sequence of the specific N- and C-terminal deletions. Polynucleotides encoding these polypeptides are also encompassed by the invention.  
       [0167] Any polypeptide sequence encoded by, for example, the polynucleotide sequences set forth as SEQ ID NO: X or the complement thereof, (presented, for example, in Tables 1A and 2), the cDNA contained in Clone ID NO: Z, or the polynucleotide sequence as defined in column 6 of Table 1B, may be analyzed to determine certain preferred regions of the polypeptide. For example, the amino acid sequence of a polypeptide encoded by a polynucleotide sequence of SEQ ID NO: X (e.g., the polypeptide of SEQ ID NO: Y and the polypeptide encoded by the portion of SEQ ID NO: X as defined in columns 8 and 9 of Table 2) or the EDNA contained in Clone ID NO: Z may be analyzed using the default parameters of the DNASTAR computer algorithm (DNASTAR, Inc., 1228 S. Park St., Madison, Wis. 53715 USA; http://www.dnastar.com/).  
       [0168] Polypeptide regions that may be routinely obtained using the DNASTAR computer algorithm include, but are not limited to, Garnier-Robson alpha-regions, beta-regions, turn-regions, and coil-regions; Chou-Fasman alpha-regions, beta-regions, and turn-regions; Kyte-Doolittle hydrophilic regions and hydrophobic regions; Eisenberg alpha- and beta-amphipathic regions; Karplus-Schulz flexible regions; Emini surface-forming regions; and Jameson-Wolf regions of high antigenic index. Among highly preferred polynucleotides of the invention in this regard are those that encode polypeptides comprising regions that combine several structural features, such as several (e.g., 1, 2, 3 or 4) of the features set out above.  
       [0169] Additionally, Kyte-Doolittle hydrophilic regions and hydrophobic regions, Emini surface-forming regions, and Jameson-Wolf regions of high antigenic index (i.e., containing four or more contiguous amino acids having an antigenic index of greater than or equal to 1.5, as identified using the default parameters of the Jameson-Wolf program) can routinely be used to determine polypeptide regions that exhibit a high degree of potential for antigenicity. Regions of high antigenicity are determined from data by DNASTAR analysis by choosing values which represent regions of the polypeptide which are likely to be exposed on the surface of the polypeptide in an environment in which antigen recognition may occur in the process of initiation of an immune response.  
       [0170] Preferred polypeptide fragments of the invention are fragments comprising, or alternatively, consisting of, an amino acid sequence that displays a functional activity (e.g. biological activity) of the polypeptide sequence of which the amino acid sequence is a fragment. By a polypeptide displaying a “functional activity” is meant a polypeptide capable of one or more known functional activities associated with a full-length protein, such as, for example, biological activity, antigenicity, immunogenicity, and/or multimerization, as described herein.  
       [0171] Other preferred polypeptide fragments are biologically active fragments. Biologically active fragments are those exhibiting activity similar, but not necessarily identical, to an activity of the polypeptide of the present invention. The biological activity of the fragments may include an improved desired activity, or a decreased undesirable activity.  
       [0172] In preferred embodiments, polypeptides of the invention comprise, or alternatively consist of, one, two, three, four, five or more of the antigenic fragments of the polypeptide of SEQ ID NO: Y, or portions thereof. Polynucleotides encoding these polypeptides are also encompassed by the invention.  
       [0173] The present invention encompasses polypeptides comprising, or alternatively consisting of, an epitope of: the polypeptide sequence shown in SEQ ID NO: Y; a polypeptide sequence encoded by SEQ ID NO: X or the complementary strand thereto; the polypeptide sequence encoded by the portion of SEQ ID NO: X as defined in columns 8 and 9 of Table 2; the polypeptide sequence encoded by the portion of SEQ ID NO: B as defined in column 6 of Table 1B or the complement thereto; the polypeptide sequence encoded by the cDNA contained in Clone ID NO: Z; or the polypeptide sequence encoded by a polynucleotide that hybridizes to the sequence of SEQ ID NO: X, the complement of the sequence of SEQ ID NO: X, the complement of a portion of SEQ ID NO: X as defined in columns 8 and 9 of Table 2, or the cDNA sequence contained in Clone ID NO: Z under stringent hybridization conditions or alternatively, under lower stringency hybridization as defined supra. The present invention further encompasses polynucleotide sequences encoding an epitope of a polypeptide sequence of the invention (such as, for example, the sequence disclosed in SEQ ID NO: X, or a fragment thereof), polynucleotide sequences of the complementary strand of a polynucleotide sequence encoding an epitope of the invention, and polynucleotide sequences which hybridize to the complementary strand under stringent hybridization conditions or alternatively, under lower stringency hybridization conditions defined supra.  
       [0174] The term “epitopes,” as used herein, refers to portions of a polypeptide having antigenic or immunogenic activity in an animal, preferably a mammal, and most preferably in a human. In a preferred embodiment, the present invention encompasses a polypeptide comprising an epitope, as well as the polynucleotide encoding this polypeptide. An “immunogenic epitope,” as used herein, is defined as a portion of a protein that elicits an antibody response in an animal, as determined by any method known in the art, for example, by the methods for generating antibodies described infra. (See, for example, Geysen et al., Proc. Natl. Acad. Sci. USA 81:3998-4002 (1983)). The term “antigenic epitope,” as used herein, is defined as a portion of a protein to which an antibody can immunospecifically bind its antigen as determined by any method well known in the art, for example, by the immunoassays described herein. Immunospecific binding excludes non-specific binding but does not necessarily exclude cross-reactivity with other antigens. Antigenic epitopes need not necessarily be immunogenic.  
       [0175] Fragments which function as epitopes may be produced by any conventional means. (See, e.g., Houghten, R. A., Proc. Natl. Acad. Sci. USA 82:5131-5135 (1985) further described in U.S. Pat. No. 4,631,211.)  
       [0176] In the present invention, antigenic epitopes preferably contain a sequence of at least 4, at least 5, at least 6, at least 7, more preferably at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 25, at least 30, at least 40, at least 50, and, most preferably, between about 15 to about 30 amino acids. Preferred polypeptides comprising immunogenic or antigenic epitopes are at least 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 amino acid residues in length. Additional non-exclusive preferred antigenic epitopes include the antigenic epitopes disclosed herein, as well as portions thereof. Antigenic epitopes are useful, for example, to raise antibodies, including monoclonal antibodies, that specifically bind the epitope. Preferred antigenic epitopes include the antigenic epitopes disclosed herein, as well as any combination of two, three, four, five or more of these antigenic epitopes. Antigenic epitopes can be used as the target molecules in immunoassays. (See, for instance, Wilson et al., Cell 37:767-778 (1984); Sutcliffe et al., Science 219:660-666 (1983)).  
       [0177] Non-limiting examples of epitopes of polypeptides that can be used to generate antibodies of the invention include a polypeptide comprising, or alternatively consisting of, at least one, two, three, four, five, six or more of the portion(s) of SEQ ID NO: Y specified in column 6 of Table 1A. These polypeptide fragments have been determined to bear antigenic epitopes of the proteins of the invention by the analysis of the Jameson-Wolf antigenic index, which is included in the DNAStar suite of computer programs. By “comprise” it is intended that a polypeptide contains at least one, two, three, four, five, six or more of the portion(s) of SEQ ID NO: Y shown in column 6 of Table 1A, but it may contain additional flanking residues on either the amino or carboxyl termini of the recited portion. Such additional flanking sequences are preferably sequences naturally found adjacent to the portion; i.e., contiguous sequence shown in SEQ ID NO: Y. The flanking sequence may, however, be sequences from a heterologous polypeptide, such as from another protein described herein or from a heterologous polypeptide not described herein. In particular embodiments, epitope portions of a polypeptide of the invention comprise one, two, three, or more of the portions of SEQ ID NO: Y shown in column 6 of Table 1A. Polynucleotides encoding these polypeptides are also encompassed by the invention.  
       [0178] Similarly, immunogenic epitopes can be used, for example, to induce antibodies according to methods well known in the art. See, for instance, Sutcliffe et al., supra; Wilson et al., supra; Chow et al., Proc. Natl. Acad. Sci. USA 82:910-914; and Bittle et al., J. Gen. Virol. 66:2347-2354 (1985). Preferred immunogenic epitopes include the immunogenic epitopes disclosed herein, as well as any combination of two, three, four, five or more of these immunogenic epitopes. The polypeptides comprising one or more immunogenic epitopes may be presented for eliciting an antibody response together with a carrier protein, such as an albumin, to an animal system (such as rabbit or mouse), or, if the polypeptide is of sufficient length (at least about 25 amino acids), the polypeptide may be presented without a carrier. However, immunogenic epitopes comprising as few as 8 to 10 amino acids have been shown to be sufficient to raise antibodies capable of binding to, at the very least, linear epitopes in a denatured polypeptide (e.g., in Western blotting).  
       [0179] Epitope-bearing polypeptides of the present invention may be used to induce antibodies according to methods well known in the art including, but not limited to, in vivo immunization, in vitro immunization, and phage display methods. See, e.g., Sutcliffe et al., supra; Wilson et al., supra, and Bittle et al., J. Gen. Virol., 66:2347-2354 (1985). If in vivo immunization is used, animals may be immunized with free peptide; however, anti-peptide antibody titer may be boosted by coupling the peptide to a macromolecular carrier, such as keyhole limpet hemacyanin (KLH) or tetanus toxoid. For instance, peptides containing cysteine residues may be coupled to a carrier using a linker such as maleimidobenzoyl-N-hydroxysuccinimide ester (MBS), while other peptides may be coupled to carriers using a more general linking agent such as glutaraldehyde. Animals such as rabbits, rats and mice are immunized with either free or carrier-coupled peptides, for instance, by intraperitoneal and/or intradermal injection of emulsions containing about 100 μg of peptide or carrier protein and Freund&#39;s adjuvant or any other adjuvant known for stimulating an immune response. Several booster injections may be needed, for instance, at intervals of about two weeks, to provide a useful titer of anti-peptide antibody which can be detected, for example, by ELISA assay using free peptide adsorbed to a solid surface. The titer of anti-peptide antibodies in serum from an immunized animal may be increased by selection of anti-peptide antibodies, for instance, by adsorption to the peptide on a solid support and elution of the selected antibodies according to methods well known in the art.  
       [0180] As one of skill in the art will appreciate, and as discussed above, the polypeptides of the present invention (e.g., those comprising an immunogenic or antigenic epitope) can be fused to heterologous polypeptide sequences. For example, polypeptides of the present invention (including fragments or variants thereof), may be fused with the constant domain of immunoglobulins (IgA, IgE, IgG, IgM), or portions thereof (CH1, CH2, CH3, or any combination thereof and portions thereof, resulting in chimeric polypeptides. By way of another non-limiting example, polypeptides and/or antibodies of the present invention (including fragments or variants thereof) may be fused with albumin (including but not limited to recombinant human serum albumin or fragments or variants thereof (see, e.g., U.S. Pat. No. 5,876,969, issued Mar. 2, 1999, EP Patent 0 413 622, and U.S. Pat. No. 5,766,883, issued Jun. 16, 1998, herein incorporated by reference in their entirety)). In a preferred embodiment, polypeptides and/or antibodies of the present invention (including fragments or variants thereof) are fused with the mature form of human serum albumin (i.e., amino acids 1-585 of human serum albumin as shown in FIGS. 1 and 2 of EP Patent 0 322 094) which is herein incorporated by reference in its entirety. In another preferred embodiment, polypeptides and/or antibodies of the present invention (including fragments or variants thereof) are fused with polypeptide fragments comprising, or alternatively consisting of, amino acid residues 1 -z of human serum albumin, where z is an integer from 369 to 419, as described in U.S. Pat. 5,766,883 herein incorporated by reference in its entirety. Polypeptides and/or antibodies of the present invention (including fragments or variants thereof) may be fused to either the N- or C-terminal end of the heterologous protein (e.g., immunoglobulin Fc polypeptide or human serum albumin polypeptide). Polynucleotides encoding fusion proteins of the invention are also encompassed by the invention.  
       [0181] Such fusion proteins as those described above may facilitate purification and may increase half-life in vivo. This has been shown for chimeric proteins consisting of the first two domains of the human CD4-polypeptide and various domains of the constant regions of the heavy or light chains of mammalian immunoglobulins. See, e.g., EP 394,827; Traunecker et al., Nature, 331:84-86 (1988). Enhanced delivery of an antigen across the epithelial barrier to the immune system has been demonstrated for antigens (e.g., insulin) conjugated to an FcRn binding partner such as IgG or Fc fragments (see, e.g., PCT Publications WO 96/22024 and WO 99/04813). IgG Fusion proteins that have a disulfide-linked dimeric structure due to the IgG portion desulfide bonds have also been found to be more efficient in binding and neutralizing other molecules than monomeric polypeptides or fragments thereof alone. See, e.g., Fountoulakis et al., J. Biochem., 270:3958-3964 (1995). Nucleic acids encoding the above epitopes can also be recombined with a gene of interest as an epitope tag (e.g., the hemagglutinin (HA) tag or flag tag) to aid in detection and purification of the expressed polypeptide. For example, a system described by Janknecht et al. allows for the ready purification of non-denatured fusion proteins expressed in human cell lines (Janknecht et al., 1991, Proc. Natl. Acad. Sci. USA 88:8972-897). In this system, the gene of interest is subcloned into a vaccinia recombination plasmid such that the open reading frame of the gene is translationally fused to an amino-terminal tag consisting of six histidine residues. The tag serves as a matrix binding domain for the fusion protein. Extracts from cells infected with the recombinant vaccinia virus are loaded onto Ni2+ nitriloacetic acid-agarose column and histidine-tagged proteins can be selectively eluted with imidazole-containing buffers.  
       [0182] Fission Proteins  
       [0183] Any polypeptide of the present invention can be used to generate fusion proteins. For example, the polypeptide of the present invention, when fused to a second protein, can be used as an antigenic tag. Antibodies raised against the polypeptide of the present invention can be used to indirectly detect the second protein by binding to the polypeptide. Moreover, because secreted proteins target cellular locations based on trafficking signals, polypeptides of the present invention which are shown to be secreted can be used as targeting molecules once fused to other proteins.  
       [0184] Examples of domains that can be fused to polypeptides of the present invention include not only heterologous signal sequences, but also other heterologous functional regions. The fusion does not necessarily need to be direct, but may occur through linker sequences.  
       [0185] In certain preferred embodiments, proteins of the invention are fusion proteins comprising an amino acid sequence that is an N and/or C-terminal deletion of a polypeptide of the invention. In preferred embodiments, the invention is directed to a fusion protein comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to a polypeptide sequence of the invention. Polynucleotides encoding these proteins are also encompassed by the invention.  
       [0186] Moreover, fusion proteins may also be engineered to improve characteristics of the polypeptide of the present invention. For instance, a region of additional amino acids, particularly charged amino acids, may be added to the N-terminus of the polypeptide to improve stability and persistence during purification from the host cell or subsequent handling and storage. Also, peptide moieties may be added to the polypeptide to facilitate purification. Such regions may be removed prior to final preparation of the polypeptide. The addition of peptide moieties to facilitate handling of polypeptides are familiar and routine techniques in the art.  
       [0187] As one of skill in the art will appreciate that, as discussed above, polypeptides of the present invention, and epitope-bearing fragments thereof, can be combined with heterologous polypeptide sequences. For example, the polypeptides of the present invention may be fused with heterologous polypeptide sequences, for example, the polypeptides of the present invention may be fused with the constant domain of immunoglobulins (IgA, IgE, IgG, IgM) or portions thereof (CH1, CH2, CH3, and any combination thereof, including both entire domains and portions thereof), or albumin (including, but not limited to, native or recombinant human albumin or fragments or variants thereof (see, e.g., U.S. Pat. No. 5,876,969, issued Mar. 2, 1999, EP Patent 0 413 622, and U.S. Pat. No. 5,766,883, issued Jun. 16, 1998, herein incorporated by reference in their entirety)), resulting in chimeric polypeptides. For example, EP-A-O 464 533 (Canadian counterpart 2045869) discloses fusion proteins comprising various portions of constant region of immunoglobutin molecules together with another human protein or part thereof. In many cases, the Fc part in a fusion protein is beneficial in therapy and diagnosis, and thus can result in, for example, improved pharmacokinetic properties (EP-A 0232 262). Alternatively, deleting the Fc part after the fusion protein has been expressed, detected, and purified, would be desired. For example, the Fc portion may hinder therapy and diagnosis if the fusion protein is used as an antigen for immunizations. In drug discovery, for example, human proteins, such as hIL-5, have been fused with Fc portions for the purpose of high-throughput screening assays to identify antagonists of hIL-5. See, D. Bennett et al., J. Molecular Recognition 8:52-58 (1995); K. Johanson et al., J. Biol. Chem. 270:9459-9471 (1995).  
       [0188] Moreover, the polypeptides of the present invention can be fused to marker sequences, such as a polypeptide, which facilitates purification of the fused polypeptide. In preferred embodiments, the marker amino acid sequence is a hexa-histidine peptide, such as the tag provided in a pQE vector (QIAGEN, Inc., 9259 Eton Avenue, Chatsworth, Calif., 91311), among others, many of which are commercially available. As described in Gentz et al., Proc. Natl. Acad. Sci. USA 86:821-824 (1989), for instance, hexa-histidine provides for convenient purification of the fusion protein. Another peptide tag useful for purification, the “HA” tag, corresponds to an epitope derived from the influenza hemagglutinin protein (Wilson et al., Cell 37:767 (1984).)  
       [0189] Additional fusion proteins of the invention may be generated through the techniques of gene-shuffling, motif-shuffling, exon-shuffling, and/or codon-shuffling (collectively referred to as “DNA shuffling”), briefly described below, and further described herein. DNA shuffling may be employed to modulate the activities of polypeptides of the invention, such methods can be used to generate polypeptides with altered activity, as well as agonists and antagonists of the polypeptides. See, generally, U.S. Pat. Nos. 5,605,793; 5,811,238; 5,830,721; 5,834,252; and 5,837,458, and Patten et al., Curr. Opinion Biotechnol. 8:724-33 (1997); Harayama, Trends Biotechnol. 16(2):76-82 (1998); Hansson et al., J. Mol. Biol. 287:265-76 (1999); and Lorenzo and Blasco, Biotechniques 24(2):308-13 (1998); each of these patents and publications are hereby incorporated by reference in its entirety). In a preferred embodiment, one or more components, motifs, sections, parts, domains, fragments, etc., of a polynucleotide encoding a polypeptide of the invention may be recombined with one or more components, motifs, sections, parts, domains, fragments, etc., of one or more heterologous molecules encoding a heterologous polypeptide.  
       [0190] Thus, any of these above fusions can be engineered using the polynucleotides or the polypeptides of the present invention.  
       [0191] Recombinant and Synthetic Production of Polypeptides of the Invention  
       [0192] The present invention also relates to vectors containing the polynucleotide of the present invention, host cells, and the production of polypeptides by synthetic and recombinant techniques. The vector may be, for example, a phage, plasmid, viral, or retroviral vector. Retroviral vectors may be replication competent or replication defective. In the latter case, viral propagation generally will occur only in complementing host cells.  
       [0193] The polynucleotides of the invention may be joined to a vector containing a selectable marker for propagation in a host. Generally, a plasmid vector is introduced in a precipitate, such as a calcium phosphate precipitate, or in a complex with a charged lipid. If the vector is a virus, it may be packaged in vitro using an appropriate packaging cell line and then transduced into host cells.  
       [0194] The polynucleotide insert should be operatively linked to an appropriate promoter, such as the phage lambda PL promoter, the  E. coli  lac, trp, phoA and tac promoters, the SV40 early and late promoters and promoters of retroviral LTRs, to name a few. Other suitable promoters will be known to the skilled artisan. The expression constructs will further contain sites for transcription initiation, termination, and, in the transcribed region, a ribosome binding site for translation. The coding portion of the transcripts expressed by the constructs will preferably include a translation initiating codon at the beginning and a termination codon (UAA, UGA or UAG) appropriately positioned at the end of the polypeptide to be translated.  
       [0195] As indicated, the expression vectors will preferably include at least one selectable marker. Such markers include dihydrofolate reductase, G418 or neomycin resistance, glutamine synthase, for eukaryotic cell culture and tetracycline, kanamycin or ampicillin resistance genes for culturing in  E. coli  and other bacteria. Representative examples of appropriate hosts include, but are not limited to, bacterial cells, such as  E. coli,  Streptomyces and  Salmonella typhimurinim  cells; fungal cells, such as yeast cells (e.g.,  Saccharomyces cerevisiae  or  Pichia pastoris  (ATCC Accession No. 201178)); insect cells such as Drosophila S2 and Spodoptera Sf9 cells; animal cells such as CHO, COS, 293, NSO and Bowes melanoma cells; and plant cells. Appropriate culture mediums and conditions for the above-described host cells are known in the art.  
       [0196] Among vectors preferred for use in bacteria include pQE70, pQE60 and pQE-9, available from QIAGEN, Inc.; pBluescript vectors, Phagescript vectors, pNH8A, pNE16a, pNH18A, pNH46A, available from Stratagene Cloning Systems, Inc.; and ptrc99a, pKK223-3, pKK233-3, pDR540, pRIT5 available from Pharmacia Biotech, Inc. Among preferred eukaryotic vectors are pWLNEO, pSV2CAT, pOG44, pXT1 and pSG available from Stratagene; and pSVK3, pBPV, pMSG and pSVL available from Pharmacia. Preferred expression vectors for use in yeast systems include, but are not limited to pYES2, pYD1, pTEF1/Zeo, pYES2/GS, pPICZ, pGAPZ, pGAPZalph, pPIC9, pPIC3.5, pHIL-D2, pHIL-S1, pPIC3.5K, pPIC9K, and PAO815 (all available from Invitrogen, Carlsbad, Calif.). Other suitable vectors will be readily apparent to the skilled artisan.  
       [0197] Vectors which use glutamine synthase (GS) or DHFR as the selectable markers can be amplified in the presence of the drugs methionine sulphoximine or methotrexate, respectively. An advantage of glutamine synthase based vectors are the availabilty of cell lines (e.g., the murine myeloma cell line, NS0) which are glutamine synthase negative. Glutamine synthase expression systems can also function in glutamine synthase expressing cells (e.g., Chinese Hamster Ovary (CHO) cells) by providing additional inhibitor to prevent the functioning of the endogenous gene. A glutamine synthase expression system and components thereof are detailed in PCT publications: WO87/04462; WO86/05807; WO89/01036; WO89/10404; and WO91/06657, which are hereby incorporated in their entireties by reference herein. Additionally, glutamine synthase expression vectors can be obtained from Lonza Biologics, Inc. (Portsmouth, N.H.). Expression and production of monoclonal antibodies using a GS expression system in murine myeloma cells is described in Bebbington et al.,  Bio/technology  10:169(1992) and in Biblia and Robinson  Biotechnol. Prog.  11:1 (1995) which are herein incorporated by reference.  
       [0198] The present invention also relates to host cells containing the above-described vector constructs described herein, and additionally encompasses host cells containing nucleotide sequences of the invention that are operably associated with one or more heterologous control regions (e.g., promoter and/or enhancer) using techniques known of in the art. The host cell can be a higher eukaryotic cell, such as a mammalian cell (e.g., a human derived cell), or a lower eukaryotic cell, such as a yeast cell, or the host cell can be a prokaryotic cell, such as a bacterial cell. A host strain may be chosen, which modulates the expression of the inserted gene sequences, or modifies and processes the gene product in the specific fashion desired. Expression from certain promoters can be elevated in the presence of certain inducers; thus expression of the genetically engineered polypeptide may be controlled. Furthermore, different host cells have characteristics and specific mechanisms for the translational and post-translational processing and modification (e.g., phosphorylation, cleavage) of proteins. Appropriate cell lines can be chosen to ensure the desired modifications and processing of the foreign protein expressed.  
       [0199] Introduction of the nucleic acids and nucleic acid constructs of the invention into the host cell can be effected by calcium phosphate transfection, DEAE-dextran mediated transfection, cationic lipid-mediated transfection, electroporation, transduction, infection, or other methods. Such methods are described in many standard laboratory manuals, such as Davis et al., Basic Methods In Molecular Biology (1986). It is specifically contemplated that the polypeptides of the present invention may in fact be expressed by a host cell lacking a recombinant vector.  
       [0200] In addition to encompassing host cells containing the vector constructs discussed herein, the invention also encompasses primary, secondary, and immortalized host cells of vertebrate origin, particularly mammalian origin, that have been engineered to delete or replace endogenous genetic material (e.g., excretory system antigen coding sequence), and/or to include genetic material (e.g., heterologous polynucleotide sequences) that is operably associated with excretory system associated polynucleotides of the invention, and which activates, alters, and/or amplifies endogenous excretory system associated polynucleotides. For example, techniques known in the art may be used to operably associate heterologous control regions (e.g., promoter and/or enhancer) and endogenous excretory system associated polynucleotide sequences via homologous recombination (see, e.g., U.S. Pat. No. 5,641,670, issued Jun. 24, 1997; International Publication Number WO 96/29411; International Publication Number WO 94/12650; Koller et al.,  Proc. Natl. Acad. Sci. USA  86:8932-8935 (1989); and Zijlstra et al.,  Nature  342:435-438 (1989), the disclosures of each of which are incorporated by reference in their entireties).  
       [0201] Polypeptides of the present invention can also be recovered from: products purified from natural sources, including bodily fluids, tissues and cells, whether directly isolated or cultured; products of chemical synthetic procedures; and products produced by recombinant techniques from a prokaryotic or eukaryotic host, including, for example, bacterial, yeast, higher plant, insect, and mammalian cells. Depending upon the host employed in a recombinant production procedure, the polypeptides of the present invention may be glycosylated or may be non-glycosylated. In addition, polypeptides of the invention may also include an initial modified methionine residue, in some cases as a result of host-mediated processes. Thus, it is well known in the art that the N-terminal methionine encoded by the translation initiation codon generally is removed with high efficiency from any protein after translation in all eukaryotic cells. While the N-terminal methionine on most proteins also is efficiently removed in most prokaryotes, for some proteins, this prokaryotic removal process is inefficient, depending on the nature of the amino acid to which the N-terminal methionine is covalently linked.  
       [0202] In one embodiment, the yeast Pichia pastoris is used to express polypeptides of the invention in a eukaryotic system.  Pichia pastoris  is a methylotrophic yeast which can metabolize methanol as its sole carbon source. A main step in the methanol metabolization pathway is the oxidation of methanol to formaldehyde using O 2 . This reaction is catalyzed by the enzyme alcohol oxidase. In order to metabolize methanol as its sole carbon source,  Pichia pastoris  must generate high levels of alcohol oxidase due, in part, to the relatively low affinity of alcohol oxidase for O 2 . Consequently, in a growth medium depending on methanol as a main carbon source, the promoter region of one of the two alcohol oxidase genes (AOX1) is highly active. In the presence of methanol, alcohol oxidase produced from the AOX1 gene comprises up to approximately 30% of the total soluble protein in  Pichia pastoris.  See, Ellis, S. B., et al.,  Mol. Cell. Biol.  5:1111-21 (1985); Koutz, P. J, et al.,  Yeast  5:167-77 (1989); Tschopp, J. F., et al.,  Nucl. Acids Res.  15:3859-76 (1987). Thus, a heterologous coding sequence, such as, for example, a polynucleotide of the present invention, under the transcriptional regulation of all or part of the AOX1 regulatory sequence is expressed at exceptionally high levels in Pichia yeast grown in the presence of methanol.  
       [0203] In one example, the plasmid vector pPIC9K is used to express DNA encoding a polypeptide of the invention, as set forth herein, in a Pichea yeast system essentially as described in “Pichia Protocols: Methods in Molecular Biology,” D. R. Higgins and J. Cregg, eds. The Humana Press, Totowa, N.J., 1998. This expression vector allows expression and secretion of a polypeptide of the invention by virtue of the strong AOX1 promoter linked to the  Pichia pastoris  alkaline phosphatase (PHO) secretory signal peptide (i.e., leader) located upstream of a multiple cloning site.  
       [0204] Many other yeast vectors could be used in place of pPIC9K, such as, pYES2, pYD1, pTEF1/Zeo, pYES2/GS, pPICZ, pGAPZ, pGAPZalpha, pPIC9, pPIC3.5, pHIL-D2, pHIL-S1, pPIC3.5K, and PAO815, as one skilled in the art would readily appreciate, as long as the proposed expression construct provides appropriately located signals for transcription, translation, secretion (if desired), and the like, including an in-frame AUG as required.  
       [0205] In another embodiment, high-level expression of a heterologous coding sequence, such as, for example, a polynucleotide of the present invention, may be achieved by cloning the heterologous polynucleotide of the invention into an expression vector such as, for example, pGAPZ or pGAPZalpha, and growing the yeast culture in the absence of methanol.  
       [0206] In addition to encompassing host cells containing the vector constructs discussed herein, the invention also encompasses primary, secondary, and immortalized host cells of vertebrate origin, particularly mammalian origin, that have been engineered to delete or replace endogenous genetic material (e.g., coding sequence), and/or to include genetic material (e.g., heterologous polynucleotide sequences) that is operably associated with polynucleotides of the invention, and which activates, alters, and/or amplifies endogenous polynucleotides. For example, techniques known in the art may be used to operably associate heterologous control regions (e.g., promoter and/or enhancer) and endogenous polynucleotide sequences via homologous recombination (see, e.g., U.S. Pat. No. 5,641,670, issued Jun. 24, 1997; International Publication No. WO 96/29411, published Sep. 26, 1996; International Publication No. WO 94/12650, published Aug. 4, 1994; Koller et al., Proc. Natl. Acad. Sci. USA 86:8932-8935 (1989); and Zijlstra et al., Nature 342:435-438 (1989), the disclosures of each of which are incorporated by reference in their entireties).  
       [0207] In addition, polypeptides of the invention can be chemically synthesized using techniques known in the art (e.g., see Creighton, 1983, Proteins: Structures and Molecular Principles, W. H. Freeman &amp; Co., N.Y., and Hunkapiller et al.,  Nature,  310:105-111 (1984)). For example, a polypeptide corresponding to a fragment of a polypeptide can be synthesized by use of a peptide synthesizer. Furthermore, if desired, nonclassical amino acids or chemical amino acid analogs can be introduced as a substitution or addition into the polypeptide sequence. Non-classical amino acids include, but are not limited to, to the D-isomers of the common amino acids, 2,4-diaminobutyric acid, a-amino isobutyric acid, 4-aminobutyric acid, Abu, 2-amino butyric acid, g-Abu, e-Ahx, 6-amino hexanoic acid, Aib, 2-amino isobutyric acid, 3-amino propionic acid, ornithine, norleucine, norvaline, hydroxyproline, sarcosine, citrulline, homocitrulline, cysteic acid, t-butylglycine, t-butylalanine, phenylglycine, cyclohexylalanine, b-alanine, fluoro-amino acids, designer amino acids such as b-methyl amino acids, Ca-methyl amino acids, Na-methyl amino acids, and amino acid analogs in general. Furthermore, the amino acid can be D (dextrorotary) or L (levorotary).  
       [0208] The invention encompasses polypeptides of the present invention which are differentially modified during or after translation, e.g., by glycosylation, acetylation, phosphorylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, linkage to an antibody molecule or other cellular ligand, etc. Any of numerous chemical modifications may be carried out by known techniques, including but not limited, to specific chemical cleavage by cyanogen bromide, trypsin, chymotrypsin, papain, V8 protease, NaBH 4 ; acetylation, formylation, oxidation, reduction; metabolic synthesis in the presence of tunicamycin; etc.  
       [0209] Additional post-translational modifications encompassed by the invention include, for example, e.g., N-linked or O-linked carbohydrate chains, processing of N-terminal or C-terminal ends), attachment of chemical moieties to the amino acid backbone, chemical modifications of N-linked or O-linked carbohydrate chains, and addition or deletion of an N-terminal methionine residue as a result of procaryotic host cell expression. The polypeptides may also be modified with a detectable label, such as an enzymatic, fluorescent, isotopic or affinity label to allow for detection and isolation of the protein.  
       [0210] Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, beta-galactosidase, or acetylcholinesterase; examples of suitable prosthetic group complexes include streptavidinlbiotin and avidin/biotin; examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; an example of a luminescent material includes luminol; examples of bioluminescent materials include luciferase, luciferin, and aequorin; and examples of suitable radioactive material include iodine ( 121 I,  123 I,  125 I,  131 I), carbon ( 14 C), sulfur ( 35 S), tritium ( 3 H), indium ( 111 In,  112 In,  113m In,  115m In), technetium ( 99 Tc,  99m Tc), thallium ( 201 Ti), gallium ( 68 Ga,  67 Ga), palladium ( 103 Pd), molybdenum ( 99 Mo), xenon ( 33 Xe), fluorine ( 18 F),  53 Sm,  177 Lu,  159 Gd,  149 Pm,  140 La,  175 Yb,  166 Ho,  90 Y,  47 Sc,  186 Re,  188 Re,  142 Pr,  105 Rh, and  97 Ru.  
       [0211] In specific embodiments, a polypeptide of the present invention or fragment or variant thereof is attached to macrocyclic chelators that associate with radiometal ions, including but not limited to,  177 Lu,  90 Y,  166 Ho, and  153 Sm, to polypeptides. In a preferred embodiment, the radiometal ion associated with the macrocyclic chelators is  111 In. In another preferred embodiment, the radiometal ion associated with the macrocyclic chelator is  90 Y. In specific embodiments, the macrocyclic chelator is 1,4,7,10-tetraazacyclododecane-N,N′,N″,N′″-tetraacetic acid (DOTA). In other specific embodiments, DOTA is attached to an antibody of the invention or fragment thereof via a linker molecule. Examples of linker molecules useful for conjugating DOTA to a polypeptide are commonly known in the art—see, for example, DeNardo et al., Clin Cancer Res. 4(10):2483-90 (1998); Peterson et al., Bioconjug. Chem. 10(4):553-7 (1999); and Zimmerman et al, Nucl. Med. Biol. 26(8):943-50 (1999); which are hereby incorporated by reference in their entirety.  
       [0212] As mentioned, the excretory system associated proteins of the invention may be modified by either natural processes, such as posttranslational processing, or by chemical modification techniques which are well known in the art. It will be appreciated that the same type of modification may be present in the same or varying degrees at several sites in a given excretory system associated polypeptide. excretory system associated polypeptides may be branched, for example, as a result of ubiquitination, and they may be cyclic, with or without branching. Cyclic, branched, and branched cyclic excretory system associated polypeptides may result from posttranslation natural processes or may be made by synthetic methods. Modifications include acetylation, acylation, ADP-ribosylation, amidation, covalent attachment of flavin, covalent attachment of a heme moiety, covalent attachment of a nucleotide or nucleotide derivative, covalent attachment of a lipid or lipid derivative, covalent attachment of phosphotidylinositol, cross-linking, cyclization, disulfide bond formation, demethylation, formation of covalent cross-links, formation of cysteine, formation of pyroglutamate, formylation, gamma-carboxylation, glycosylation, GPI anchor formation, hydroxylation, iodination, methylation, myristoylation, oxidation, pegylation, proteolytic processing, phosphorylation, prenylation, racemization, selenoylation, sulfation, transfer-RNA mediated addition of amino acids to proteins such as arginylation, and ubiquitination. (See, for instance, PROTEINS—STRUCTURE AND MOLECULAR PROPERTIES, 2nd Ed., T. E. Creighton, W. H. Freeman and Company, New York (1993); POSTTRANSLATIONAL COVALENT MODIFICATION OF PROTEINS, B. C. Johnson, Ed., Academic Press, New York, pgs. 1-12 (1983); Seifter et al., Meth. Enzymol. 182:626-646 (1990); Rattan et al., Ann. N.Y. Acad. Sci. 663:48-62 (1992)).  
       [0213] Also provided by the invention are chemically modified derivatives of the polypeptides of the invention which may provide additional advantages such as increased solubility, stability and circulating time of the polypeptide, or decreased immunogenicity (see U.S. Pat. No. 4,179,337). The chemical moieties for derivitization may be selected from water soluble polymers such as polyethylene glycol, ethylene glycoupropylene glycol copolymers, carboxymethylcellulose, dextran, polyvinyl alcohol and the like. The polypeptides may be modified at random positions within the molecule, or at predetermined positions within the molecule and may include one, two, three or more attached chemical moieties.  
       [0214] The polymer may be of any molecular weight, and may be branched or unbranched. For polyethylene glycol, the preferred molecular weight is between about 1 kDa and about 100 kDa (the term “about” indicating that in preparations of polyethylene glycol, some molecules will weigh more, some less, than the stated molecular weight) for ease in handling and manufacturing. Other sizes may be used, depending on the desired therapeutic profile (e.g., the duration of sustained release desired, the effects, if any on biological activity, the ease in handling, the degree or lack of antigenicity and other known effects of the polyethylene glycol to a therapeutic protein or analog). For example, the polyethylene glycol may have an average molecular weight of about 200, 500, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, 7000, 7500, 8000, 8500, 9000, 9500, 10,000, 10,500, 11,000, 11,500, 12,000, 12,500, 13,000, 13,500, 14,000, 14,500, 15,000, 15,500, 16,000, 16,500, 17,000, 17,500, 18,000, 18,500, 19,000, 19,500, 20,000, 25,000, 30,000, 35,000, 40,000, 50,000, 55,000, 60,000, 65,000, 70,000, 75,000, 80,000, 85,000, 90,000, 95,000, or 100,000 kDa.  
       [0215] As noted above, the polyethylene glycol may have a branched structure. Branched polyethylene glycols are described, for example, in U.S. Pat. No. 5,643,575; Morpurgo et al., Appl. Biochem. Biotechnol. 56:59-72 (1996); Vorobjev et al., Nucleosides Nucleotides 18:2745-2750 (1999); and Caliceti et al., Bioconjug. Chem. 10:638-646 (1999), the disclosures of each of which are incorporated herein by reference.  
       [0216] The polyethylene glycol molecules (or other chemical moieties) should be attached to the protein with consideration of effects on functional or antigenic domains of the protein. There are a number of attachment methods available to those skilled in the art, such as, for example, the method disclosed in EP 0 401 384 (coupling PEG to G-CSF), herein incorporated by reference; see also Malik et al., Exp. Hematol. 20:1028-1035 (1992), reporting pegylation of GM-CSF using tresyl chloride. For example, polyethylene glycol may be covalently bound through amino acid residues via a reactive group, such as a free amino or carboxyl group. Reactive groups are those to which an activated polyethylene glycol molecule may be bound. The amino acid residues having a free amino group may include lysine residues and the N-terminal amino acid residues; those having a free carboxyl group may include aspartic acid residues glutamic acid residues and the C-terminal amino acid residue. Sulfhydryl groups may also be used as a reactive group for attaching the polyethylene glycol molecules. Preferred for therapeutic purposes is attachment at an amino group, such as attachment at the N-terminus or lysine group.  
       [0217] As suggested above, polyethylene glycol may be attached to proteins via linkage to any of a number of amino acid residues. For example, polyethylene glycol can be linked to proteins via covalent bonds to lysine, histidine, aspartic acid, glutamic acid, or cysteine residues. One or more reaction chemistries may be employed to attach polyethylene glycol to specific amino acid residues (e.g., lysine, histidine, aspartic acid, glutamic acid, or cysteine) of the protein or to more than one type of amino acid residue (e.g., lysine, histidine, aspartic acid, glutamic acid, cysteine and combinations thereof) of the protein.  
       [0218] One may specifically desire proteins chemically modified at the N-terminus. Using polyethylene glycol as an illustration of the present composition, one may select from a variety of polyethylene glycol molecules (by molecular weight, branching, etc.), the proportion of polyethylene glycol molecules to protein (polypeptide) molecules in the reaction mix, the type of pegylation reaction to be performed, and the method of obtaining the selected N-terminally pegylated protein. The method of obtaining the N-terminally pegylated preparation (i.e., separating this moiety from other monopegylated moieties if necessary) may be by purification of the N-terminally pegylated material from a population of pegylated protein molecules. Selective proteins chemically modified at the N-terminus modification may be accomplished by reductive alkylation which exploits differential reactivity of different types of primary amino groups (lysine versus the N-terminal) available for derivatization in a particular protein. Under the appropriate reaction conditions, substantially selective derivatization of the protein at the N-terminus with a carbonyl group containing polymer is achieved.  
       [0219] As indicated above, pegylation of the proteins of the invention may be accomplished by any number of means. For example, polyethylene glycol may be attached to the protein either directly or by an intervening linker. Linkerless systems for attaching polyethylene glycol to proteins are described in Delgado et al., Crit. Rev. Thera. Drug Carrier Sys. 9:249-304 (1992); Francis et al., Intern. J. of Hematol. 68:1-18 (1998); U.S. Pat. No. 4,002,531; U.S. Pat. No. 5,349,052; WO 95/06058; and WO 98/32466, the disclosures of each of which are incorporated herein by reference.  
       [0220] One system for attaching polyethylene glycol directly to amino acid residues of proteins without an intervening linker employs tresylated MPEG, which is produced by the modification of monmethoxy polyethylene glycol (MPEG) using tresylchloride (CISO 2 CH 2 CF 3 ). Upon reaction of protein with tresylated MPEG, polyethylene glycol is directly attached to amine groups of the protein. Thus, the invention includes protein-polyethylene glycol conjugates produced by reacting proteins of the invention with a polyethylene glycol molecule having a 2,2,2-trifluoreothane sulphonyl group.  
       [0221] Polyethylene glycol can also be attached to proteins using a number of different intervening linkers. For example, U.S. Pat. No. 5,612,460, the entire disclosure of which is incorporated herein by reference, discloses urethane linkers for connecting polyethylene glycol to proteins. Protein-polyethylene glycol conjugates wherein the polyethylene glycol is attached to the protein by a linker can also be produced by reaction of proteins with compounds such as MPEG-succinimidylsuccinate, MPEG activated with 1,1′-carbonyldiimidazole, MPEG-2,4,5-trichloropenylcarbonate, MPEG-p-nitrophenolcarbonate, and various MPEG-succinate derivatives. A number of additional polyethylene glycol derivatives and reaction chemistries for attaching polyethylene glycol to proteins are described in International Publication No. WO 98/32466, the entire disclosure of which is incorporated herein by reference. Pegylated protein products produced using the reaction chemistries set out herein are included within the scope of the invention.  
       [0222] The number of polyethylene glycol moieties attached to each protein of the invention (i.e., the degree of substitution) may also vary. For example, the pegylated proteins of the invention may be linked, on average, to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 17, 20, or more polyethylene glycol molecules. Similarly, the average degree of substitution within ranges such as 1-3, 2-4, 3-5, 4-6, 5-7, 6-8, 7-9, 8-10, 9-11, 10-12, 11-13, 12-14, 13-15, 14-16, 15-17, 16-18, 17-19, or 18-20 polyethylene glycol moieties per protein molecule. Methods for determining the degree of substitution are discussed, for example, in Delgado et al., Crit. Rev. Thera. Drug Carrier Sys. 9:249-304 (1992).  
       [0223] The excretory system associated polypeptides of the invention can be recovered and purified from chemical synthesis and recombinant cell cultures by standard methods which include, but are not limited to, ammonium sulfate or ethanol precipitation, acid extraction, anion or cation exchange chromatography, phosphocellulose chromatography, hydrophobic interaction chromatography, affinity chromatography, hydroxylapatite chromatography and lectin chromatography. Most preferably, high performance liquid chromatography (“HPLC”) is employed for purification. Well known techniques for refolding protein may be employed to regenerate active conformation when the polypeptide is denatured during isolation and/or purification.  
       [0224] Excretory system associated polynucleotides and polypeptides may be used in accordance with the present invention for a variety of applications, particularly those that make use of the chemical and biological properties of excretory system associated antigens. Among these are applications in the detection, prevention, diagnosis and/or treatment of diseases associated with excretory system, such as e.g., excretory system cancer, tumors, renal disorders (e.g., kidney failure, nephritis, blood vessel disorders of kidney, metabolic and congenital kidney disorders, urinary disorders of the kidney, autoimmune disorders, sclerosis and necrosis, and electrolyte imbalance, and kidney cancer), bladder disorders (e.g, urinary tract infection, bladder obstruction, urination disorders, and bladder cancer), urether disorders (e.g., obstruction of the ureter and ureter cancer), urethra disorders (e.g., obstruction of the urethra and urethra cancers) and/or those disorders as discribed under “Urinary System Disorders” below. Additional applications relate to diagnosis and to treatment of disorders of cells, tissues and organisms. These aspects of the invention are discussed further below.  
       [0225] In a preferred embodiment, polynucleotides expressed in a particular tissue type are used to detect, diagnose, treat, prevent and/or prognose disorders associated with the tissue type.  
       [0226] The polypeptides of the invention may be in monomers or multimers (i.e., dimers, trimers, tetramers and higher multimers). Accordingly, the present invention relates to monomers and multimers of the polypeptides of the invention, their preparation, and compositions (preferably, Therapeutics) containing them. In specific embodiments, the polypeptides of the invention are monomers, dimers, trimers or tetramers. In additional embodiments, the multimers of the invention are at least dimers, at least trimers, or at least tetramers.  
       [0227] Multimers encompassed by the invention may be homomers or heteromers. As used herein, the term homomer refers to a multimer containing only polypeptides corresponding to a protein of the invention (e.g., the amino acid sequence of SEQ ID NO: Y, an amino acid sequence encoded by SEQ ID NO: X or the complement of SEQ ID NO: X, the amino acid sequence encoded by the portion of SEQ ID NO: X as defined in columns 8 and 9 of Table 2, and/or an amino acid sequence encoded by cDNA contained in Clone ID NO: Z (including fragments, variants, splice variants, and fusion proteins, corresponding to these as described herein)). These homomers may contain polypeptides having identical or different amino acid sequences. In a specific embodiment, a homomer of the invention is a multimer containing only polypeptides having an identical amino acid sequence. In another specific embodiment, a homomer of the invention is a multimer containing polypeptides having different amino acid sequences. In specific embodiments, the multimer of the invention is a homodimer (e.g., containing two polypeptides having identical or different amino acid sequences) or a homotrimer (e.g., containing three polypeptides having identical and/or different amino acid sequences). In additional embodiments, the homomeric multimer of the invention is at least a homodimer, at least a homotrimer, or at least a homotetramer.  
       [0228] As used herein, the term heteromer refers to a multimer containing two or more heterologous polypeptides (i.e., polypeptides of different proteins) in addition to the polypeptides of the invention. In a specific embodiment, the multimer of the invention is a heterodimer, a heterotrimer, or a heterotetramer. In additional embodiments, the heteromeric multimer of the invention is at least a heterodimer, at least a heterotrimer, or at least a heterotetramer.  
       [0229] Multimers of the invention may be the result of hydrophobic, hydrophilic, ionic and/or covalent associations and/or may be indirectly linked by, for example, liposome formation. Thus, in one embodiment, multimers of the invention, such as, for example, homodimers or homotrimers, are formed when polypeptides of the invention contact one another in solution. In another embodiment, heteromultimers of the invention, such as, for example, heterotrimers or heterotetramers, are formed when polypeptides of the invention contact antibodies to the polypeptides of the invention (including antibodies to the heterologous polypeptide sequence in a fusion protein of the invention) in solution. In other embodiments, multimers of the invention are formed by covalent associations with and/or between the polypeptides of the invention. Such covalent associations may involve one or more amino acid residues contained in the polypeptide sequence (e.g., that recited in SEQ ID NO: Y, encoded by the portion of SEQ ID NO: X as defined in columns 8 and 9 of Table 2, and/or encoded by the cDNA contained in Clone ID NO: Z). In one instance, the covalent associations are cross-linking between cysteine residues located within the polypeptide sequences which interact in the native (i.e., naturally occurring) polypeptide. In another instance, the covalent associations are the consequence of chemical or recombinant manipulation. Alternatively, such covalent associations may involve one or more amino acid residues contained in the heterologous polypeptide sequence in a fusion protein. In one example, covalent associations are between the heterologous sequence contained in a fusion protein of the invention (see, e.g., U.S. Pat. No. 5,478,925). In a specific example, the covalent associations are between the heterologous sequence contained in a Fc fusion protein of the invention (as described herein). In another specific example, covalent associations of fusion proteins of the invention are between heterologous polypeptide sequence from another protein that is capable of forming covalently associated multimers, such as for example, osteoprotegerin (see, e.g., International Publication NO: WO 98/49305, the contents of which are herein incorporated by reference in its entirety). In another embodiment, two or more polypeptides of the invention are joined through peptide linkers. Examples include those peptide linkers described in U.S. Pat. No. 5,073,627 (hereby incorporated by reference). Proteins comprising multiple polypeptides of the invention separated by peptide linkers may be produced using conventional recombinant DNA technology.  
       [0230] Another method for preparing multimer polypeptides of the invention involves use of polypeptides of the invention fused to a leucine zipper or isoleucine zipper polypeptide sequence. Leucine zipper and isoleucine zipper domains are polypeptides that promote multimerization of the proteins in which they are found. Leucine zippers were originally identified in several DNA-binding proteins (Landschulz et al., Science 240:1759, (1988)), and have since been found in a variety of different proteins. Among the known leucine zippers are naturally occurring peptides and derivatives thereof that dimerize or trimerize. Examples of leucine zipper domains suitable for producing soluble multimeric proteins of the invention are those described in PCT application WO 94/10308, hereby incorporated by reference. Recombinant fusion proteins comprising a polypeptide of the invention fused to a polypeptide sequence that dimerizes or trimerizes in solution are expressed in suitable host cells, and the resulting soluble multimeric fusion protein is recovered from the culture supernatant using techniques known in the art.  
       [0231] Trimeric polypeptides of the invention may offer the advantage of enhanced biological activity. Preferred leucine zipper moieties and isoleucine moieties are those that preferentially form trimers. One example is a leucine zipper derived from lung surfactant protein D (SPD), as described in Hoppe et al. (FEBS Letters 344:191, (1994)) and in U.S. patent application Ser. No. 08/446,922, hereby incorporated by reference. Other peptides derived from naturally occurring trimeric proteins may be employed in preparing trimeric polypeptides of the invention  
       [0232] In another example, proteins of the invention are associated by interactions between Flag® polypeptide sequence contained in fusion proteins of the invention containing Flag® polypeptide sequence. In a further embodiment, proteins of the invention are associated by interactions between heterologous polypeptide sequence contained in Flag® fusion proteins of the invention and anti-Flag® antibody.  
       [0233] The multimers of the invention may be generated using chemical techniques known in the art. For example, polypeptides desired to be contained in the multimers of the invention may be chemically cross-linked using linker molecules and linker molecule length optimization techniques known in the art (see, e.g., U.S. Pat. No. 5,478,925, which is herein incorporated by reference in its entirety). Additionally, multimers of the invention may be generated using techniques known in the art to form one or more inter-molecule cross-links between the cysteine residues located within the sequence of the polypeptides desired to be contained in the multimer (see, e.g., U.S. Pat. No. 5,478,925, which is herein incorporated by reference in its entirety). Further, polypeptides of the invention may be routinely modified by the addition of cysteine or biotin to the C-terminus or N-terminus of the polypeptide and techniques known in the art may be applied to generate multimers containing one or more of these modified polypeptides (see, e.g., U.S. Pat. No. 5,478,925, which is herein incorporated by reference in its entirety). Additionally, techniques known in the art may be applied to generate liposomes containing the polypeptide components desired to be contained in the multimer of the invention (see, e.g., U.S. Pat. No. 5,478,925, which is herein incorporated by reference in its entirety).  
       [0234] Alternatively, multimers of the invention may be generated using genetic engineering techniques known in the art. In one embodiment, polypeptides contained in multimers of the invention are produced recombinantly using fusion protein technology described herein or otherwise known in the art (see, e.g., U.S. Pat. No. 5,478,925, which is herein incorporated by reference in its entirety). In a specific embodiment, polynucleotides coding for a homodimer of the invention are generated by ligating a polynucleotide sequence encoding a polypeptide of the invention to a sequence encoding a linker polypeptide and then further to a synthetic polynucleotide encoding the translated product of the polypeptide in the reverse orientation from the original C-terminus to the N-terminus (lacking the leader sequence) (see, e.g., U..S Pat. No. 5,478,925, which is herein incorporated by reference in its entirety). In another embodiment, recombinant techniques described herein or otherwise known in the art are applied to generate recombinant polypeptides of the invention which contain a transmembrane domain (or hydrophobic or signal peptide) and which can be incorporated by membrane reconstitution techniques into liposomes (see, e.g., U.S. Pat. No. 5,478,925, which is herein incorporated by reference in its entirety).  
       [0235] Antibodies  
       [0236] Further polypeptides of the invention relate to antibodies and T-cell antigen receptors (TCR) which immunospecifically bind a polypeptide, polypeptide fragment, or variant of the invention (e.g., a polypeptide or fragment or variant of the amino acid sequence of SEQ ID NO: Y or a polypeptide encoded by the cDNA contained in Clone ID NO: Z, and/or an epitope, of the present invention) as determined by immunoassays well known in the art for assaying specific antibody-antigen binding. Antibodies of the invention include, but are not limited to, polyclonal, monoclonal, multispecific, human, humanized or chimeric antibodies, single chain antibodies, Fab fragments, F(ab′) fragments, fragments produced by a Fab expression library, anti-idiotypic (anti-Id) antibodies (including, e.g., anti-Id antibodies to antibodies of the invention), intracellularly-made antibodies (i.e., intrabodies), and epitope-binding fragments of any of the above. The term “antibody,” as used herein, refers to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e., molecules that contain an antigen binding site that immunospecifically binds an antigen. The immunoglobulin molecules of the invention can be of any type (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) or subclass of immunoglobulin molecule. In preferred embodiments, the immunoglobulin molecules of the invention are IgG1. In other preferred embodiments, the immunoglobulin molecules of the invention are IgG4.  
       [0237] Most preferably the antibodies are human antigen-binding antibody fragments of the present invention and include, but are not limited to, Fab, Fab′ and F(ab′)2, Fd, single-chain Fvs (scFv), single-chain antibodies, disulfide-linked Fvs (sdFv) and fragments comprising either a VL or VH domain. Antigen-binding antibody fragments, including single-chain antibodies, may comprise the variable region(s) alone or in combination with the entirety or a portion of the following: hinge region, CH1, CH2, and CH3 domains. Also included in the invention are antigen-binding fragments also comprising any combination of variable region(s) with a hinge region, CH1, CH2, and CH3 domains. The antibodies of the invention may be from any animal origin including birds and mammals. Preferably, the antibodies are human, murine (e.g., mouse and rat), donkey, ship rabbit, goat, guinea pig, camel, horse, or chicken. As used herein, “human” antibodies include antibodies having the amino acid sequence of a human immunoglobulin and include antibodies isolated from human immunoglobulin libraries or from animals transgenic for one or more human immunoglobulin and that do not express endogenous immunoglobulins, as described infra and, for example in, U.S. Pat. No. 5,939,598 by Kucherlapati et al.  
       [0238] The antibodies of the present invention may be monospecific, bispecific, trispecific or of greater multispecificity. Multispecific antibodies may be specific for different epitopes of a polypeptide of the present invention or may be specific for both a polypeptide of the present invention as well as for a heterologous epitope, such as a heterologous polypeptide or solid support material. See, e.g., PCT publications WO 93/17715; WO 92/08802; WO 91/00360; WO,92/05793; Tutt, et al., J. Immunol. 147:60-69 (1991); U.S. Pat. Nos. 4,474,893; 4,714,681; 4,925,648; 5,573,920; 5,601,819; Kostelny et al., J. Immunol. 148:1547-1553 (1992).  
       [0239] Antibodies of the present invention may be described or specified in terms of the epitope(s) or portion(s) of a polypeptide of the present invention, which they recognize or specifically bind. The epitope(s) or polypeptide portion(s) may be specified as described herein, e.g., by N-terminal and C-terminal positions, or by size in contiguous amino acid residues, or listed in the Tables and Figures. Preferred epitopes of the invention include those shown in column 6 of Table 1A, as well as polynucleotides that encode these epitopes. Antibodies which specifically bind any epitope or polypeptide of the present invention may also be excluded. Therefore, the present invention includes antibodies that specifically bind polypeptides of the present invention, and allows for the exclusion of the same.  
       [0240] Antibodies of the present invention may also be described or specified in terms of their cross-reactivity. Antibodies that do not bind any other analog, ortholog, or homolog of a polypeptide of the present invention are included. Antibodies that bind polypeptides with at least 95%, at least 90%, at least 85%, at least 80%, at least 75%, at least 70%, at least 65%, at least 60%, at least 55%, and at least 50% identity (as calculated using methods known in the art and described herein) to a polypeptide of the present invention are also included in the present invention. In specific embodiments, antibodies of the present invention cross-react with murine, rat and/or rabbit homologs of human proteins and the corresponding epitopes thereof. Antibodies that do not bind polypeptides with less than 95%, less than 90%, less than 85%, less than 80%, less than 75%, less than 70%, less than 65%, less than 60%, less than 55%, and less than 50% identity (as calculated using methods known in the art and described herein) to a polypeptide of the present invention are also included in the present invention. In a specific embodiment, the above-described cross-reactivity is with respect to any single specific antigenic or immunogenic polypeptide, or combination(s) of 2, 3, 4, 5, or more of the specific antigenic and/or immunogenic polypeptides disclosed herein. Further included in the present invention are antibodies, which bind polypeptides encoded by polynucleotides which hybridize to a polynucleotide of the present invention under stringent hybridization conditions (as described herein). Antibodies of the present invention may also be described or specified in terms of their binding affinity to a polypeptide of the invention. Preferred binding affinities include those with a dissociation constant or Kd less than 5×10 −2  M, 10 −2  M, 5×10 −3  M, 10 −3  M, 5×10 −4  M, 10 −4  M, 5×10 −5  M, 10 −5  M, 5×10 −6  M, 10 −6 M, 5×10 −7  M, 10 7  M, 5×10 −8  M, 10 −8  M, 5×10 −9  M, 10 −9  M, 5×10 −10  M, 10 −10  M, 5×10 −11  M, 10 −11  M, 5×10 −12  M, 10 −12  M, 5×10 −13  M, 10 −13  M, 5×10 −14  M, 10 −14  M, 5×10 −15  M, or 10 −15  M.  
       [0241] The invention also provides antibodies that competitively inhibit binding of an antibody to an epitope of the invention as determined by any method known in the art for determining competitive binding, for example, the immunoassays described herein. In preferred embodiments, the antibody competitively inhibits binding to the epitope by at least 95%, at least 90%, at least 85%, at least 80%, at least 75%, at least 70%, at least 60%, or at least 50%.  
       [0242] Antibodies of the present invention may act as agonists or antagonists of the polypeptides of the present invention. For example, the present invention includes antibodies, which disrupt the receptor/ligand interactions with the polypeptides of the invention either partially or fully. Preferably, antibodies of the present invention bind an antigenic epitope disclosed herein, or a portion thereof. The invention features both receptor-specific antibodies and ligand-specific antibodies. The invention also features receptor-specific antibodies, which do not prevent ligand binding but prevent receptor activation. Receptor activation (i.e., signaling) may be determined by techniques described herein or otherwise known in the art. For example, receptor activation can be determined by detecting the phosphorylation (e.g., tyrosine or serine/threonine) of the receptor or its substrate by immunoprecipitation followed by western blot analysis (for example, as described supra). In specific embodiments, antibodies are provided that inhibit ligand activity or receptor activity by at least 95%, at least 90%, at least 85%, at least 80%, at least 75%, at least 70%, at least 60%, or at least 50% of the activity in absence of the antibody.  
       [0243] The invention also features receptor-specific antibodies which both prevent ligand binding and receptor activation as well as antibodies that recognize the receptor-ligand complex, and, preferably, do not specifically recognize the unbound receptor or the unbound ligand. Likewise, included in the invention are neutralizing antibodies which bind the ligand and prevent binding of the ligand to the receptor, as well as antibodies which bind the ligand, thereby preventing receptor activation, but do not prevent the ligand from binding the receptor. Further included in the invention are antibodies, which activate the receptor. These antibodies may act as receptor agonists, i.e., potentiate or activate either all or a subset of the biological activities of the ligand-mediated receptor activation, for example, by inducing dimerization of the receptor. The antibodies may be specified as agonists, antagonists or inverse agonists for biological activities comprising the specific biological activities of the peptides of the invention disclosed herein. The above antibody agonists can be made using methods known in the art. See, e.g., PCT publication WO 96/40281; U.S. Pat. No. 5,811,097; Deng et al., Blood 92(6):1981-1988 (1998); Chen et al., Cancer Res. 58(16):3668-3678 (1998); Harrop et al., J. Immunol. 161(4):1786-1794 (1998); Zhu et al., Cancer Res. 58(15):3209-3214 (1998); Yoon et al., J. Immunol. 160(7):3170-3179 (1998); Prat et al., J. Cell. Sci. 111(Pt2):237-247 (1998); Pitard et al., J. Immunol. Methods 205(2):177-190 (1997); Liautard et al., Cytokine 9(4):233-241 (1997); Carlson et al., J. Biol. Chem. 272(17):11295-11301 (1997); Taryman et al., Neuron 14(4):755-762 (1995); Muller et al., Structure 6(9):1153-1167 (1998); Bartunek et al., Cytokine 8(1):14-20 (1996) (which are all incorporated by reference herein in their entireties).  
       [0244] Antibodies of the present invention may be used, for example, to purify, detect, and target the polypeptides of the present invention, including both in vitro and in vivo diagnostic and therapeutic methods. For example, the antibodies have utility in immunoassays for qualitatively and quantitatively measuring levels of the polypeptides of the present invention in biological samples. See, e.g., Harlow et al., Antibodies: A Laboratory Manual, (Cold Spring Harbor Laboratory Press, 2nd ed. 1988); incorporated by reference herein in its entirety.  
       [0245] As discussed in more detail below, the antibodies of the present invention may be used either alone or in combination with other compositions. The antibodies may further be recombinantly fused to a heterologous polypeptide at the N- or C-terminus or chemically conjugated (including covalent and non-covalent conjugations) to polypeptides or other compositions. For example, antibodies of the present invention may be recombinantly fused or conjugated to molecules useful as labels in detection assays and effector molecules such as heterologous polypeptides, drugs, radionuclides, or toxins. See, e.g., PCT publications WO 92/08495; WO 91/14438; WO 89/12624; U.S. Pat. No. 5,314,995; and EP 396,387; the disclosures of which are incorporated herein by reference in their entireties.  
       [0246] The antibodies of the invention include derivatives that are modified, i.e., by the covalent attachment of any type of molecule to the antibody such that covalent attachment does not prevent the antibody from generating an anti-idiotypic response. For example, but not by way of limitation, the antibody derivatives include antibodies that have been modified, e.g., by glycosylation, acetylation, pegylation, phosphylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, linkage to a cellular ligand or other protein, etc. Any of numerous chemical modifications may be carried out by known techniques, including, but not limited to specific chemical cleavage, acetylation, formylation, metabolic synthesis of tunicamycin, etc. Additionally, the derivative may contain one or more non-classical amino acids.  
       [0247] The antibodies of the present invention may be generated by any suitable method known in the art. Polyclonal antibodies to an antigen-of-interest can be produced by various procedures well known in the art. For example, a polypeptide of the invention can be administered to various host animals including, but not limited to, rabbits, mice, rats, etc. to induce the production of sera containing polyclonal antibodies specific for the antigen. Various adjuvants may be used to increase the immunological response, depending on the host species, and include but are not limited to, Freund&#39;s (complete and incomplete), mineral gels such as aluminum hydroxide, surface active substances such as lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, keyhole limpet hemocyanins, dinitrophenol, and potentially useful human adjuvants such as BCG (bacille Calmette-Guerin) and corynebacterium parvum. Such adjuvants are also well known in the art.  
       [0248] Monoclonal antibodies can be prepared using a wide variety of techniques known in the art including the use of hybridoma, recombinant, and phage display technologies, or a combination thereof. For example, monoclonal antibodies can be produced using hybridoma techniques including those known in the art and taught, for example, in Harlow et al., Antibodies: A Laboratory Manual, (Cold Spring Harbor Laboratory Press, 2nd ed. 1988); Hammerling, et al., in: Monoclonal Antibodies and T-Cell Hybridomas 563-681 (Elsevier, N.Y., 1981) (said references incorporated by reference in their entireties). The term “monoclonal antibody” as used herein is not limited to antibodies produced through hybridoma technology. The term “monoclonal antibody” refers to an antibody that is derived from a single clone, including any eukaryotic, prokaryotic, or phage clone, and not the method by which it is produced.  
       [0249] Methods for producing and screening for specific antibodies using hybridoma technology are routine and well known in the art and are discussed in detail in the Examples. In a non-limiting example, mice can be immunized with a polypeptide of the invention or a cell expressing such peptide. Once an immune response is detected, e.g., antibodies specific for the antigen are detected in the mouse serum, the mouse spleen is harvested and splenocytes isolated. The splenocytes are then fused by well known techniques to any suitable myeloma cells, for example cells from cell line SP20 available from the ATCC. Hybridomas are selected and cloned by limited dilution. The hybridoma clones are then assayed by methods known in the art for cells that secrete antibodies capable of binding a polypeptide of the invention. Ascites fluid, which generally contains high levels of antibodies, can be generated by immunizing mice with positive hybridoma clones.  
       [0250] Accordingly, the present invention provides methods of generating monoclonal antibodies as well as antibodies produced by the method comprising culturing a hybridoma cell secreting an antibody of the invention wherein, preferably, the hybridoma is generated by fusing splenocytes isolated from a mouse immunized with an antigen of the invention with myeloma cells and then screening the hybridomas resulting from the fusion for hybridoma clones that secrete an antibody able to bind a polypeptide of the invention.  
       [0251] Another well known method for producing both polyclonal and monoclonal human B cell lines is transformation using Epstein Barr Virus (EBV). Protocols for generating EBV-transformed B cell lines are commonly known in the art, such as, for example, the protocol outlined in Chapter 7.22 of Current Protocols in Immunology, Coligan et al., Eds., 1994, John Wiley &amp; Sons, NY, which is hereby incorporated in its entirety by reference herein. The source of B cells for transformation is commonly human peripheral blood, but B cells for transformation may also be derived from other sources including, but not limited to, lymph nodes, tonsil, spleen, tumor tissue, and infected tissues. Tissues are generally made into single cell suspensions prior to EBV transformation. Additionally, steps may be taken to either physically remove or inactivate T cells (e.g., by treatment with cyclosporin A) in B cell-containing samples, because T cells from individuals seropositive for anti-EBV antibodies can suppress B cell immortalization by EBV.  
       [0252] In general, the sample containing human B cells is innoculated with EBV, and cultured for 3-4 weeks. A typical source of EBV is the culture supernatant of the B95-8 cell line (ATCC #VR-1492). Physical signs of EBV transformation can generally be seen towards the end of the 3-4 week culture period. By phase-contrast microscopy, transformed cells may appear large, clear, hairy and tend to aggregate in tight clusters of cells. Initially, EBV lines are generally polyclonal. However, over prolonged periods of cell cultures, EBV lines may become monoclonal or polyclonal as a result of the selective outgrowth of particular B cell clones. Alternatively, polyclonal EBV transformed lines may be subcloned (e.g., by limiting dilution culture) or fused with a suitable fusion partner and plated at limiting dilution to obtain monoclonal B cell lines. Suitable fusion partners for EBV transformed cell lines include mouse myeloma cell lines (e.g., SP2/0, X63-Ag8.653), heteromyeloma cell lines (human x mouse; e.g, SPAM-8, SBC-H20, and CB-F7), and human cell lines (e.g., GM 1500, SKO-007, RPMI 8226, and KR-4). Thus, the present invention also provides a method of generating polyclonal or monoclonal human antibodies against polypeptides of the invention or fragments thereof, comprising EBV-transformation of human B cells.  
       [0253] Antibody fragments, which recognize specific epitopes may be generated by known techniques. For example, Fab and F(ab′)2 fragments of the invention may be produced by proteolytic cleavage of immunoglobulin molecules, using enzymes such as papain (to produce Fab fragments) or pepsin (to produce F(ab′)2 fragments). F(ab′)2 fragments contain the variable region, the light chain constant region and the CH1 domain of the heavy chain. For example, the antibodies of the present invention can also be generated using various phage display methods known in the art and as discussed in detail in the Examples (e.g., Example 10). In phage display methods, functional antibody domains are displayed on the surface of phage particles, which carry the polynucleotide sequences encoding them. In a particular embodiment, such phage can be utilized to display antigen-binding domains expressed from a repertoire or combinatorial antibody library (e.g., human or murine). Phage expressing an antigen binding domain that binds the antigen of interest can be selected or identified with antigen, e.g., using labeled antigen or antigen bound or captured to a solid surface or bead. Phage used in these methods are typically filamentous phage including fd and M13 binding domains expressed from phage with Fab, Fv or disulfide stabilized Fv antibody domains recombinantly fused to either the phage gene III or gene VIII protein. Examples of phage display methods that can be used to make the antibodies of the present invention include those disclosed in Brinkman et al., J. Immunol. Methods 182:41-50 (1995); Ames et al., J. Immunol. Methods 184:177-186 (1995); Kettleborough et al., Eur. J. Immunol. 24:952-958 (1994); Persic et al., Gene 187 9-18 (1997); Burton et al., Advances in Immunology 57:191-280 (1994); PCT application No. PCT/GB91/01134; PCT publications WO 90/02809; WO 91/10737; WO 92/01047; WO 92/18619; WO 93/11236; WO 95/15982; WO 95/20401; and U.S. Pat. Nos. 5,698,426; 5,223,409; 5,403,484; 5,580,717; 5,427,908; 5,750,753; 5,821,047; 5,571,698; 5,427,908; 5,516,637; 5,780,225; 5,658,727; 5,733,743 and 5,969,108; each of which is incorporated herein by reference in its entirety.  
       [0254] As described in the above references, after phage selection, the antibody coding regions from the phage can be isolated and used to generate whole antibodies, including human antibodies, or any other desired antigen binding fragment, and expressed in any desired host, including mammalian cells, insect cells, plant cells, yeast, and bacteria, e.g., as described in detail below. For example, techniques to recombinantly produce Fab, Fab′ and F(ab′)2 fragments can also be employed using methods known in the art such as those disclosed in PCT publication WO 92/22324; Mullinax et al., BioTechniques 12(6):864-869 (1992); and Sawai et al., AJRI 34:26-34 (1995); and Better et al., Science 240:1041-1043 (1988) (said references incorporated by reference in their entireties).  
       [0255] Examples of techniques which can be used to produce single-chain Fvs and antibodies include those described in U.S. Pat. Nos. 4,946,778 and 5,258,498; Huston et al., Methods in Enzymology 203:46-88 (1991); Shu et al., PNAS 90:7995-7999 (1993); and Skerra et al., Science 240:1038-1040 (1988). For some uses, including in vivo use of antibodies in humans and in vitro detection assays, it may be preferable to use chimeric, humanized, or human antibodies. A chimeric antibody is a molecule in which different portions of the antibody are derived from different animal species, such as antibodies having a variable region derived from a murine monoclonal antibody and a human immunoglobulin constant region. Methods for producing chimeric antibodies are known in the art. See e.g., Morrison, Science 229:1202 (1985); Oi et al., BioTechniques 4:214 (1986); Gillies et al., (1989) J. Immunol. Methods 125:191-202; U.S. Pat. Nos. 5,807,715; 4,816,567; and 4,816397, which are incorporated herein by reference in their entirety. Humanized antibodies are antibody molecules from non-human species antibody that binds the desired antigen having one or more complementarity determining regions (CDRs) from the non-human species and a framework regions from a human immunoglobulin molecule. Often, framework residues in the human framework regions will be substituted with the corresponding residue from the CDR donor antibody to alter, preferably improve, antigen binding. These framework substitutions are identified by methods well known in the art, e.g., by modeling of the interactions of the CDR and framework residues to identify framework residues important for antigen binding and sequence comparison to identify unusual framework residues at particular positions. (See, e.g., Queen et al., U.S. Pat. No. 5,585,089; Riechmann et al., Nature 332:323 (1988), which are incorporated herein by reference in their entireties.) Antibodies can be humanized using a variety of techniques known in the art including, for example, CDR-grafting (EP 239,400; PCT publication WO 91/09967; U.S. Pat. Nos. 5,225,539; 5,530,101; and 5,585,089), veneering or resurfacing (EP 592,106; EP 519,596; Padlan, Molecular Immunology 28(⅘):489-498 (1991); Studnicka et al., Protein Engineering 7(6):805-814 (1994); Roguska. et al., PNAS 91:969-973 (1994)), and chain shuffling (U.S. Pat. No. 5,565,332).  
       [0256] Completely human antibodies are particularly desirable for therapeutic treatment of human patients. Human antibodies can be made by a variety of methods known in the art including phage display methods described above using antibody libraries derived from human immunoglobulin sequences. See also, U.S. Pat. Nos. 4,444,887 and 4,716,111; and PCT publications WO 98/46645, WO 98/50433, WO 98/24893, WO 98/16654, WO 96/34096, WO 96/33735, and WO 91/10741; each of which is incorporated herein by reference in its entirety.  
       [0257] Human antibodies can also be produced using transgenic mice which are incapable of expressing functional endogenous immunoglobulins, but which can express human immunoglobulin genes. For example, the human heavy and light chain immunoglobulin gene complexes may be introduced randomly or by homologous recombination into mouse embryonic stem cells. Alternatively, the human variable region, constant region, and diversity region may be introduced into mouse embryonic stem cells in addition to the human heavy and light chain genes. The mouse heavy and light chain immunoglobulin genes may be rendered non-functional separately or simultaneously with the introduction of human immunoglobulin loci by homologous recombination. In particular, homozygous deletion of the JH region prevents endogenous antibody production. The modified embryonic stem cells are expanded and microinjected into blastocysts to produce chimeric mice. The chimeric mice are then bred to produce homozygous offspring, which express human antibodies. The transgenic mice are immunized in the normal fashion with a selected antigen, e.g., all or a portion of a polypeptide of the invention. Monoclonal antibodies directed against the antigen can be obtained from the immunized, transgenic mice using conventional hybridoma technology. The human immunoglobulin transgenes harbored by the transgenic mice rearrange during B cell differentiation, and subsequently undergo class switching and somatic mutation. Thus, using such a technique, it is possible to produce therapeutically useful IgG, IgA, IgM and IgE antibodies. For an overview of this technology for producing human antibodies, see Lonberg and Huszar, Int. Rev. Immunol. 13:65-93 (1995). For a detailed discussion of this technology for producing human antibodies and human monoclonal antibodies and protocols for producing such antibodies, see, e.g., PCT publications WO 98/24893; WO 92/01047; WO 96/34096; WO 96/33735; European Patent No. 0 598 877; U.S. Pat. Nos. 5,413,923; 5,625,126; 5,633,425; 5,569,825; 5,661,016; 5,545,806; 5,814,318; 5,885,793; 5,916,771; 5,939,598; 6,075,181 and 6,114,598, which are incorporated by reference herein in their entirety. In addition, companies such as Abgenix, Inc. (Freemont, Calif.) and Genpharm (San Jose, Calif.) can be engaged to provide human antibodies directed against a selected antigen using technology similar to that described above.  
       [0258] Completely human antibodies, which recognize a selected epitope can be generated using a technique referred to as “guided selection.” In this approach a selected non-human monoclonal antibody, e.g., a mouse antibody, is used to guide the selection of a completely human antibody recognizing the same epitope. (Jespers et al., Bio/technology 12:899-903 (1988)).  
       [0259] Further, antibodies to the polypeptides of the invention can, in turn, be utilized to generate anti-idiotype antibodies that “mimic” polypeptides of the invention using techniques well known to those skilled in the art. (See, e.g., Greenspan &amp; Bona, FASEB J. 7(5):437-444; (1989) and Nissinoff, J. Immunol. 147(8):2429-2438 (1991)). For example, antibodies which bind to and competitively inhibit polypeptide multimerization and/or binding of a polypeptide of the invention to a ligand can be used to generate anti-idiotypes that “mimic” the polypeptide multimerization and/or binding domain and, as a consequence, bind to and neutralize polypeptide and/or its ligand. Such neutralizing anti-idiotypes or Fab fragments of such anti-idiotypes can be used in therapeutic regimens to neutralize polypeptide ligand/receptor. For example, such anti-idiotypic antibodies can be used to bind a polypeptide of the invention and/or to bind its ligand(s)/receptor(s), and thereby block its biological activity. Alternatively, antibodies, which bind to and enhance polypeptide multimerization and/or binding, and/or receptor/ligand multimerization, binding and/or signaling can be used to generate anti-idiotypes that function as agonists of a polypeptide of the invention and/or its ligand/receptor. Such agonistic anti-idiotypes or Fab fragments of such anti-idiotypes can be used in therapeutic regimens as agonists of the polypeptides of the invention or its ligand(s)/receptor(s). For example, such anti-idiotypic antibodies can be used to bind a polypeptide of the invention and/or to bind its ligand(s)/receptor(s), and thereby promote or enhance its biological activity.  
       [0260] Intrabodies of the invention can be produced using methods known in the art, such as those disclosed and reviewed in Chen et al., Hum. Gene Ther. 5:595-601 (1994); Marasco, W. A., Gene Ther. 4:11-15 (1997); Rondon and Marasco, Annu. Rev. Microbiol. 51:257-283 (1997); Proba et al., J. Mol. Biol. 275:245-253 (1998); Cohen et al., Oncogene 17:2445-2456 (1998); Ohage and Steipe, J. Mol. Biol. 291:1119-1128 (1999); Ohage et al., J. Mol. Biol. 291:1129-1134 (1999); Wirtz and Steipe, Protein Sci. 8:2245-2250 (1999); Zhu et al., J. Immunol. Methods 231:207-222 (1999); and references cited therein.  
       [0261] Polynucleotides Encoding Antibodies  
       [0262] The invention further provides polynucleotides comprising a nucleotide sequence encoding an antibody of the invention and fragments thereof. The invention also encompasses polynucleotides that hybridize under stringent or alternatively, under lower stringency hybridization conditions, e.g., as defined supra, to polynucleotides that encode an antibody, preferably, that specifically binds to a polypeptide of the invention, preferably, an antibody that binds to a polypeptide having the amino acid sequence of SEQ ID NO: Y, to a polypeptide encoded by a portion of SEQ ID NO: X as defined in columns 8 and 9 of Table 2, and/or to a polypeptide encoded by the cDNA contained in Clone ID NO: Z.  
       [0263] The polynucleotides may be obtained, and the nucleotide sequence of the polynucleotides determined, by any method known in the art. For example, if the nucleotide sequence of the antibody is known, a polynucleotide encoding the antibody may be assembled from chemically synthesized oligonucleotides (e.g., as described in Kutmeler et al., BioTechniques 17:242 (1994)), which, briefly, involves the synthesis of overlapping oligonucleotides containing portions of the sequence encoding the antibody, annealing and ligating of those oligonucleotides, and then amplification of the ligated oligonucleotides by PCR.  
       [0264] Alternatively, a polynucleotide encoding an antibody may be generated from nucleic acid from a suitable source. If a clone containing a nucleic acid encoding a particular antibody is not available, but the sequence of the antibody molecule is known, a nucleic acid encoding the immunoglobulin may be chemically synthesized or obtained from a suitable source (e.g., an antibody cDNA library, or a cDNA library generated from, or nucleic acid, preferably poly A+ RNA, isolated from, any tissue or cells expressing the antibody, such as hybridoma cells selected to express an antibody of the invention) by PCR amplification using synthetic primers hybridizable to the 3′ and 5′ ends of the sequence or by cloning using an oligonucleotide probe specific for the particular gene sequence to identify, e.g., a cDNA clone from a cDNA library that encodes the antibody. Amplified nucleic acids generated by PCR may then be cloned into replicable cloning vectors using any method well known in the art.  
       [0265] Once the nucleotide sequence and corresponding amino acid sequence of the antibody is determined, the nucleotide sequence of the antibody may be manipulated using methods well known in the art for the manipulation of nucleotide sequences, e.g., recombinant DNA techniques, site directed mutagenesis, PCR, etc. (see, for example, the techniques described in Sambrook et al., 1990, Molecular Cloning, A Laboratory Manual, 2d Ed., Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y. and Ausubel et al., eds., 1998, Current Protocols in Molecular Biology, John Wiley &amp; Sons, NY, which are both incorporated by reference herein in their entireties ), to generate antibodies having a different amino acid sequence, for example to create amino acid substitutions, deletions, and/or insertions.  
       [0266] In a specific embodiment, the amino acid sequence of the heavy and/or light chain variable domains may be inspected to identify the sequences of the complementarity determining regions (CDRs) by methods that are well know in the art, e.g., by comparison to known amino acid sequences of other heavy and light chain variable regions to determine the regions of sequence hypervariability. Using routine recombinant DNA techniques, one or more of the CDRs may be inserted within framework regions, e.g., into human framework regions to humanize a non-human antibody, as described stipra. The framework regions may be naturally occurring or consensus framework regions, and preferably human framework regions (see, e.g., Chothia et al., J. Mol. Biol. 278: 457-479 (1998) for a listing of human framework regions). Preferably, the polynucleotide generated by the combination of the framework regions and CDRs encodes an antibody that specifically binds a polypeptide of the invention. Preferably, as discussed supra, one or more amino acid substitutions may be made within the framework regions, and, preferably, the amino acid substitutions improve binding of the antibody to its antigen. Additionally, such methods may be used to make amino acid substitutions or deletions of one or more variable region cysteine residues participating in an intrachain disulfide bond to generate antibody-molecules lacking one or more intrachain disulfide bonds. Other alterations to the polynucleotide are encompassed by the present invention and within the skill of the art.  
       [0267] In addition, techniques developed for the production of “chimeric antibodies” (Morrison et al., Proc. Natl. Acad. Sci. 81:851-855 (1984); Neuberger et al., Nature 312:604-608 (1984); Takeda et al., Nature 314:452-454 (1985)) by splicing genes from a mouse antibody molecule of appropriate antigen specificity together with genes from a human antibody molecule of appropriate biological activity can be used. As described supra, a chimeric antibody is a molecule in which different portions are derived from different animal species, such as those having a variable region derived from a murine mAb and a human immunoglobulin constant region, e.g., humanized antibodies.  
       [0268] Alternatively, techniques described for the production of single chain antibodies (U.S. Pat. No. 4,946,778; Bird, Science 242:423-42 (1988); Huston et al., Proc. Natl. Acad. Sci. USA 85:5879-5883 (1988); and Ward et al., Nature 334:544-54 (1989)) can be adapted to produce single chain antibodies. Single chain antibodies are formed by linking the heavy and light chain fragments of the Fv region via an amino acid bridge, resulting in a single chain polypeptide. Techniques for the assembly of functional Fv fragments in  E. coli  may also be used (Skerra et al., Science 242:1038-1041 (1988)).  
       [0269] Methods of Producing Antibodies  
       [0270] The antibodies of the invention can be produced by any method known in the art for the synthesis of antibodies, in particular, by chemical synthesis or preferably, by recombinant expression techniques. Methods of producing antibodies include, but are not limited to, hybridoma technology, EBV transformation, and other methods discussed herein as well as through the use recombinant DNA technology, as discussed below.  
       [0271] Recombinant expression of an antibody of the invention, or fragment, derivative or analog thereof, (e.g., a heavy or light chain of an antibody of the invention or a single chain antibody of the invention), requires construction of an expression vector containing a polynucleotide that encodes the antibody. Once a polynucleotide encoding an antibody molecule or a heavy or light chain of an antibody, or portion thereof (preferably containing the heavy or light chain variable domain), of the invention has been obtained, the vector for the production of the antibody molecule may be produced by recombinant DNA technology using techniques well known in the art. Thus, methods for preparing a protein by expressing a polynucleotide containing an antibody encoding nucleotide sequence are described herein. Methods which are well known to those skilled in the art can be used to construct expression vectors containing antibody coding sequences and appropriate transcriptional and translational control signals. These methods include, for example, in vitro recombinant DNA techniques, synthetic techniques, and in vivo genetic recombination. The invention, thus, provides replicable vectors comprising a nucleotide sequence encoding an antibody molecule of the invention, or a heavy or light chain thereof, or a heavy or light chain variable domain, operably linked to a promoter. Such vectors may include the nucleotide sequence encoding the constant region of the antibody molecule (see, e.g., PCT Publication WO 86/05807; PCT Publication WO 89/01036; and U.S. Pat. No. 5,122,464) and the variable domain of the antibody may be cloned into such a vector for expression of the entire heavy or light chain.  
       [0272] The expression vector is transferred to a host cell by conventional techniques and the transfected cells are then cultured by conventional techniques to produce an antibody of the invention. Thus, the invention includes host cells containing a polynucleotide encoding an antibody of the invention, or a heavy or light chain thereof, or a single chain antibody of the invention, operably linked to a heterologous promoter. In preferred embodiments for the expression of double-chained antibodies, vectors encoding both the heavy and light chains may be co-expressed in the host cell for expression of the entire immunoglobulin molecule, as detailed below.  
       [0273] A variety of host-expression vector systems may be utilized to express the antibody molecules of the invention. Such host-expression systems represent vehicles by which the coding sequences of interest may be produced and subsequently purified, but also represent cells which may, when transformed or transfected with the appropriate nucleotide coding sequences, express an antibody molecule of the invention in situ. These include but are not limited to microorganisms such as bacteria (e.g.,  E. coli, B. subtilis ) transformed with recombinant bacteriophage DNA, plasmid DNA or cosmid DNA expression vectors containing antibody coding sequences; yeast (e.g., Saccharomyces, Pichia) transformed with recombinant yeast expression vectors containing antibody coding sequences; insect cell systems infected with recombinant virus expression vectors (e.g., baculovirus) containing antibody coding sequences; plant cell systems infected with recombinant virus expression vectors (e.g., cauliflower mosaic virus, CaMV; tobacco mosaic virus, TMV) or transformed with recombinant plasmid expression vectors (e.g., Ti plasmid) containing antibody coding sequences; or mammalian cell systems (e.g., COS, CHO, BHK, 293, 3T3 cells) harboring recombinant expression constructs containing promoters derived from the genome of mammalian cells (e.g., metallothionein promoter) or from mammalian viruses (e.g., the adenovirus late promoter; the vaccinia virus 7.5K promoter). Preferably, bacterial cells such as  Escherichia coli,  and more preferably, eukaryotic cells, especially for the expression of whole recombinant antibody molecule, are used for the expression of a recombinant antibody molecule. For example, mammalian cells such as Chinese hamster ovary cells (CHO), in conjunction with a vector such as the major intermediate early gene promoter element from human cytomegalovirus is an effective expression system for antibodies (Foecking et al., Gene 45:101 (1986); Cockett et al., Bio/Technology 8:2 (1990)).  
       [0274] In bacterial systems, a number of expression vectors may be advantageously selected depending upon the use intended for the antibody molecule being expressed. For example, when a large quantity of such a protein is to be produced, for the generation of pharmaceutical compositions of an antibody molecule, vectors which direct the expression of high levels of fusion protein products that are readily purified may be desirable. Such vectors include, but are not limited, to the  E. coli  expression vector pUR278 (Ruther et al., EMBO J. 2:1791 (1983)), in which the antibody coding sequence may be ligated individually into the vector in frame with the lac Z coding region so that a fusion protein is produced; pIN vectors (Inouye &amp; Inouye, Nucleic Acids Res. 13:3101-3109 (1985); Van Heeke &amp; Schuster, J. Biol. Chem. 24:5503-5509 (1989)); and the like. pGEX vectors may also be used to express foreign polypeptides as fusion proteins with glutathione S-transferase (GST). In general, such fusion proteins are soluble and can easily be purified from lysed cells by adsorption and binding to matrix glutathione-agarose beads followed by elution in the presence of free glutathione. The pGEX vectors are designed to include thrombin or factor Xa protease cleavage sites so that the cloned target gene product can be released from the GST moiety.  
       [0275] In an insect system, Autographa californica nuclear polyhedrosis virus (AcNPV) is used as a vector to express foreign genes. The virus grows in  Spodoptera frugiperda  cells. The antibody coding sequence may be cloned individually into non-essential regions (for example the polyhedrin gene) of the virus and placed under control of an AcNPV promoter (for example the polyhedrin promoter).  
       [0276] In mammalian host cells, a number of viral-based expression systems may be utilized. In cases where an adenovirus is used as an expression vector, the antibody coding sequence of interest may be ligated to an adenovirus transcriptionltranslation control complex, e.g., the late promoter and tripartite leader sequence. This chimeric gene may then be inserted in the adenovirus genome by in vitro or in vivo recombination. Insertion in a non- essential region of the viral genome (e.g., region E1 or E3) will result in a recombinant virus that is viable and capable of expressing the antibody molecule in infected hosts. (e.g., see Logan &amp; Shenk, Proc. Natl. Acad. Sci. USA 81:355-359 (1984)). Specific initiation signals may also be required for efficient translation of inserted antibody coding sequences. These signals include the ATG initiation codon and adjacent sequences. Furthermore, the initiation codon must be in phase with the reading frame of the desired coding sequence to ensure translation of the entire insert. These exogenous translational control signals and initiation codons can be of a variety of origins, both natural and synthetic. The efficiency of expression may be enhanced by the inclusion of appropriate transcription enhancer elements, transcription terminators, etc. (see Bittner et al., Methods in Enzymol. 153:51-544 (1987)).  
       [0277] In addition, a host cell strain may be chosen which modulates the expression of the inserted sequences, or modifies and processes the gene product in the specific fashion desired. Such modifications (e.g., glycosylation) and processing (e.g., cleavaoe) of protein products may be important for the function of the protein. Different host cells have characteristic and specific mechanisms for the post-translational processing and modification of proteins and gene products. Appropriate cell lines or host systems can be chosen to ensure the correct modification and processing of the foreign protein expressed. To this end, eukaryotic host cells which possess the cellular machinery for proper processing of the primary transcript, glycosylation, and phosphorylation of the gene product may be used. Such mammalian host cells include but are not limited to CHO, VERY, BH-K, Hela, COS, MDCK, 293, 3T3, WI38, and in particular, breast cancer cell lines such as, for example, BT483, Hs578T, HTB2, BT20 and T47D, and normal mammary gland cell line such as, for example, CRL7030 and Hs578Bst.  
       [0278] For long-term, high-yield production of recombinant proteins, stable expression is preferred. For example, cell lines, which stably express the antibody molecule may be engineered. Rather than using expression vectors which contain viral origins of replication, host cells can be transformed with DNA controlled by appropriate expression control elements (e.g., promoter, enhancer, sequences, transcription terminators, polyadenylation sites, etc.), and a selectable marker. Following the introduction of the foreign DNA, engineered cells may be allowed to grow for 1-2 days in an enriched media, and then are switched to a selective media. The selectable marker in the recombinant plasmid confers resistance to the selection and allows cells to stably integrate the plasmid into their chromosomes and grow to form foci which in turn can be cloned and expanded into cell lines. This method may advantageously be used to engineer cell lines, which express the antibody molecule. Such engineered cell lines may be particularly useful in screening and evaluation of compounds that interact directly or indirectly with the antibody molecule.  
       [0279] A number of selection systems may be used, including but not limited to the herpes simplex virus thymidine kinase (Wigler et al., Cell 11:223 (1977)), hypoxanthine-guanine phosphoribosyltransferase (Szybalska &amp; Szybalski, Proc. Natl. Acad. Sci. USA 48:202 (1992)), and adenine phosphoribosyltransferase (Lowy et al., Cell 22:817 (1980)) genes can be employed in tk-, hgprt- or aprt- cells, respectively. Also, antimetabolite resistance can be used as the basis of selection for the following genes: dhfr, which confers resistance to methotrexate (Wigler et al., Natl. Acad. Sci. USA 77:357 (1980); O&#39;Hare et al., Proc. Natl. Acad. Sci. USA 78:1527 (1981)); gpt, which confers resistance to mycophenolic acid (Mulligan &amp; Berg, Proc. Natl. Acad. Sci. USA 78:2072 (1981)); neo, which confers resistance to the aminoglycoside G-418 Clinical Pharmacy 12:488-505; Wu and Wu, Biotherapy 3:87-95 (1991); Tolstoshev, Ann. Rev. Pharmacol. Toxicol. 32:573-596 (1993); Mulligan, Science 260:926-932 (1993); and Morgan and Anderson, Ann. Rev. Biochem. 62:191-217 (1993); TIB TECH 11(5):155-215 (1993)); and hygro, which confers resistance to hygromycin (Santerre et al., Gene 30:147 (1984)). Methods commonly known in the art of recombinant DNA technology may be routinely applied to select the desired recombinant clone, and such methods are described, for example, in Ausubel et al. (eds.), Current Protocols in Molecular Biology, John Wiley &amp; Sons, NY (1993); Kriegler, Gene Transfer and Expression, A Laboratory Manual, Stockton Press, NY (1990); and in Chapters 12 and 13, Dracopoli et al. (eds), Current Protocols in Human Genetics, John Wiley &amp; Sons, NY (1994); Colberre-Garapin et al., J. Mol. Biol. 150:1 (1981), which are incorporated by reference herein in their entireties.  
       [0280] The expression levels of an antibody molecule can be increased by vector amplification (for a review, see Bebbington and Hentschel, The use of vectors based on gene amplification for the expression of cloned genes in mammalian cells in DNA cloning, Vol.3. (Academic Press, New York, 1987)). When a marker in the vector system expressing antibody is amplifiable, increase in the level of inhibitor present in culture of host cell will increase the number of copies of the marker gene. Since the amplified region is associated with the antibody gene, production of the antibody will also increase (Crouse et al., Mol. Cell. Biol. 3:257 (1983)).  
       [0281] Vectors which use glutamine synthase (GS) or DHFR as the selectable markers can be amplified in the presence of the drugs methionine sulphoximine or methotrexate, respectively. An advantage of glutamine synthase based vectors are the availabilty of cell lines (e.g., the murine myeloma cell line, NS0) which are glutamine synthase negative. Glutamine synthase expression systems can also function in glutamine synthase expressing cells (e.g., Chinese Hamster Ovary (CHO) cells) by providing additional inhibitor to prevent the functioning of the endogenous gene. A glutamine synthase expression system and components thereof are detailed in PCT publications: WO87/04462; WO86/05807; WO89/011036; WO89/10404; and WO91/06657, which are incorporated in their entireties by reference herein. Additionally, glutamine synthase expression vectors that may be used according to the present invention are commercially available from suplliers, including, for example Lonza Biologics, Inc. (Portsmouth, N.H.). Expression and production of monoclonal antibodies using a GS expression system in murine myeloma cells is described in Bebbington et al., Bio/technology 10:169(1992) and in Biblia and Robinson Biotechnol. Prog. 11:1 (1995) which are incorporated in their entirities by reference herein.  
       [0282] The host cell may be co-transfected with two expression vectors of the invention, the first vector encoding a heavy chain derived polypeptide and the second vector encoding a light chain derived polypeptide. The two vectors may contain identical selectable markers, which enable equal expression of heavy and light chain polypeptides. Alternatively, a single vector may be used which encodes, and is capable of expressing, both heavy and light chain polypeptides. In such situations, the light chain should be placed before the heavy chain to avoid an excess of toxic free heavy chain (Proudfoot, Nature 322:52 (1986); Kohler, Proc. Natl. Acad. Sci. USA 77:2197 (1980)). The coding sequences for the heavy and light chains may comprise cDNA or genomic DNA.  
       [0283] Once an antibody molecule of the invention has been produced by an animal, chemically synthesized, or recombinantly expressed, it may be purified by any method known in the art for purification of an immunoglobulin molecule, for example, by chromatography (e.g., ion exchange, affinity, particularly by affinity for the specific antigen after Protein A, and sizing column chromatography), centrifugation, differential solubility, or by any other standard technique for the purification of proteins. In addition, the antibodies of the present invention or fragments thereof can be fused to heterologous polypeptide sequences described herein or otherwise known in the art, to facilitate purification.  
       [0284] The present invention encompasses antibodies recombinantly fused or chemically conjugated (including both covalently and non-covalently conjugations) to a polypeptide (or portion thereof, preferably at least 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 amino acids of the polypeptide) of the present invention to generate fusion proteins. The fusion does not necessarily need to be direct, but may occur through linker sequences. The antibodies may be specific for antigens other than polypeptides (or portion thereof, preferably at least 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 amino acids of the polypeptide) of the present invention. For example, antibodies may be used to target the polypeptides of the present invention to particular cell types, either in vitro or in vivo, by fusing or conjugating the polypeptides of the present invention to antibodies specific for particular cell surface receptors. Antibodies fused or conjugated to the polypeptides of the present invention may also be used in in vitro immunoassays and purification methods using methods known in the art. See e.g., Harbor et al., supra, and PCT publication WO 93/21232; EP 439,095; Naramura et al., Immunol. Lett. 39:91-99 (1994); U.S. Pat. No. 5,474,981; Gillies et al., PNAS 89:1428-1432 (1992); Fell et al., J. Immunol. 146:2446-2452 (1991), which are incorporated by reference in their entireties.  
       [0285] The present invention further includes compositions comprising the polypeptides of the present invention fused or conjugated to antibody domains other than the variable regions. For example, the polypeptides of the present invention may be fused or conjugated to an antibody Fc region, or portion thereof. The antibody portion fused to a polypeptide of the present invention may comprise the constant region, hinge region, CH1 domain, CH2 domain, and CH3 domain or any combination of whole domains or portions thereof. The polypeptides may also be fused or conjugated to the above antibody portions to form multimers. For example, Fc portions fused to the polypeptides of the present invention can form dimers through disulfide bonding between the Fc portions. Higher multimeric forms can be made by fusing the polypeptides to portions of IgA and IgM. Methods for fusing or conjugating the polypeptides of the present invention to antibody portions are known in the art. See, e.g., U.S. Pat. Nos. 5,336,603; 5,622,929; 5,359,046; 5,349,053; 5,447,851; 5,112,946; EP 307,434; EP 367,166; PCT publications WO 96/04388; WO 91/06570; Ashkenazi et al., Proc. Natl. Acad. Sci. USA 88:10535-10539 (1991); Zheng et al., J. Immunol. 154:5590-5600 (1995); and Vil et al., Proc. Natl. Acad. Sci. USA 89:11337-11341 (1992) (said references incorporated by reference in their entireties).  
       [0286] As discussed, supra, the polypeptides corresponding to a polypeptide, polypeptide fragment, or a variant of SEQ ID NO: Y may be fused or conjugated to the above antibody portions to increase the in vivo half life of the polypeptides or for use in immunoassays using methods known in the art. Further, the polypeptides corresponding to SEQ ID NO: Y may be fused or conjugated to the above antibody portions to facilitate purification. One reported example describes chimeric proteins consisting of the first two domains of the human CD4-polypeptide and various domains of the constant regions of the heavy or light chains of mammalian immunoglobulins. See EP 394,827; Traunecker et al., Nature 331:84-86 (1988). The polypeptides of the present invention fused or conjugated to an antibody having disulfide-linked dimeric structures (due to the IgG) may also be more efficient in binding and neutralizing other molecules, than the monomeric secreted protein or protein fragment alone. See, for example, Fountoulakis et al., J. Biochem. 270:3958-3964 (1995). In many cases, the Fc part in a fusion protein is beneficial in therapy and diagnosis, and thus can result in, for example, improved pharmacokinetic properties. See, for example, EP A 232,262. Alternatively, deleting the Fc part after the fusion protein has been expressed, detected, and purified, would be desired. For example, the Fc portion may hinder therapy and diagnosis if the fusion protein is used as an antigen for immunizations. In drug discovery, for example, human proteins, such as hIL-5, have been fused with Fc portions for the purpose of high-throughput screening assays to identify antagonists of hIL-5. (See, Bennett et al., J. Molecular Recognition 8:52-58 (1995); Johanson et al., J. Biol. Chem. 270:9459-9471 (1995)).  
       [0287] Moreover, the antibodies or fragments thereof of the present invention can be fused to marker sequences, such as a peptide to facilitate purification. In preferred embodiments, the marker amino acid sequence is a hexa-histidine peptide, such as the tag provided in a pQE vector (QIAGEN, Inc., 9259 Eton Avenue, Chatsworth, Calif., 91311), among others, many of which are commercially available. As described in Gentz et al., Proc. Natl. Acad. Sci. USA 86:821-824 (1989), for instance, hexa-histidine provides for convenient purification of the fusion protein. Other peptide tags useful for purification include, but are not limited to, the “HA” tag, which corresponds to an epitope derived from the influenza hemagglutinin protein (Wilson et al., Cell 37:767 (1984)) and the “flag” tag.  
       [0288] The present invention further encompasses antibodies or fragments thereof conjugated to a diagnostic or therapeutic agent. The antibodies can be used diagnostically to, for example, monitor the development or progression of a tumor as part of a clinical testing procedure to, e.g., determine the efficacy of a given treatment regimen. Detection can be facilitated by coupling the antibody to a detectable substance. Examples of detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, radioactive materials, positron emitting metals using various positron emission tomographies, and nonradioactive paramagnetic metal ions. The detectable substance may be coupled or conjugated either directly to the antibody (or fragment thereof) or indirectly, through an intermediate (such as, for example, a linker known in the art) using techniques known in the art. See, for example, U.S. Pat. No. 4,741,900 for metal ions, which can be conjugated to antibodies for use as diagnostics according to the present invention.  
       [0289] Further, an antibody or fragment thereof may be conjugated to a therapeutic moiety such as a cytotoxin, e.g., a cytostatic or cytocidal agent, a therapeutic agent or a radioactive metal ion, e.g., alpha-emitters such as, for example, 213Bi. A cytotoxin or cytotoxic agent includes any agent that is detrimental to cells. Examples include paclitaxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, coichicin, doxorubicin, daunorubicin, dihydroxy anthracin dione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, and puromycin and analogs or homologs thereof. Therapeutic agents include, but are not limited to, antimetabolites (e.g., methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil decarbazine), alkylating agents (e.g., mechlorethamine, thioepa chlorambucil, melphalan, carmustine (BSNU) and lomustine (CCNU), cyclothosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C, and cis-dichlorodiamine platinum (II) (DDP) cisplatin), anthracyclines (e.g., daunorubicin (formerly daunomycin) and doxorubicin), antibiotics (e.g., dactinomycin (formerly actinomycin), bleomycin, mithramycin, and anthramycin (AMC)), and anti-mitotic agents (e.g., vincristine and vinblastine).  
       [0290] The conjugates of the invention can be used for modifying a given biological response, the therapeutic agent or drug moiety is not to be construed as limited to classical chemical therapeutic agents. For example, the drug moiety may be a protein or polypeptide possessing a desired biological activity. Such proteins may include, for example, a toxin such as abrin, ricin A, pseudomonas exotoxin, or diphtheria toxin; a protein such as tumor necrosis factor, α-interferon, β-interferon, nerve growth factor, platelet derived growth factor, tissue plasminogen activator, an apoptotic agent, e.g., TNF-alpha, TNF-beta, AIM I (See, International Publication No. WO 97/33899), AIM II (See, International Publication No. WO 97/34911), Fas Ligand (Takahashi et al.,  Int. Immunol.,  6:1567-1574 (1994)), VEGI (See, International Publication No. WO 99/23105), a thrombotic agent or an anti-angiogenic agent, e.g., angiostatin or endostatin; or, biological response modifiers such as, for example, lymphokines, interleukin-1 (“IL-1”), interleukin-2 (“IL-2”), interleukin-6 (“IL-6”), granulocyte macrophage colony stimulating factor (“GM-CSF”), granulocyte colony stimulating factor (“G-CSF”), or other growth factors.  
       [0291] Antibodies may also be attached to solid supports, which are particularly useful for immunoassays or purification of the target antigen. Such solid supports include, but are not limited to, glass, cellulose, polyacrylamide, nylon, polystyrene, polyvinyl chloride or polypropylene.  
       [0292] Techniques for conjugating such therapeutic moiety to antibodies are well known. See, for example, Arnon et al., “Monoclonal Antibodies For Immunotargeting Of Drugs In Cancer Therapy”, in Monoclonal Antibodies And Cancer Therapy, Reisfeld et al. (eds.), pp. 243-56 (Alan R. Liss, Inc. 1985); Hellstrom et al., “Antibodies For Drug Delivery”, in Controlled Drug Delivery (2nd Ed.), Robinson et al. (eds.), pp. 623-53 (Marcel Dekker, Inc. 1987); Thorpe, “Antibody Carriers Of Cytotoxic Agents In Cancer Therapy: A Review”, in Monoclonal Antibodies &#39;84: Biological And Clinical Applications, Pinchera et al. (eds.), pp. 475-506 (1985); “Analysis, Results, And Future Prospective Of The Therapeutic Use Of Radiolabeled Antibody In Cancer Therapy”, in Monoclonal Antibodies For Cancer Detection And Therapy, Baldwin et al. (eds.), pp. 303-16 (Academic Press 1985), and Thorpe et al., “The Preparation And Cytotoxic Properties Of Antibody-Toxin Conjugates”, Immunol. Rev. 62:119-58 (1982).  
       [0293] Alternatively, an antibody can be conjugated to a second antibody to form an antibody heteroconjugate as described by Segal in U.S. Pat. No. 4,676,980, which is incorporated herein by reference in its entirety.  
       [0294] An antibody, with or without a therapeutic moiety conjugated to it, administered alone or in combination with cytotoxic factor(s) and/or cytokine(s) can be used as a therapeutic.  
       [0295] Immunophenotyping  
       [0296] The antibodies of the invention may be utilized for immunophenotyping of cell lines and biological samples. Translation products of the genes of the present invention may be useful as cell specific markers, or more specifically as cellular markers that are differentially expressed at various stages of differentiation and/or maturation of particular cell types. Monoclonal antibodies directed against a specific epitope, or combination of epitopes, will allow for the screening of cellular populations expressing the marker. Various techniques can be utilized using monoclonal antibodies to screen for cellular populations expressing the marker(s), and include magnetic separation using antibody-coated magnetic beads, “panning” with antibody attached to a solid matrix (i.e., plate), and flow cytometry (See, e.g., U.S. Pat. No. 5,985,660; and Morrison et al., Cell, 96:737-49 (1999)).  
       [0297] These techniques allow for the screening of particular populations of cells, such as might be found with hematological malignancies (i.e. minimal residual disease (MRD) in acute leukemic patients) and “non-self” cells in transplantations to prevent Graft-versus-Host Disease (GVHD). Alternatively, these techniques allow for the screening of hematopoietic stem and progenitor cells capable of undergoing proliferation and/or differentiation, as might be found in human umbilical cord blood.  
       [0298] Assays For Antibody Binding  
       [0299] The antibodies of the invention may be assayed for immunospecific binding by any method known in the art. The immunoassays, which can be used include, but are not limited to, competitive and non-competitive assay systems using techniques such as western blots, radioimmunoassays, ELISA (enzyme linked immunosorbent assay), “sandwich” immunoassays, immunoprecipitation assays, precipitin reactions, gel diffusion precipitin reactions, immunodiffusion assays, agglutination assays, complement-fixation assays, immunoradiometric assays, fluorescent immunoassays, and protein A immunoassays, to name but a few. Such assays are routine and well known in the art (see, e.g., Ausubel et al, eds, 1994, Current Protocols in Molecular Biology, Vol. 1, John Wiley &amp; Sons, Inc., New York, which is incorporated by reference herein in its entirety). Exemplary immunoassays are described briefly below (but are not intended by way of limitation).  
       [0300] Immunoprecipitation protocols generally comprise lysing a population of cells in a lysis buffer such as RIPA buffer (1% NP-40 or Triton X-100, 1% sodium deoxycholate, 0.1% SDS, 0.15 M NaCl, 0.01 M sodium phosphate at pH 7.2, 1% Trasylol) supplemented with protein phosphatase and/or protease inhibitors (e.g., EDTA, PMSF, aprotinin, sodium vanadate), adding the antibody of interest to the cell lysate, incubating for a period of time (e.g., 1-4 hours) at 4° C., adding protein A and/or protein G sepharose beads to the cell lysate, incubating for about an hour or more at 4° C., washing the beads in lysis buffer and resuspending the beads in SDS/sample buffer. The ability of the antibody of interest to immunoprecipitate a particular antigen can be assessed by, e.g., western blot analysis. One of skill in the art would be knowledgeable as to the parameters that can be modified to increase the binding of the antibody to an antigen and decrease the background (e.g., pre-clearing the cell lysate with sepharose beads). For further discussion regarding immunoprecipitation protocols see, e.g., Ausubel et al., eds., (1994), Current Protocols in Molecular Biology, Vol. 1, John Wiley &amp; Sons, Inc., New York, section 10.16.1.  
       [0301] Western blot analysis generally comprises preparing protein samples, electrophoresis of the protein samples in a polyacrylamide gel (e.g., 8%-20% SDS-PAGE depending on the molecular weight of the antigen), transferring the protein sample from the polyacrylamide gel to a membrane such as nitrocellulose, PVDF or nylon, blocking the membrane in blocking solution (e.g., PBS with 3% BSA or non-fat milk), washing the membrane in washing buffer (e.g., PBS-Tween 20), blocking the membrane with primary antibody (the antibody of interest) diluted in blocking buffer, washing the membrane in washing buffer, blocking the membrane with a secondary antibody (which recognizes the primary antibody, e.g., an anti-human antibody) conjugated to an enzymatic substrate (e.g., horseradish peroxidase or alkaline phosphatase) or radioactive molecule (e.g., 32P or 125I) diluted in blocking buffer, washing the membrane in wash buffer, and detecting the presence of the antigen. One of skill in the art would be knowledgeable as to the parameters that can be modified to increase the signal detected and to reduce the background noise. For further discussion regarding western blot protocols see, e.g., Ausubel et al., eds., (1994), Current Protocols in Molecular Biology, Vol. 1, John Wiley &amp; Sons, Inc., New York, section 10.8.1.  
       [0302] ELISAs comprise preparing antigen, coating the well of a 96 well microtiter plate with the antigen, adding the antibody of interest conjugated to a detectable compound such as an enzymatic substrate (e.g., horseradish peroxidase or alkaline phosphatase) to the well and incubating for a period of time, and detecting the presence of the antigen. In ELISAs the antibody of interest does not have to be conjugated to a detectable compound; instead, a second antibody (which recognizes the antibody of interest) conjugated to a detectable compound may be added to the well. Further, instead of coating the well with the antigen, the antibody may be coated to the well. In this case, a second antibody conjugated to a detectable compound may be added following the addition of the antigen of interest to the coated well. One of skill in the art would be knowledgeable as to the parameters that can be modified to increase the signal detected as well as other variations of ELISAs known in the art. For further discussion regarding ELISAs see, e.g., Ausubel et al., eds., (1994), Current Protocols in Molecular Biology, Vol. 1, John Wiley &amp; Sons, Inc., New York, section 11.2.1.  
       [0303] The binding affinity of an antibody to an antigen and the off-rate of an antibody-antigen interaction can be determined by competitive binding assays. One example of a competitive binding assay is a radioimmunoassay comprising the incubation of labeled antigen (e.g., 3H or 125I) with the antibody of interest in the presence of increasing amounts of unlabeled antigen, and the detection of the antibody bound to the labeled antigen. The affinity of the antibody of interest for a particular antigen and the binding off-rates can be determined from the data by scatchard plot analysis. Competition with a second antibody can also be determined using radioimmunoassays. In this case, the antigen is incubated with antibody of interest conjugated to a labeled compound (e.g., 3H or 125I) in the presence of increasing amounts of an unlabeled second antibody.  
       [0304] Antibodies of the invention may be characterized using immunocytochemisty methods on cells (e.g., mammalian cells, such as CHO cells) transfected with a vector enabling the expression of a excretory system antigen or with vector alone using techniques commonly known in the art. Antibodies that bind excretory system antigen transfected cells, but not vector-only transfected cells, are excretory system antigen specific.  
       [0305] Therapeuitic Uses  
       [0306] The present invention is further directed to antibody-based therapies which involve administering antibodies of the invention to an animal, preferably a mammal, and most preferably a human, patient for treating one or more of the disclosed diseases, disorders, or conditions. Therapeutic compounds of the invention include, but are not limited to, antibodies of the invention (including fragments, analogs and derivatives thereof as described herein) and nucleic acids encoding antibodies of the invention (including fragments, analogs and derivatives thereof and anti-idiotypic antibodies as described herein). The antibodies of the invention can be used to treat, inhibit or prevent diseases, disorders or conditions associated with aberrant expression and/or activity of a polypeptide of the invention, including, but not limited to, any one or more of the diseases, disorders, or conditions described herein. The treatment and/or prevention of diseases, disorders, or conditions associated with aberrant expression and/or activity of a polypeptide of the invention includes, but is not limited to, alleviating symptoms associated with those diseases, disorders or conditions. Antibodies of the invention may be provided in pharmaceutically acceptable compositions as known in the art or as described herein.  
       [0307] In a specific and preferred embodiment, the present invention is directed to antibody-based therapies which involve administering antibodies of the invention to an animal, preferably a mammal, and most preferably a human, patient for treating one or more of the diseases, disorders, or conditions of the excretory system, including, but not limited to, renal disorders (e.g., kidney failure, nephritis, blood vessel disorders of kidney, metabolic and congenital kidney disorders, urinary disorders of the kidney, autoimmune disorders, sclerosis and necrosis, and electrolyte imbalance, and kidney cancer), bladder disorders (e.g, urinary tract infection, bladder obstruction, urination disorders, and bladder cancer), urether disorders (e.g., obstruction of the ureter and ureter cancer), urethra disorders (e.g., obstruction of the urethra and urethra cancers) and/or those disorders as discribed under “Urinary System Disorders” below. Therapeutic compounds of the invention include, but are not limited to, antibodies of the invention (e.g., antibodies directed to the full length protein expressed on the cell surface of a mammalian cell; antibodies directed to an epitope of an excretory system associated polypeptide of the invention (such as, a linear epitope (shown in Table 1A, column 6) or a conformational epitope), including fragments, analogs and derivatives thereof as described herein) and nucleic acids encoding antibodies of the invention (including fragments, analogs and derivatives thereof and anti-idiotypic antibodies as described herein). The antibodies of the invention can be used to treat, inhibit or prevent diseases, disorders or conditions associated with aberrant expression and/or activity of a polypeptide of the invention, including, but not limited to, any one or more of the diseases, disorders, or conditions of the excretory system described herein. The treatment and/or prevention of diseases, disorders, or conditions of the excretory system associated with aberrant expression and/or activity of a polypeptide of the invention includes, but is not limited to, alleviating symptoms associated with those diseases, disorders or conditions. Antibodies of the invention may be provided in pharmaceutically acceptable compositions as known in the art or as described herein.  
       [0308] A summary of the ways in which the antibodies of the present invention may be used therapeutically includes binding polynucleotides or polypeptides of the present invention locally or systemically in the body or by direct cytotoxicity of the antibody, e.g. as mediated by complement (CDC) or by effector cells (ADCC). Some of these approaches are described in more detail below. Armed with the teachings provided herein, one of ordinary skill in the art will know how to use the antibodies of the present invention for diagnostic, monitoring or therapeutic purposes without undue experimentation.  
       [0309] The antibodies of this invention may be advantageously utilized in combination with other monoclonal or chimeric antibodies, or with lymphokines or hematopoietic growth factors (such as, e.g., IL-2, IL-3 and IL-7), for example, which serve to increase the number or activity of effector cells, which interact with the antibodies.  
       [0310] The antibodies of the invention may be administered alone or in combination with other types of treatments (e.g., radiation therapy, chemotherapy, hormonal therapy, immunotherapy and anti-tumor agents). Generally, administration of products of a species origin or species reactivity (in the case of antibodies) that is the same species as that of the patient is preferred. Thus, in a preferred embodiment, human antibodies, fragments derivatives, analogs, or nucleic acids, are administered to a human patient for therapy or prophylaxis.  
       [0311] It is preferred to use high affinity and/or potent in vivo inhibiting and/or neutralizing antibodies against polypeptides or polynucleotides of the present invention, fragments or regions thereof, for both immunoassays directed to and therapy of disorders related to polynucleotides or polypeptides, including fragments thereof, of the present invention. Such antibodies, fragments, or regions, will preferably have an affinity for polynucleotides or polypeptides of the invention, including fragments thereof. Preferred binding affinities include those with a dissociation constant or Kd less than 5×10 −2  M, 10 −2  M, 5×10 −3  M, 10 −3  M, 5×10 −4 M, 10 −4  M, 5×10 −5  M, 10 −5  M, 5×10 −6  M, 10 −6  M, 5×10 −7  M, 10 −7  M, 5×10 −8  M, 10 −8  M, 5×10 −9  M, 10 −9  M, 5×10 −10  M, 10 −10  M, 5×10 −11  M, 10 −11  M, 5×10 −12  M, 10 −12  M, 5×10 −13  M, 10 −13  M, 5×10 −14  M, 10 −14  M, 5×10 −15  M, and 10 −15  M.  
       [0312] Gene Therapy  
       [0313] In a specific embodiment, nucleic acids comprising sequences encoding antibodies or functional derivatives thereof, are administered to treat, inhibit or prevent a disease or disorder associated with aberrant expression and/or activity of a polypeptide of the invention, by way of gene therapy. Gene therapy refers to therapy performed by the administration to a subject of an expressed or expressible nucleic acid. In this embodiment of the invention, the nucleic acids produce their encoded protein that mediates a therapeutic effect.  
       [0314] Any of the methods for gene therapy available in the art can be used according to the present invention. Exemplary methods are described below.  
       [0315] For general reviews of the methods of gene therapy, see Goldspiel et al., Clinical Pharmacy 12:488-505 (1993); Wu and Wu, Biotherapy 3:87-95 (1991); Tolstoshev, Ann. Rev. Pharmacol. Toxicol. 32:573-596 (1993); Mulligan, Science 260:926-932 (1993); and Morgan and Anderson, Ann. Rev. Biochem. 62:191-217 (1993); May, TIBTECH 11(5):155-215 (1993). Methods commonly known in the art of recombinant DNA technology which can be used are described in Ausubel et al. (eds.), Current Protocols in Molecular Biology, John Wiley &amp; Sons, NY (1993); and Kriegler, Gene Transfer and Expression, A Laboratory Manual, Stockton Press, NY (1990).  
       [0316] In a preferred embodiment, the compound comprises nucleic acid sequences encoding an antibody, said nucleic acid sequences being part of expression vectors that express the antibody or fragments or chimeric proteins or heavy or light chains thereof in a suitable host. In particular, such nucleic acid sequences have promoters operably linked to the antibody coding region, said promoter being inducible or constitutive, and, optionally, tissue-specific. In another particular embodiment, nucleic acid molecules are used in which the antibody coding sequences and any other desired sequences are flanked by regions that promote homologous recombination at a desired site in the genome, thus providing for intrachromosomal expression of the antibody encoding nucleic acids (Koller and Smithies, Proc. Natl. Acad. Sci. USA 86:8932-8935 (1989); Zijistra et al., Nature 342:435-438 (1989). In specific embodiments, the expressed antibody molecule is a single chain antibody; alternatively, the nucleic acid sequences include sequences encoding both the heavy and light chains, or fragments thereof, of the antibody.  
       [0317] Delivery of the nucleic acids into a patient may be either direct, in which case the patient is directly exposed to the nucleic acid or nucleic acid-carrying vectors, or indirect, in which case, cells are first transformed with the nucleic acids in vitro, then transplanted into the patient. These two approaches are known, respectively, as in vivo or ex vivo gene therapy.  
       [0318] In a specific embodiment, the nucleic acid sequences are directly administered in vivo, where it is expressed to produce the encoded product. This can be accomplished by any of numerous methods known in the art, e.g., by constructing them as part of an appropriate nucleic acid expression vector and administering it so that they become intracellular, e.g., by infection using defective or attenuated retrovirals or other viral vectors (see U.S. Pat. No. 4,980,286), or by direct injection of naked DNA, or by use of microparticle bombardment (e.g., a gene gun; Biolistic, Dupont), or coating with lipids or cell-surface receptors or transfecting agents, encapsulation in liposomes, microparticles, or microcapsules, or by administering them in linkage to a peptide which is known to enter the nucleus, by administering it in linkage to a ligand subject to receptor-mediated endocytosis (see, e.g., Wu and Wu, J. Biol. Chem. 262:4429-4432 (1987)) (which can be used to target cell types specifically expressing the receptors), etc. In another embodiment, nucleic acid-ligand complexes can be formed in which the ligand comprises a fusogenic viral peptide to disrupt endosomes, allowing the nucleic acid to avoid lysosomal degradation. In yet another embodiment, the nucleic acid can be targeted in vivo for cell specific uptake and expression, by targeting a specific receptor (see, e.g., PCT Publications WO 92/06180; WO 92/22635; WO92/20316; WO93/14188, WO 93/20221). Alternatively, the nucleic acid can be introduced intracellularly and incorporated within host cell DNA for expression, by homologous recombination (Koller and Smithies, Proc. Natl. Acad. Sci. USA 86:8932-8935 (1989); Zijlstra et al., Nature 342:435-438 (1989)).  
       [0319] In a specific embodiment, viral vectors that contains nucleic acid sequences encoding an antibody of the invention are used. For example, a retroviral vector can be used (see Miller et al., Meth. Enzymol. 217:581-599 (1993)). These retroviral vectors contain the components necessary for the correct packaging of the viral genome and integration into the host cell DNA. The nucleic acid sequences encoding the antibody to be used in gene therapy are cloned into one or more vectors, which facilitates delivery of the gene into a patient. More detail about retroviral vectors can be found in Boesen et al., Biotherapy 6:291-302 (1994), which describes the use of a retroviral vector to deliver the mdr1 gene to hematopoietic stem cells in order to make the stem cells more resistant to chemotherapy. Other references illustrating the use of retroviral vectors in gene therapy are: Clowes et al., J. Clin. Invest. 93:644-651 (1994); Kiem et al., Blood 83:1467-1473 (1994); Salmons and Gunzberg, Human Gene Therapy 4:129-141 (1993); and Grossman and Wilson, Curr. Opin. in Genetics and Devel. 3:110-114 (1993).  
       [0320] Adenoviruses are other viral vectors that can be used in gene therapy. Adenoviruses are especially attractive vehicles for delivering genes to respiratory epithelia. Adenoviruses naturally infect respiratory epithelia where they cause a mild disease. Other targets for adenovirus-based delivery systems are liver, the central nervous system, endothelial cells, and muscle. Adenoviruses have the advantage of being capable of infecting non-dividing cells. Kozarsky and Wilson, Current Opinion in Genetics and Development 3:499-503 (1993) present a review of adenovirus-based gene therapy. Bout et al., Human Gene Therapy 5:3-10 (1994) demonstrated the use of adenovirus vectors to transfer genes to the respiratory epithelia of rhesus monkeys. Other instances of the use of adenoviruses in gene therapy can be found in Rosenfeld et al., Science 252:431-434 (1991); Rosenfeld et al., Cell 68:143-155 (1992); Mastrangeli et al., J. Clin. Invest. 91:225-234 (1993); PCT Publication WO94/12649; and Wang, et al., Gene Therapy 2:775-783 (1995). In a preferred embodiment, adenovirus vectors are used.  
       [0321] Adeno-associated virus (AAV) has also been proposed for use in gene therapy (Walsh et al., Proc. Soc. Exp. Biol. Med. 204:289-300 (1993); U.S. Pat. No. 5,436,146).  
       [0322] Another approach to gene therapy involves transferring a gene to cells in tissue culture by such methods as electroporation, lipofection, calcium phosphate mediated transfection, or viral infection. Usually, the method of transfer includes the transfer of a selectable marker to the cells. The cells are then placed under selection to isolate those cells that have taken up and are expressing the transferred gene. Those cells are then delivered to a patient.  
       [0323] In this embodiment, the nucleic acid is introduced into a cell prior to administration in vivo of the resulting recombinant cell. Such introduction can be carried out by any method known in the art, including but not limited to transfection, electroporation, microinjection, infection with a viral or bacteriophage vector containing the nucleic acid sequences, cell fusion, chromosome-mediated gene transfer, microcell-mediated gene transfer, spheroplast fusion, etc. Numerous techniques are known in the art for the introduction of foreign genes into cells (see, e.g., Loeffler and Behr, Meth. Enzymol. 217:599-618 (1993); Cohen et al., Meth. Enzymol. 217:618-644 (1993); Cline, Pharmac. Ther. 29:69-92 m (1985) and may be used in accordance with the present invention, provided that the necessary developmental and physiological functions of the recipient cells are not disrupted. The technique should provide for the stable transfer of the nucleic acid to the cell, so that the nucleic acid is expressible by the cell and preferably heritable and expressible by its cell progeny.  
       [0324] The resulting recombinant cells can be delivered to a patient by various methods known in the art. Recombinant blood cells (e.g., hematopoietic stem or progenitor cells) are preferably administered intravenously. The amount of cells envisioned for use depends on the desired effect, patient state, etc., and can be determined by one skilled in the art.  
       [0325] Cells into which a nucleic acid can be introduced for purposes of gene therapy encompass any desired, available cell type, and include but are not limited to, epithelial cells, endothelial cells, keratinocytes, fibroblasts, muscle cells, hepatocytes; blood cells such as T lymphocytes, B lymphocytes, monocytes, macrophages, neutrophils, eosinophils, megakaryocytes, granulocytes; various stem or progenitor cells, in particular hematopoietic stem or progenitor cells, e.g., as obtained from bone marrow, umbilical cord blood, peripheral blood, fetal liver, etc.  
       [0326] In a preferred embodiment, the cell used for gene therapy is autologous to the patient.  
       [0327] In an embodiment in which recombinant cells are used in gene therapy, nucleic acid sequences encoding an antibody are introduced into the cells such that they are expressible by the cells or their progeny, and the recombinant cells are then administered in vivo for therapeutic effect. In a specific embodiment, stem or progenitor cells are used. Any stem and/or progenitor cells which can be isolated and maintained in vitro can potentially be used in accordance with this embodiment of the present invention (see e.g. PCT Publication WO 94/08598; Stemple and Anderson, Cell 71:973-985 (1992); Rheinwald, Meth. Cell Bio. 21A:229 (1980); and Pittelkow and Scott, Mayo Clinic Proc. 61:771 (1986)).  
       [0328] In a specific embodiment, the nucleic acid to be introduced for purposes of gene therapy comprises an inducible promoter operably linked to the coding region, such that expression of the nucleic acid is controllable by the presence or absence of an appropriate inducer of transcription.  
       [0329] Demonstration of Therapeutic or Prophylactic Activity  
       [0330] The compounds or pharmaceutical compositions of the invention are preferably tested in vitro, and then in vivo for the desired therapeutic or prophylactic activity, prior to use in humans. For example, in vitro assays to demonstrate the therapeutic or prophylactic utility of a compound or pharmaceutical composition include, the effect of a compound on a cell line or a patient tissue sample. The effect of the compound or composition on the cell line and/or tissue sample can be determined utilizing techniques known to those of skill in the art including, but not limited to, rosette formation assays and cell lysis assays. In accordance with the invention, in vitro assays which can be used to determine whether administration of a specific compound is indicated, include in vitro cell culture assays in which a patient tissue sample is grown in culture, and exposed to or otherwise administered a compound, and the effect of such compound upon the tissue sample is observed.  
       [0331] Therapeutic/Prophylactic Administration and Composition  
       [0332] The invention provides methods of treatment, inhibition and prophylaxis by administration to a subject of an effective amount of a compound or pharmaceutical composition of the invention, preferably a polypeptide or antibody of the invention. In a preferred embodiment, the compound is substantially purified (e.g., substantially free from substances that limit its effect or produce undesired side-effects). The subject is preferably an animal, including but not limited to animals such as cows, pigs, horses, chickens, cats, dogs, etc., and is preferably a mammal, and most preferably human.  
       [0333] Formulations and methods of administration that can be employed when the compound comprises a nucleic acid or an immunoglobulin are described above; additional appropriate formulations and routes of administration can be selected from among those described herein below.  
       [0334] Various delivery systems are known and can be used to administer a compound of the invention, e.g., encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing the compound, receptor-mediated endocytosis (see, e.g., Wu and Wu, J. Biol. Chem. 262:4429-4432 (1987)), construction of a nucleic acid as part of a retroviral or other vector, etc. Methods of introduction include but are not limited to intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral-routes. The compounds or compositions may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and may be administered together with other biologically active agents. Administration can be systemic or local. In addition, it may be desirable to introduce the pharmaceutical compounds or compositions of the invention into the central nervous system by any suitable route, including intraventricular and intrathecal injection; intraventricular injection may be facilitated by an intraventricular catheter, for example, attached to a reservoir, such as an Ommaya reservoir. Pulmonary administration can also be employed, e.g., by use of an inhaler or nebulizer, and formulation with an aerosolizing agent.  
       [0335] In a specific embodiment, it may be desirable to administer the pharmaceutical compounds or compositions of the invention locally to the area in need of treatment; this may be achieved by, for example, and not by way of limitation, local infusion during surgery, topical application, e.g., in conjunction with a wound dressing after surgery, by injection, by means of a catheter, by means of a suppository, or by means of an implant, said implant being of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers. Preferably, when administering a protein, including an antibody, of the invention, care must be taken to use materials to which the protein does not absorb.  
       [0336] In another embodiment, the compound or composition can be delivered in a vesicle, in particular a liposome (see Langer, Science 249:1527-1533 (1990); Treat et al., in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-Berestein and Fidler (eds.), Liss, N.Y., pp. 353-365 (1989); Lopez-Berestein, ibid., pp. 317-327; see generally ibid.)  
       [0337] In yet another embodiment, the compound or composition can be delivered in a controlled release system. In one embodiment, a pump may be used (see Langer, supra; Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574 (1989)). In another embodiment, polymeric materials can be used (see Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Fla. (1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, N.Y. (1984); Ranger and Peppas, J., Macromol. Sci. Rev. Macromol. Chem. 23:61 (1983); see also Levy et al., Science 228:190 (1985); During et al., Ann. Neurol. 25:351 (1989); Howard et al., J.Neurosurg. 71:105 (1989)). In yet another embodiment, a controlled release system can be placed in proximity of the therapeutic target, e.g., the brain, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984)).  
       [0338] Other controlled release systems are discussed in the review by Langer (Science 249:1527-1533 (1990)).  
       [0339] In a specific embodiment where the compound of the invention is a nucleic acid encoding a protein, the nucleic acid can be administered in vivo to promote expression of its encoded protein, by constructing it as part of an appropriate nucleic acid expression vector and administering it so that it becomes intracellular, e.g., by use of a retroviral vector (see U.S. Pat. No. 4,980,286), or by direct injection, or by use of microparticle bombardment (e.g., a gene gun; Biolistic, Dupont), or coating with lipids or cell-surface receptors or transfecting agents, or by administering it in linkage to a homeobox-like peptide which is known to enter the nucleus (see e.g., Joliot et al., Proc. Natl. Acad. Sci. USA 88:1864-1868 (1991)), etc. Alternatively, a nucleic acid can be introduced intracellularly and incorporated within host cell DNA for expression, by homologous recombination.  
       [0340] The present invention also provides pharmaceutical compositions. Such compositions comprise a therapeutically effective amount of a compound, and a pharmaceutically acceptable carrier. In a specific embodiment, the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. The term “carrier” refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a preferred carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. These compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like. The composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides. Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described in “Remington&#39;s Pharmaceutical Sciences” by E. W. Martin. Such compositions will contain a therapeutically effective amount of the compound, preferably in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient. The formulation should suit the mode of administration.  
       [0341] In a preferred embodiment, the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous administration to human beings. Typically, compositions for intravenous administration are solutions in sterile isotonic aqueous buffer. Where necessary, the composition may also include a solubilizing agent and a local anesthetic such as lignocaine to ease pain at the site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent. Where the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the composition is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.  
       [0342] The compounds of the invention can be formulated as neutral or salt forms. Pharmaceutically acceptable salts include those formed with anions such as those derived from hydrochloric, phosphoric, acetic, oxalic, tartaric acids, etc., and those formed with cations such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxides, isopropylamine, triethylamine, 2-ethylamino ethanol, histidine, procaine, etc.  
       [0343] The amount of the compound of the invention which will be effective in the treatment, inhibition and prevention of a disease or disorder associated with aberrant expression and/or activity of a polypeptide of the invention can be determined by standard clinical techniques. In addition, in vitro assays may optionally be employed to help identify optimal dosage ranges. The precise dose to be employed in the formulation will also depend on the route of administration, and the seriousness of the disease or disorder, and should be decided according to the judgment of the practitioner and each patient&#39;s circumstances. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.  
       [0344] For antibodies, the dosage administered to a patient is typically 0.1 mg/kg to 100 mg/kg of the patient&#39;s body weight. Preferably, the dosage administered to a patient is between 0.1 mg/kg and 20 mg/kg of the patient&#39;s body weight, more preferably 1 mg/kg to 10 mg/kg of the patient&#39;s body weight. Generally, human antibodies have a longer half-life within the human body than antibodies from other species due to the immune response to the foreign polypeptides. Thus, lower dosages of human antibodies and less frequent administration is often possible. Further, the dosage and frequency of administration of antibodies of the invention may be reduced by enhancing uptake and tissue penetration (e.g., into the brain) of the antibodies by modifications such as, for example, lipidation.  
       [0345] The invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention. Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.  
       [0346] Diagnosis and Imaging  
       [0347] Labeled antibodies, and derivatives and analogs thereof, which specifically bind to a polypeptide of interest can be used for diagnostic purposes to detect, diagnose, or monitor diseases, disorders, and/or conditions associated with the aberrant expression and/or activity of a polypeptide of the invention. The invention provides for the detection of aberrant expression of a polypeptide of interest, comprising (a) assaying the expression of the polypeptide of interest in cells or body fluid of an individual using one or more antibodies specific to the polypeptide interest and (b) comparing the level of gene expression with a standard gene expression level, whereby an increase or decrease in the assayed polypeptide gene expression level compared to the standard expression level is indicative of aberrant expression.  
       [0348] The invention provides a diagnostic assay for diagnosing an excretory system disorder, comprising (a) assaying the expression of the polypeptide of interest in cells or body fluid of an individual using one or more antibodies specific to the polypeptide interest and (b) comparing the level of gene expression with a standard gene expression level, whereby an increase or decrease in the assayed polypeptide gene expression level compared to the standard expression level is indicative of a particular disorder. With respect to cancer, the presence of a relatively high amount of transcript in biopsied tissue from an individual may indicate a predisposition for the development of the disease, or may provide a means for detecting the disease prior to the appearance of actual clinical symptoms. A more definitive diagnosis of this type may allow health professionals to employ preventative measures or aggressive treatment earlier thereby preventing the development or further progression of the cancer.  
       [0349] Antibodies of the invention can be used to assay protein levels in a biological sample using classical immunohistological methods known to those of skill in the art (e.g., see Jalkanen et al., J. Cell. Biol. 101:976-985 (1985); Jalkanen et al., J. Cell . Biol. 105:3087-3096 (1987)). Other antibody-based methods useful for detecting protein gene expression include immunoassays, such as the enzyme linked immunosorbent assay (ELISA) and the radioimmunoassay (RIA). Suitable antibody assay labels are known in the art and include enzyme labels, such as, glucose oxidase; radioisotopes, such as iodine (125I, 121I), carbon (14C), sulfur (35S), tritium (3H), indium (112In), and technetium (99Tc); luminescent labels, such as luminol; and fluorescent labels, such as fluorescein and rhodamine, and biotin.  
       [0350] One facet of the invention is the detection and diagnosis of a disease or disorder associated with aberrant expression of a polypeptide of interest in an animal, preferably a mammal and most preferably a human. A preferred embodiment of the invention is the detection and diagnosis of a disease or disorder of the excretory system associated with aberrant expression of an excretory system antigen in an animal, preferably a mammal and most preferably a human. In one embodiment, diagnosis comprises: a) administering (for example, parenterally, subcutaneously, or intraperitoneally) to a subject an effective amount of a labeled molecule which specifically binds to the polypeptide of interest; b) waiting for a time interval following the administering for permitting the labeled molecule to preferentially concentrate at sites in the subject where the polypeptide is expressed (and for unbound labeled molecule to be cleared to background level); c) determining background level; and d) detecting the labeled molecule in the subject, such that detection of labeled molecule above the background level indicates that the subject has a particular disease or disorder associated with aberrant expression of the polypeptide of interest. Background level can be determined by various methods including, comparing the amount of labeled molecule detected to a standard value previously determined for a particular system.  
       [0351] It will be understood in the art that the size of the subject and the imaging system used will determine the quantity of imaging moiety needed to produce diagnostic images. In the case of a radioisotope moiety, for a human subject, the quantity of radioactivity injected will normally range from about 5 to 20 millicuries of 99 mTc. The labeled antibody or antibody fragment will then preferentially accumulate at the location of cells which contain the specific protein. In vivo tumor imaging is described in S. W. Burchiel et al., “Immunopharmacokinetics of Radiolabeled Antibodies and Their Fragments.” (Chapter 13 in Tumor Imaging: The Radiochemical Detection of Cancer, S. W. Burchiel and B. A. Rhodes, eds., Masson Publishing Inc. (1982)).  
       [0352] Depending on several variables, including the type of label used and the mode of administration, the time interval following the administration for permitting the labeled molecule to preferentially concentrate at sites in the subject and for unbound labeled molecule to be cleared to background level is 6 to 48 hours or 6 to 24 hours or 6 to 12 hours. In another embodiment the time interval following administration is 5 to 20 days or 5 to 10 days.  
       [0353] In an embodiment, monitoring of the disease or disorder is carried out by repeating the method for diagnosing the disease or disorder, for example, one month after initial diagnosis, six months after initial diagnosis, one year after initial diagnosis, etc.  
       [0354] Presence of the labeled molecule can be detected in the patient using methods known in the art for in vivo scanning. These methods depend upon the type of label used. Skilled artisans will be able to determine the appropriate method for detecting a particular label. Methods and devices that may be used in the diagnostic methods of the invention include, but are not limited to, computed tomography (CT), whole body scan such as position emission tomography (PET), magnetic resonance imaging (MRI), and sonography.  
       [0355] In a specific embodiment, the molecule is labeled with a radioisotope and is detected in the patient using a radiation responsive surgical instrument (Thurston et al., U.S. Pat. No. 5,441,050). In another embodiment, the molecule is labeled with a fluorescent compound and is detected in the patient using a fluorescence responsive scanning instrument. In another embodiment, the molecule is labeled with a positron emitting metal and is detected in the patent using positron emission-tomography. In yet another embodiment, the molecule is labeled with a paramagnetic label and is detected in a patient using magnetic resonance imaging (MRI).  
       [0356] Kits  
       [0357] The present invention provides kits that can be used in the above methods. In one embodiment, a kit comprises an antibody of the invention, preferably a purified antibody, in one or more containers. In a specific embodiment, the kits of the present invention contain a substantially isolated polypeptide comprising an epitope, which is specifically immunoreactive with an antibody included in the kit. Preferably, the kits of the present invention further comprise a control antibody which does not react with the polypeptide of interest. In another specific embodiment, the kits of the present invention contain a means for detecting the binding of an antibody to a polypeptide of interest (e.g., the antibody may be conjugated to a detectable substrate such as a fluorescent compound, an enzymatic substrate, a radioactive compound or a luminescent compound, or a second antibody which recognizes the first antibody may be conjugated to a detectable substrate).  
       [0358] In another specific embodiment of the present invention, the kit is a diagnostic kit for use in screening serum-containing antibodies specific against proliferative and/or cancerous polynucleotides and polypeptides. Such a kit may include a control antibody that does not react with the polypeptide of interest. Such a kit may include a substantially isolated polypeptide antigen comprising an epitope which is specifically immunoreactive with at least one anti-polypeptide antigen antibody. Further, such a kit includes means for detecting the binding of said antibody to the antigen (e.g., the antibody may be conjugated to a fluorescent compound such as fluorescein or rhodamine, which can be detected by flow cytometry). In specific embodiments, the kit may include a recombinantly produced or chemically synthesized polypeptide antigen. The polypeptide antigen of the kit may also be attached to a solid support.  
       [0359] In a more specific embodiment, the detecting means of the above-described kit includes a solid support to which said polypeptide antigen is attached. Such a kit may also include a non-attached reporter-labeled anti-human antibody. In this embodiment, binding of the antibody to the polypeptide antigen can be detected by binding of the said reporter-labeled antibody.  
       [0360] In an additional embodiment, the invention includes a diagnostic kit for use in screening serum-containing antigens of the polypeptide of the invention. The diagnostic kit includes a substantially isolated antibody specifically immunoreactive with polypeptide or polynucleotide antigens, and means for detecting the binding of the polynucleotide or polypeptide antigen to the antibody. In one embodiment, the antibody is attached to a solid support. In a specific embodiment, the antibody may be a monoclonal antibody. The detecting means of the kit may include a second, labeled monoclonal antibody. Alternatively, or in addition, the detecting means may include a labeled, competing antigen.  
       [0361] In one diagnostic configuration, test serum is reacted with a solid phase reagent having a surface-bound antigen obtained by the methods of the present invention. After binding with specific antigen antibody to the reagent and removing unbound serum components by washing, the reagent is reacted with reporter-labeled anti-human antibody to bind reporter to the reagent in proportion to the amount of bound anti-antigen antibody on the solid support. The reagent is again washed to remove unbound labeled antibody, and the amount of reporter associated with the reagent is determined. Typically, the reporter is an enzyme, which is detected by incubating the solid phase in the presence of a suitable fluorometric, luminescent or colorimetric substrate (Sigma, St. Louis, Mo.).  
       [0362] The solid surface reagent in the above assay is prepared by known techniques for attaching protein material to solid support material, such as polymeric beads, dip sticks, 96-well plate or filter material. These attachment methods generally include non-specific adsorption of the protein to the support or covalent attachment of the protein, typically through a free amine group, to a chemically reactive group on the solid support, such as an activated carboxyl, hydroxyl, or aldehyde group. Alternatively, streptavidin coated plates can be used in conjunction with biotinylated antigen(s).  
       [0363] Thus, the invention provides an assay system or kit for carrying out this diagnostic method. The kit generally includes a support with surface-bound recombinant antigens, and a reporter-labeled anti-human antibody for detecting surface-bound anti-antigen antibody.  
       [0364] Uses of the Polynucleotides  
       [0365] Each of the polynucleotides identified herein can be used in numerous ways as reagents. The following description should be considered exemplary and utilizes known techniques.  
       [0366] The polynucleotides of the present invention are useful for chromosome identification. There exists an ongoing need to identify new chromosome markers, since few chromosome marking reagents, based on actual sequence data (repeat polymorphisms), are presently available. Each sequence is specifically targeted to and can hybridize with a particular location on an individual human chromosome, thus each polynucleotide of the present invention can routinely be used as a chromosome marker using techniques known in the art. Table 1A, column 8 provides the chromosome location of some of the polynucleotides of the invention.  
       [0367] Briefly, sequences can be mapped to chromosomes by preparing PCR primers (preferably at least 15 bp (e.g., 15-25 bp) from the sequences shown in SEQ ID NO: X. Primers can optionally be selected using computer analysis so that primers do not span more than one predicted exon in the genomic DNA. These primers are then used for PCR screening of somatic cell hybrids containing individual human chromosomes. Only those hybrids containing the human gene corresponding to SEQ ID NO: X will yield an amplified fragment.  
       [0368] Similarly, somatic hybrids provide a rapid method of PCR mapping the polynucleotides to particular chromosomes. Three or more clones can be assigned per day using a single thermal cycler. Moreover, sublocalization of the polynucleotides can be achieved with panels of specific chromosome fragments. Other gene mapping strategies that can be used include in situ hybridization, prescreening with labeled flow-sorted chromosomes, preselection by hybridization to construct chromosome specific-cDNA libraries, and computer mapping techniques (See, e.g., Shuler, Trends Biotechnol 16:456-459 (1998) which is hereby incorporated by reference in its entirety).  
       [0369] Precise chromosomal location of the polynucleotides can also be achieved using fluorescence in situ hybridization (FISH) of a metaphase chromosomal spread. This technique uses polynucleotides as short as 500 or 600 bases; however, polynucleotides 2,000-4,000 bp are preferred. For a review of this technique, see Verma et al., “Human Chromosomes: a Manual of Basic Techniques,” Pergamon Press, New York (1988).  
       [0370] For chromosome mapping, the polynucleotides can be used individually (to mark a single chromosome or a single site on that chromosome) or in panels (for marking multiple sites and/or multiple chromosomes).  
       [0371] Thus, the present invention also provides a method for chromosomal localization which involves (a) preparing PCR primers from the polynucleotide sequences in Table 1A and/or Table 2 and SEQ ID NO: X and (b) screening somatic cell hybrids containing individual chromosomes.  
       [0372] The polynucleotides of the present invention would likewise be useful for radiation hybrid mapping, HAPPY mapping, and long range restriction mapping. For a review of these techniques and others known in the art, see, e.g. Dear, “Genome Mapping: A Practical Approach,” IRL Press at Oxford University Press, London (1997); Aydin, J. Mol. Med. 77:691-694 (1999); Hacia et al., Mol. Psychiatry 3:483-492 (1998); Herrick et al., Chromosome Res. 7:409-423 (1999); Hamilton et al., Methods Cell Biol. 62:265-280 (2000); and/or Ott, J. Hered. 90:68-70 (1999), each of which is hereby incorporated by reference in its entirety.  
       [0373] Once a polynucleotide has been mapped to a precise chromosomal location, the physical position of the polynucleotide can be used in linkage analysis. Linkage analysis establishes coinheritance between a chromosomal location and presentation of a particular disease. (Disease mapping data are found, for example, in V. McKusick, Mendelian Inheritance in Man (available on line through Johns Hopkins University Welch Medical Library).) Column 9 of Table 1A provides an OMIM reference identification number of diseases associated with the cytologic band disclosed in column 8 of Table 1A, as determined using techniques described herein and by reference to Table 5. Assuming 1 megabase mapping resolution and one gene per 20 kb, a cDNA precisely localized to a chromosomal region associated with the disease could be one of 50-500 potential causative genes.  
       [0374] Thus, once coinheritance is established, differences in a polynucleotide of the invention and the corresponding gene between affected and unaffected individuals can be examined. First, visible structural alterations in the chromosomes, such as deletions or translocations, are examined in chromosome spreads or by PCR. If no structural alterations exist, the presence of point mutations are ascertained. Mutations observed in some or all affected individuals, but not in normal individuals, indicates that the mutation may cause the disease. However, complete sequencing of the polypeptide and the corresponding gene from several normal individuals is required to distinguish the mutation from a polymorphism. If a new polymorphism is identified, this polymorphic polypeptide can be used for further linkage analysis.  
       [0375] Furthermore, increased or decreased expression of the gene in affected individuals as compared to unaffected individuals can be assessed using the polynucleotides- of the invention. Any of these alterations (altered expression, chromosomal rearrangement, or mutation) can be used as a diagnostic or prognostic marker. Diagnostic and prognostic methods, kits and reagents encompassed by the present invention are briefly described below and more thoroughly elsewhere herein (see e.g., the sections labeled “Antibodies”, “Diagnostic Assays”, and “Methods for Detecting Excretory System Disease, Including Cancer”).  
       [0376] Thus, the invention also provides a diagnostic method useful during diagnosis of a disorder, involving measuring the expression level of polynucleotides of the present invention in cells or body fluid from an individual and comparing the measured gene expression level with a standard level of polynucleotide expression level, whereby an increase or decrease in the gene expression level compared to the standard is indicative of a disorder. Additional non-limiting examples of diagnostic methods encompassed by the present invention are more thoroughly described elsewhere herein (see, e.g., Example 12).  
       [0377] In still another embodiment, the invention includes a kit for analyzing samples for the presence of proliferative and/or cancerous polynucleotides derived from a test subject, as further described herein. In a general embodiment, the kit includes at least one polynucleotide probe containing a nucleotide sequence that will specifically hybridize with a polynucleotide of the invention and a suitable container. In a specific embodiment, the kit includes two polynucleotide probes defining an internal region of the polynucleotide of the invention, where each probe has one strand containing a 31′mer-end internal to the region. In a further embodiment, the probes may be useful as primers for polymerase chain reaction amplification.  
       [0378] Where a diagnosis of a related disorder, including, for example, diagnosis of a tumor, has already been made according to conventional methods, the present invention is useful as a prognostic indicator, whereby patients exhibiting enhanced or depressed polynucleotide of the invention expression will experience a worse clinical outcome relative to patients expressing the gene at a level nearer the standard level.  
       [0379] By “measuring the expression level of polynucleotides of the invention” is intended qualitatively or quantitatively measuring or estimating the level of the polypeptide of the invention or the level of the mRNA encoding the polypeptide of the invention in a first biological sample either directly (e.g., by determining or estimating absolute protein level or mRNA level) or relatively (e.g., by comparing to the polypeptide level or mRNA level in a second biological sample). Preferably, the polypeptide level or mRNA level in the first biological sample is measured or estimated and compared to a standard polypeptide level or mRNA level, the standard being taken from a second biological sample obtained from an individual not having the related disorder or being determined by averaging levels from a population of individuals not having a related disorder. As will be appreciated in the art, once a standard polypeptide level or mRNA level is known, it can be used repeatedly as a standard for comparison.  
       [0380] By “biological sample” is intended any biological sample obtained from an individual, body fluid, cell line, tissue culture, or other source which contains polypeptide of the present invention or the corresponding mRNA. As indicated, biological samples include body fluids (such as semen, lymph, vaginal pool, sera, plasma, urine, synovial fluid and spinal fluid) which contain the polypeptide of the present invention, and tissue sources found to express the polypeptide of the present invention. Methods for obtaining tissue biopsies and body fluids from mammals are well known in the art. Where the biological sample is to include mRNA, a tissue biopsy is the preferred source.  
       [0381] The method(s) provided above may preferably be applied in a diagnostic method and/or kits in which polynucleotides and/or polypeptides of the invention are attached to a solid support. In one exemplary method, the support may be a “gene chip” or a “biological chip” as described in U.S. Pat. Nos. 5,837,832, 5,874,219, and 5,856,174. Further, such a gene chip with polynucleotides of the invention attached may be used to identify polymorphisms between the isolated polynucleotide sequences of the invention, with polynucleotides isolated from a test subject. The knowledge of such polymorphisms (i.e., their location, as well as, their existence) would be beneficial in identifying disease loci for many disorders, such as for example, in neural disorders, immune system disorders, muscular disorders, reproductive disorders, gastrointestinal disorders, pulmonary disorders, digestive disorders, cardiovascular disorders, renal disorders, proliferative disorders, and/or cancerous diseases and conditions. Such a method is described in U.S. Pat. Nos. 5,858,659 and 5,856,104. The U.S. Patents referenced supra are hereby incorporated by reference in their entirety herein.  
       [0382] The present invention encompasses polynucleotides of the present invention that are chemically synthesized, or reproduced as peptide nucleic acids (PNA), or according to other methods known in the art. The use of PNAs would serve as the preferred form if the polynucleotides of the invention are incorporated onto a solid support, or gene chip. For the purposes of the present invention, a peptide nucleic acid (PNA) is a polyamide type of DNA analog and the monomeric units for adenine, guanine, thymine and cytosine are available commercially (Perceptive Biosystems). Certain components of DNA, such as phosphorus, phosphorus oxides, or deoxyribose derivatives, are not present in PNAs. As disclosed by Nielsen et al., Science 254:1497 (1991); and Egholm et al., Nature 365:666 (1993), PNAs bind specifically and tightly to complementary DNA strands and are not degraded by nucleases. In fact, PNA binds more strongly to DNA than DNA itself does. This is probably because there is no electrostatic repulsion between the two strands, and also the polyamide backbone is more flexible. Because of this, PNA/DNA duplexes bind under a wider range of stringency conditions than DNA/DNA duplexes, making it easier to perform multiplex hybridization. Smaller probes can be used than with DNA due to the strong binding. In addition, it is more likely that single base mismatches can be determined with PNA/DNA hybridization because a single mismatch in a PNA/DNA 15-mer lowers the melting point (T.sub.m) by 8°−20° C., vs. 4°-16° C. for the DNA/DNA 15-mer duplex. Also, the absence of charge groups in PNA means that hybridization can be done at low ionic strengths and reduce possible interference by salt during the analysis.  
       [0383] The compounds of the present invention have uses, which include, but are not limited to, detecting cancer in mammals. In particular the invention is useful during diagnosis of pathological cell proliferative neoplasias which include, but are not limited to: acute myelogenous leukemias including acute monocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute erythroleukemia, acute megakaryocytic leukemia, and acute undifferentiated leukemia, etc.; and chronic myelogenous leukemias including chronic myelomonocytic leukemia, chronic granulocytic leukemia, etc. Preferred mammals include monkeys, apes, cats, dogs, cows, pigs, horses, rabbits and humans. Particularly preferred are humans.  
       [0384] The compounds of the present invention have preferred uses, which include, but are not limited to, detecting excretory system cancer in mammals. In particular the invention is useful during diagnosis of pathological cell proliferative neoplasias which include, but are not limited to: nephroblastoma, renal cell cancer hypernephroma, transitional cell cancer, squamous cell cancer, Wilm&#39;s tumor, superficial bladder cancer, invasive bladder cancer, carcinoma of the ureter, and urethra cancer. Preferred mammals include monkeys, apes, cats, dogs, cows, pigs, horses, rabbits and humans. Particularly preferred are humans.  
       [0385] Pathological cell proliferative disorders are often associated with inappropriate activation of proto-oncogenes. (Gelmann, E. P. et al., “The Etiology of Acute Leukemia: Molecular Genetics and Viral Oncology,” in Neoplastic Diseases of the Blood, Vol 1., Wiemik, P. H. et al. eds., 161-182 (1985)). Neoplasias are now believed to result from the qualitative alteration of a normal cellular gene product, or from the quantitative modification of gene expression by insertion into the chromosome of a viral sequence, by chromosomal translocation of a gene to a more actively transcribed region, or by some other mechanism. (Gelmann et al., supra) It is likely that mutated or altered expression of specific genes is involved in the pathogenesis of some leukemias, among other tissues and cell types. (Gelmann et al., supra) Indeed, the human counterparts of the oncogenes involved in some animal neoplasias have been amplified or translocated in some cases of human leukemia and carcinoma. (Gelmann et al., stipra)  
       [0386] For example, c-myc expression is highly amplified in the non-lymphocytic leukemia cell line HL-60. When HL-60 cells are chemically induced to stop proliferation, the level of c-myc is found to be downregulated. (International Publication Number WO 91/15580). However, it has been shown that exposure of HL-60 cells to a DNA construct that is complementary to the 5′ end of c-myc or c-myb blocks translation of the corresponding mRNAs which downregulates expression of the c-myc or c-myb proteins and causes arrest of cell proliferation and differentiation of the treated cells. (International Publication Number WO 91/15580; Wickstrom et al., Proc. Natl. Acad. Sci. 85:1028 (1988); Anfossi et al., Proc. Natl. Acad. Sci. 86:3379 (1989)). However, the skilled artisan would appreciate the present invention&#39;s usefulness is not be limited to treatment, prevention, diagnosis and/or prognosis, of proliferative disorders of cells and tissues of hematopoietic origin, in light of the numerous cells and cell types of varying origins which are known to exhibit proliferative phenotypes. In preferred embodiments, the compounds and/or methods of the invention are used to treat, prevent, diagnose, and/or prognose, proliferative disorders of excretory system cells and tissues.  
       [0387] In addition to the foregoing, a polynucleotide of the present invention can be used to control gene expression through triple helix formation or through antisense DNA or RNA. Antisense techniques are discussed, for example, in Okano, J. Neurochem. 56: 560 (1991); “Oligodeoxynucleotides as Antisense Inhibitors of Gene Expression, CRC Press, Boca Raton, Fla. (1988). Triple helix formation is discussed in, for instance Lee et al., Nucleic Acids Research 6: 3073 (1979); Cooney et al., Science 241:456 (1988); and Dervan et al., Science 251: 1360 (1991). Both methods rely on binding of the polynucleotide to a complementary DNA or RNA. For these techniques, preferred polynucleotides are usually oligonucleotides 20 to 40 bases in length and complementary to either the region of the gene involved in transcription (triple helix—see Lee et al., Nucd. Acids Res. 6:3073 (1979); Cooney et al., Science 241:456 (1988); and Dervan et al., Science 251:1360 (1991)) or to the mRNA itself (antisense—Okano, J. Neurochem. 56:560 (1991); Oligodeoxy-nucleotides as Antisense Inhibitors of Gene Expression, CRC Press, Boca Raton, Fla. (1988).) Triple helix formation optimally results in a shut-off of RNA transcription from DNA, while antisense RNA hybridization blocks translation of an mRNA molecule into polypeptide. The oligonucleotide described above can also be delivered to cells such that the antisense RNA or DNA may be expressed in vivo to inhibit production of polypeptide of the present invention antigens. Both techniques are effective in model systems, and the information disclosed herein can be used to design antisense or triple helix polynucleotides in an effort to treat disease, and in particular, for the treatment of proliferative diseases and/or conditions. Non-limiting antisense and triple helix methods encompassed by the present invention are more thoroughly described elsewhere herein (see, e.g., the section labeled “Antisense and Ribozyme (Antagonists)”).  
       [0388] Polynucleotides of the present invention are also useful in gene therapy. One goal of gene therapy is to insert a normal gene into an organism having a defective gene, in an effort to correct the genetic defect. The polynucleotides disclosed in the present invention offer a means of targeting such genetic defects in a highly accurate manner. Another goal is to insert a new gene that was not present in the host genome, thereby producing a new trait in the host cell. Additional non-limiting examples of gene therapy methods encompassed by the present invention are more thoroughly described elsewhere herein (see, e.g., the sections labeled “Gene Therapy Methods” and Examples 16, 17 and 18).  
       [0389] The polynucleotides are also useful for identifying individuals from minute biological samples. The United States military, for example, is considering the use of restriction fragment length polymorphism (RFLP) for identification of its personnel. In this technique, an individual&#39;s genomic DNA is digested with one or more restriction enzymes, and probed on a Southern blot to yield unique bands for identifying personnel. This method does not suffer from the current limitations of “Dog Tags” which can be lost, switched, or stolen, making positive identification difficult. The polynucleotides of the present invention can be used as additional DNA markers for RFLP.  
       [0390] The polynucleotides of the present invention can also be used as an alternative to RFLP, by determining the actual base-by-base DNA sequence of selected portions of an individual&#39;s genome. These sequences can be used to prepare PCR primers for amplifying and isolating such selected DNA, which can then be sequenced. Using this technique, individuals can be identified because each individual will have a unique set of DNA sequences. Once an unique ID database is established for an individual, positive identification of that individual, living or dead, can be made from extremely small tissue samples.  
       [0391] Forensic biology also benefits from using DNA-based identification techniques as disclosed herein. DNA sequences taken from very small biological samples such as tissues, e.g., hair or skin, or body fluids, e.g., blood, saliva, semen, synovial fluid, amniotic fluid, breast milk, lymph, pulmonary sputum or surfactant, urine, fecal matter, etc., can be amplified using PCR. In one prior art technique, gene sequences amplified from polymorphic loci, such as DQa class II HLA gene, are used in forensic biology to identify individuals. (Erlich, H., PCR Technology, Freeman and Co. (1992).) Once these specific polymorphic loci are amplified, they are digested with one or more restriction enzymes, yielding an identifying set of bands on a Southern blot probed with DNA corresponding to the DQa class II HLA gene. Similarly, polynucleotides of the present invention can be used as polymorphic markers for forensic purposes.  
       [0392] There is also a need for reagents capable of identifying the source of a particular tissue. Such need arises, for example, in forensics when presented with tissue of unknown origin. Appropriate reagents can comprise, for example, DNA probes or primers prepared from the sequences of the present invention, specific to tissues, including but not limited to, those sequences referred to in Table 1A. Panels of such reagents can identify tissue by species and/or by organ type. In a similar fashion, these reagents can be used to screen tissue cultures for contamination. Additional non-limiting examples of such uses are further described herein.  
       [0393] Because excretory system antigens are found expressed in excretory system, the polynucleotides of the present invention are also useful as hybridization probes for differential identification of the tissue(s) or cell type(s) present in a biological sample. Similarly, polypeptides and antibodies directed to polypeptides of the present invention are useful to provide immunological probes for differential identification of the tissue(s) (e.g., immunohistochemistry assays) or cell type(s) (e.g., immunocytochemistry assays). In a specific embodiment, the polynucleotides of the present invention are also useful as hybridization probes for differential identification of excretory system tissue(s) or cell type(s) present in a biological sample. Similarly, polypeptides and antibodies directed to polypeptides of the present invention are useful to provide immunological probes for differential identification of excretory system tissue(s) (e.g., immunohistochemistry assays) or cell type(s) (e.g., immunocytochemistry assays). In addition, for a number of disorders of the above tissues or cells, significantly higher or lower levels of gene expression of the polynucleotides/polypeptides of the present invention may be detected in certain tissues (e.g., tissues expressing polypeptides and/or polynucleotides of the present invention, for example, normal excretory system or diseased excretory system tissues, and/or those tissues/cells corresponding to the library source relating to a polynucleotide sequence of the invention as disclosed in column 7 of Table 1A, and/or cancerous and/or wounded tissues) or bodily fluids (e.g., semen, lymph, vaginal pool, serum, plasma, urine, synovial fluid or spinal fluid) taken from an individual having such a disorder, relative to a “standard” gene expression level, i.e., the expression level in healthy tissue from an individual not having the disorder.  
       [0394] Thus, the invention provides a diagnostic method of a disorder, which involves: (a) assaying gene expression level in cells or body fluid of an individual; (b) comparing the gene expression level with a standard gene expression level, whereby an increase or decrease in the assayed gene expression level compared to the standard expression level is indicative of a disorder.  
       [0395] In the very least, the polynucleotides of the present invention can be used as molecular weight markers on Southern gels, as diagnostic probes for the presence of a specific mRNA in a particular cell type, as a probe to “subtract-out” known sequences in the process of discovering novel polynucleotides, for selecting and making oligomers for attachment to a “gene chip” or other support, to raise anti-DNA antibodies using DNA immunization techniques, and as an antigen to elicit an immune response.  
       [0396] Uses of the Polypeptides  
       [0397] Each of the polypeptides identified herein can be used in numerous ways. The following description should be considered exemplary and utilizes known techniques.  
       [0398] Polypeptides and antibodies directed to polypeptides of the present invention are useful to provide immunological probes for differential identification of the tissue(s) (e.g., immunohistochemistry assays such as, for example, ABC immunoperoxidase (Hsu et al., J. Histochem. Cytochem. 29:577-580 (1981)) or cell type(s) (e.g., immunocytochemistry assays).  
       [0399] Antibodies can be used to assay levels of polypeptides encoded by polynucleotides of the invention in a biological sample using classical immunohistological methods known to those of skill in the art (see, e.g., Jalkanen, et al., J. Cell. Biol. 101:976-985 (1985); Jalkanen, et al., J. Cell. Biol. 105:3087-3096 (1987)). Other antibody-based methods useful for detecting protein gene expression include immunoassays, such as the enzyme linked immunosorbent assay (ELISA) and the radioimmunoassay (RIA). Suitable antibody assay labels are known in the art and include enzyme labels, such as, glucose oxidase; radioisotopes, such as iodine ( 131 I,  125 I,  123 I,  121 I), carbon ( 14 C), sulfur ( 35 S), tritium ( 3 H), indium ( 115m In,  113m In,  112 In,  111 In), and technetium ( 99 Tc,  99m Tc), thallium ( 201 Ti), gallium ( 68 Ga,  67 Ga), palladium ( 103  Pd), molybdenum ( 99 Mo), xenon ( 133 Xe), fluorine ( 18 F),  153 Sm,  177 Lu,  159 Gd,  149 Pm,  140 La,  175 Yb,  166 Ho,  90 Y,  47 Sc,  186 Re,  188 Re,  142 Pr,  105 Rh,  97 Ru; luminescent labels, such as luminol; and fluorescent labels, such as fluorescein and rhodamine, and biotin.  
       [0400] In addition to assaying levels of polypeptide of the present invention in a biological sample, proteins can also be detected in vivo by imaging. Antibody labels or markers for in vivo imaging of protein include those detectable by X-radiography, NMR or ESR. For X-radiography, suitable labels include radioisotopes such as barium or cesium, which emit detectable radiation but are not overtly harmful to the subject. Suitable markers for NMR and ESR include those with a detectable characteristic spin, such as deuterium, which may be incorporated into the antibody by labeling of nutrients for the relevant hybridoma.  
       [0401] An excretory system antigen-specific antibody or antibody fragment which has been labeled with an appropriate detectable imaging moiety, such as a radioisotope (for example,  131 I,  112 In  99m Tc, ( 131 I,  125 I,  123 I,  121 I), carbon ( 14 C), sulfur ( 35 S), tritium ( 3 H), indium ( 115m In,  113m In,  112 In,  111 In), and technetium ( 99 Tc,  99m Tc), thallium ( 201 Ti), gallium ( 68 Ga,  67 Ga), palladium ( 103 Pd), molybdenum ( 99 Mo), xenon ( 133 Xe), fluorine ( 18 F,  153 Sm,  177 Lu,  159 Gd,  149 Pm,  140 La,  175 Yb,  166 Ho,  90 Y,  47 Sc,  186 Re,  188 Re,  142 Pr,  105 Rh,  97 Ru), a radio-opaque substance, or a material detectable by nuclear magnetic resonance, is introduced (for example, parenterally, subcutaneously or intraperitoneally) into the mammal to be examined for an excretory system disorder. It will be understood in the art that the size of the subject and the imaging system used will determine the quantity of imaging moiety needed to produce diagnostic images. In the case of a radioisotope moiety, for a human subject, the quantity of radioactivity injected will normally range from about 5 to 20 millicuries of  99m Tc. The labeled antibody or antibody fragment will then preferentially accumulate at the location of cells which express the polypeptide encoded by a polynucleotide of the invention. In vivo tumor imaging is described in S. W. Burchiel et al., “Immunopharmacokinetics of Radiolabeled Antibodies and Their Fragments” (Chapter 13 in  Tumor Imaging: The Radiochemical Detection of Cancer,  S. W. Burchiel and B. A. Rhodes, eds., Masson Publishing Inc. (1982)).  
       [0402] In one embodiment, the invention provides a method for the specific delivery of compositions of the invention to cells by administering polypeptides of the invention (e.g., polypeptides encoded by polynucleotides of the invention and/or antibodies) that are associated with heterologous polypeptides or nucleic acids. In one example, the invention provides a method for delivering a therapeutic protein into the targeted cell. In another example, the invention provides a method for delivering a single stranded nucleic acid (e.g., antisense or ribozymes) or double stranded nucleic acid (e.g., DNA that can integrate into the cell&#39;s genome or replicate episomally and that can be transcribed) into the targeted cell.  
       [0403] In another embodiment, the invention provides a method for the specific destruction of cells (e.g., the destruction of tumor cells) by administering polypeptides of the invention in association with toxins or cytotoxic prodrugs.  
       [0404] In a preferred embodiment, the invention provides a method for the specific destruction of excretory system cells (e.g., aberrant excretory system cells, excretory system neoplasm) by administering polypeptides of the invention (e.g., polypeptides encoded by polynucleotides of the invention and/or antibodies) in association with toxins or cytotoxic prodrugs. In another preferred embodiment the invention provides a method for the specific destruction of tissues/cells corresponding to the library source relating to a polynucleotide sequence of the invention as disclosed in column 7 of Table 1A by administering polypeptides of the invention in association with toxins or cytotoxic prodrugs.  
       [0405] By “toxin” is meant one or more compounds that bind and activate endogenous cytotoxic effector systems, radioisotopes, holotoxins, modified toxins, catalytic subunits of toxins, or any molecules or enzymes not normally present in or on the surface of a cell that under defined conditions cause the cell&#39;s death. Toxins that may be used according to the methods of the invention include, but are not limited to, radioisotopes known in the art, compounds such as, for example, antibodies (or complement fixing containing portions thereof) that bind an inherent or induced endogenous cytotoxic effector system, thymidine kinase, endonuclease, RNAse, alpha toxin, ricin, abrin, Pseudomonas exotoxin A, diphtheria toxin, saporin, momordin, gelonin, pokeweed antiviral protein, alpha-sarcin and cholera toxin. “Toxin” also includes a cytostatic or cytocidal agent, a therapeutic agent or a radioactive metal ion, e.g., alpha-emitters such as, for example,  213 Bi, or other radioisotopes such as, for example,  103 Pd,  133 Xe,  131 I,  111 In,  68 Ge,  57 Co,  65 Zn,  85 Sr,  32 P,  35 S,  90 Y,  153 Sm,  153 Gd,  169 Yb,  51 Cr,  54 Mn,  75 Se,  113 Sn,  90 Yttrium,  117 Tin,  186 Rhenium,  166 Holmium, and  188 Rhenium; luminescent labels, such as luminol; and fluorescent labels, such as fluorescein and rhodamine, and biotin.  
       [0406] In a specific embodiment, the invention provides a method for the specific destruction of cells (e.g., the destruction of tumor cells) by administering polypeptides of the invention or antibodies of the invention in association with the radioisotope  90 Y. In another specific embodiment, the invention provides a method for the specific destruction of cells (e.g., the destruction of tumor cells) by administering polypeptides of the invention or antibodies of the invention in association with the radioisotope  111 In. In a further specific embodiment, the invention provides a method for the specific destruction of cells (e.g., the destruction of tumor cells) by administering polypeptides of the invention or antibodies of the invention in association with the radioisotope  131 I.  
       [0407] Techniques known in the art may be applied to label polypeptides of the invention (including antibodies). Such techniques include, but are not limited to, the use of bifunctional conjugating agents (see e.g., U.S. Pat. Nos. 5,756,065; 5,714,631; 5,696,239; 5,652,361; 5,505,931; 5,489,425; 5,435,990; 5,428,139; 5,342,604; 5,274,119; 4,994,560; and 5,808,003; the contents of each of which are hereby incorporated by reference in its entirety).  
       [0408] Thus, the invention provides a diagnostic method of a disorder, which involves (a) assaying the expression level of a polypeptide of the present invention in cells or body fluid of an individual; and (b) comparing the assayed polypeptide expression level with a standard polypeptide expression level, whereby an increase or decrease in the assayed polypeptide expression level compared to the standard expression level is indicative of a disorder. With respect to cancer, the presence of a relatively high amount of transcript in biopsied tissue from an individual may indicate a predisposition for the development of the disease, or may provide a means for detecting the disease prior to the appearance of actual clinical symptoms. A more definitive diagnosis of this type may allow health professionals to employ preventative measures or aggressive treatment earlier thereby preventing the development or further progression of the cancer.  
       [0409] Moreover, polypeptides of the present invention can be used to treat or prevent diseases or conditions of the excretory system such as, for example, renal disorders (e.g., kidney failure, nephritis, blood vessel disorders of kidney, metabolic and congenital kidney disorders, urinary disorders of the kidney, autoimmune disorders, sclerosis and necrosis, and electrolyte imbalance, and kidney cancer), bladder disorders (e.g, urinary tract infection, bladder obstruction, urination disorders, and bladder cancer), urether disorders (e.g., obstruction of the ureter and ureter cancer), urethra disorders (e.g., obstruction of the urethra and urethra cancers) and/or those disorders as discribed under “Urinary System Disorders” below. In preferred embodiments, polynucleotides expressed in a particular tissue type (see, e.g., Table 1A, column 7) are used to diagnose, detect, prevent, treat and/or prognose disorders associated with the tissue type. For example, patients can be administered a polypeptide of the present invention in an effort to replace absent or decreased levels of the polypeptide (e.g., insulin), to supplement absent or decreased levels of a different polypeptide (e.g., hemoglobin S for hemoglobin B, SOD, catalase, DNA repair proteins), to inhibit the activity of a polypeptide (e.g., an oncogene or tumor supressor), to activate the activity of a polypeptide (e.g., by binding to a receptor), to reduce the activity of a membrane bound receptor by competing with it for free ligand (e.g., soluble TNF receptors used in reducing inflammation), or to bring about a desired response (e.g., blood vessel growth inhibition, enhancement of the immune response to proliferative cells or tissues).  
       [0410] Similarly, antibodies directed to a polypeptide of the present invention can also be used to treat disease (as described supra, and elsewhere herein). For example, administration of an antibody directed to a polypeptide of the present invention can bind, and/or neutralize the polypeptide, and/or reduce overproduction of the polypeptide. Similarly, administration of an antibody can activate the polypeptide, such as by binding to a polypeptide bound to a membrane (receptor).  
       [0411] At the very least, the polypeptides of the present invention can be used as molecular weight markers on SDS-PAGE gels or on molecular sieve gel filtration columns using methods well known to those of skill in the art. Polypeptides can also be used to raise antibodies, which in turn are used to measure protein expression from a recombinant cell, as a way of assessing transformation of the host cell. Moreover, the polypeptides of the present invention can be used to test the biological activities described herein.  
       [0412] Diagnostic Asssays  
       [0413] The compounds of the present invention are useful for diagnosis, treatment, prevention and/or prognosis of various excretory system related disorders in mammals, preferably humans. Such disorders include, but are not limited to, renal disorders (e.g., kidney failure, nephritis, blood vessel disorders of kidney, metabolic and congenital kidney disorders, urinary disorders of the kidney, autoimmune disorders, sclerosis and necrosis, and electrolyte imbalance, and kidney cancer), bladder disorders (e.g, urinary tract infection, bladder obstruction, urination disorders, and bladder cancer), urether disorders (e.g., obstruction of the ureter and ureter cancer), urethra disorders (e.g., obstruction of the urethra and urethra cancers) and/or those disorders as discribed under “Urinary System Disorders” below. In preferred embodiments, polynucleotides expressed in a particular tissue type (see, e.g., Table 1A, column 7) are used to diagnose, detect, prevent, treat and/or prognose disorders associated with the tissue type.  
       [0414] Excretory system antigens are expressed in the excretory system, with an increased expression level in excretory system tissues. For a number of excretory system-related disorders, substantially altered (increased or decreased) levels of excretory system antigen gene expression can be detected in excretory system tissue or other cells or bodily fluids (e.g., sera, plasma, urine, semen, synovial fluid or spinal fluid) taken from an individual having such a disorder, relative to a “standard” excretory system antigen gene expression level, that is, the excretory system antigen expression level in excretory system tissues or bodily fluids from an individual not having the excretory system disorder. Thus, the invention provides a diagnostic method useful during diagnosis of an excretory system disorder, which involves measuring the expression level of the gene encoding the excretory system associated polypeptide in excretory system tissue or other cells or body fluid from an individual and comparing the measured gene expression level with a standard excretory system antigens gene expression level, whereby an increase or decrease in the gene expression level(s) compared to the standard is indicative of an excretory system disorder.  
       [0415] In specific embodiments, the invention provides a diagnostic method useful during diagnosis of a disorder of a normal or diseased tissue/cell source corresponding to column 7 of Table 1A, which involves measuring the expression level of the coding sequence of a polynucleotide sequence associated with this tissue/cell source as disclosed in Table 1A in the tissue/cell source or other cells or body fluid from an individual and comparing the expression level of the coding sequence with a standard expression level of the coding sequence of a polynucleotide sequence, whereby an increase or decrease in the gene expression level(s) compared to the standard is indicative of a disorder of a normal or diseased tissue/cell source corresponding to column 7 of Table 1A.  
       [0416] In particular, it is believed that certain tissues in mammals with cancer of cells or tissue of the excretory system express significantly enhanced or reduced levels of normal or altered excretory system antigen expression and mRNA encoding the excretory system associated polypeptide when compared to a corresponding “standard” level. Further, it is believed that enhanced or depressed levels of the excretory system associated polypeptide can be detected in certain body fluids (e.g., sera, plasma, urine, and spinal fluid) or cells or tissue from mammals with such a cancer when compared to sera from mammals of the same species not having the cancer.  
       [0417] For example, as disclosed herein, excretory system associated polypeptides of the invention are expressed in excretory system tissues. Accordingly, polynucleotides of the invention (e.g., polynucleotide sequences complementary to all or a portion of an excretory system antigen mRNA nucleotide sequence of SEQ ID NO: X, nucleotide sequence encoding SEQ ID NO: Y, nucleotide sequence encoding a polypeptide encoded by SEQ ID NO: X and/or a nucleotide sequence delineated by columns 8 and 9 of Table 2) and antibodies (and antibody fragments) directed against the polypeptides of the invention may be used to quantitate or qualitate concentrations of cells of the excretory system expressing excretory system antigens, preferrably on their cell surfaces. These polynucleotides and antibodies additionally have diagnostic applications in detecting abnormalities in the level of excretory system antigens gene expression, or abnormalities in the structure and/or temporal, tissue, cellular, or subcellular location of excretory system antigens. These diagnostic assays may be performed in vivo or in vitro, such as, for example, on blood samples, biopsy tissue or autopsy tissue. In specific embodiments, polynucleotides and antibodies of the invention are used to quantitate or qualitate tissues/cells corresponding to the library source disclosed in column 7 of Table 1A expressing the corresponding excretory system sequence disclosed in the same row of Table 1A, preferrably on their cell surface.  
       [0418] Thus, the invention provides a diagnostic method useful during diagnosis of an excretory system disorder, including cancers, which involves measuring the expression level of the gene encoding the excretory system antigen polypeptide in excretory system tissue or other cells or body fluid from an individual and comparing the measured gene expression level with a standard excretory system antigen gene expression level, whereby an increase or decrease in the gene expression level compared to the standard is indicative of an excretory system disorder. In specific embodiments, polynucleotides and antibodies of the invention are used to quantitate or qualitate tissues/cells corresponding to the library source disclosed in column 7 of Table 1A expressing the corresponding excretory system sequence disclosed in the same row of Table 1A, preferrably on their cell surface.  
       [0419] Where a diagnosis of a disorder in the excretory system, including diagnosis of a tumor, has already been made according to conventional methods, the present invention is useful as a prognostic indicator, whereby patients exhibiting enhanced or depressed excretory system antigen gene expression will experience a worse clinical outcome relative to patients expressing the gene at a level nearer the standard level.  
       [0420] By “assaying the expression level of the gene encoding the excretory system associated polypeptide” is intended qualitatively or quantitatively measuring or estimating the level of the excretory system antigen polypeptide or the level of the mRNA encoding the excretory system antigen polypeptide in a first biological sample either directly (e.g., by determining or estimating absolute protein level or mRNA level) or relatively (e.g., by comparing to the excretory system associated polypeptide level or mRNA level in a second biological sample). Preferably, the excretory system antigen polypeptide expression level or mRNA level in the first biological sample is measured or estimated and compared to a standard excretory system antigen polypeptide level or mRNA level, the standard being taken from a second biological sample obtained from an individual not having the disorder or being determined by averaging levels from a population of individuals not having a disorder of the excretory system. As will be appreciated in the art, once a standard excretory system antigen polypeptide level or mRNA level is known, it can be used repeatedly as a standard for comparison.  
       [0421] By “biological sample” is intended any biological sample obtained from an individual, cell line, tissue culture, or other source containing excretory system antigen polypeptides (including portions thereof) or mRNA. As indicated, biological samples include body fluids (such as sera, plasma, urine, synovial fluid and spinal fluid) which contain cells expressing excretory system antigen polypeptides, excretory system tissue, and other tissue sources found to express the full length or fragments thereof of an excretory system antigen. Methods for obtaining tissue biopsies and body fluids from mammals are well known in the art. Where the biological sample is to include mRNA, a tissue biopsy is the preferred source.  
       [0422] Total cellular RNA can be isolated from a biological sample using any suitable technique such as the single-step guanidinium-thiocyanate-phenol-chloroform method described in Chomczynski and Sacchi, Anal. Biochem. 162:156-159 (1987). Levels of mRNA encoding the excretory system antigen polypeptides are then assayed using any appropriate method. These include Northern blot analysis, SI nuclease mapping, the polymerase chain reaction (PCR), reverse transcription in combination with the polymerase chain reaction (RT-PCR), and reverse transcription in combination with the ligase chain reaction (RT-LCR).  
       [0423] The present invention also relates to diagnostic assays such as quantitative and diagnostic assays for detecting levels of excretory system antigen polypeptides, in a biological sample (e.g., cells and tissues), including determination of normal and abnormal levels of polypeptides. Thus, for instance, a diagnostic assay in accordance with the invention for detecting over-expression of excretory system antigens compared to normal control tissue samples may be used to detect the presence of tumors. Assay techniques that can be used to determine levels of a polypeptide, such as an excretory system antigen polypeptide of the present invention in a sample derived from a host are well-known to those of skill in the art. Such assay methods include radioimmunoassays, competitive-binding assays, Western Blot analysis and ELISA assays. Assaying excretory system antigen polypeptide levels in a biological sample can occur using any art-known method.  
       [0424] Assaying excretory system antigen polypeptide levels in a biological sample can occur using antibody-based techniques. For example, excretory system antigen polypeptide expression in tissues can be studied with classical immunohistological methods (Jalkanen et al., J. Cell. Biol. 101:976-985 (1985); Jalkanen, M., et al., J. Cell. Biol. 105:3087-3096 (1987)). Other antibody-based methods useful for detecting excretory system antigen polypeptide gene expression include immunoassays, such as the enzyme linked immunosorbent assay (ELISA) and the radioimmunoassay (RIA). Suitable antibody assay labels are known in the art and include enzyme labels, such as, glucose oxidase, and radioisotopes, such as iodine ( 125 I,  121 I), carbon ( 14 C), sulfur ( 35 S), tritium ( 3 H), indium ( 112  In), and technetium ( 99m Tc), and fluorescent labels, such as fluorescein and rhodamine, and biotin.  
       [0425] The tissue or cell type to be analyzed will generally include those, which are known, or suspected, to express the excretory system antigen gene (such as, for example, cells of the excretory system or cancer or excretory system tissues). The protein isolation methods employed herein may, for example, be such as those described in Harlow and Lane (Harlow, E. and Lane, D., 1988, “Antibodies: A Laboratory Manual”, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.), which is incorporated herein by reference in its entirety. The isolated cells can be derived from cell culture or from a patient. The analysis of cells taken from culture may be a necessary step in the assessment of cells that could be used as part of a cell-based gene therapy technique or, alternatively, to test the effect of compounds on the expression of the excretory system antigen gene.  
       [0426] For example, antibodies, or fragments of antibodies, such as those described herein, may be used to quantitatively or qualitatively detect the presence of excretory system antigen gene products or conserved variants or peptide fragments thereof. This can be accomplished, for example, by immunofluorescence techniques employing a fluorescently labeled antibody coupled with light microscopic, flow cytometric, or fluorimetric detection.  
       [0427] In a preferred embodiment, antibodies, or fragments of antibodies directed to any one or all of the predicted epitope domains of the excretory system antigen polypeptides (Shown in Table 1A, column 6) may be used to quantitatively or qualitatively detect the presence of excretory system antigen gene products or conserved variants or peptide fragments thereof. This can be accomplished, for example, by immunofluorescence techniques employing a fluorescently labeled antibody coupled with light microscopic, flow cytometric, or fluorimetric detection.  
       [0428] In an additional preferred embodiment, antibodies, or fragments of antibodies directed to a conformational epitope of an excretory system antigen may be used to quantitatively or qualitatively detect the presence of excretory system antigen gene products or conserved variants or peptide fragments thereof. This can be accomplished, for example, by immunofluorescence techniques employing a fluorescently labeled antibody coupled with light microscopic, flow cytometric, or fluorimetric detection.  
       [0429] The antibodies (or fragments thereof), and/or excretory system antigen polypeptides of the present invention may, additionally, be employed histologically, as in immunofluorescence, immunoelectron microscopy or non-immunological assays, for in situ detection of excretory system antigen gene products or conserved variants or peptide fragments thereof. In situ detection may be accomplished by removing a histological specimen from a patient, and applying thereto a labeled antibody or excretory system antigen polypeptide of the present invention. The antibody (or fragment thereof) or excretory system antigen polypeptide is preferably applied by overlaying the labeled antibody (or fragment) onto a biological sample. Through the use of such a procedure, it is possible to determine not only the presence of the excretory system antigen gene product, or conserved variants or peptide fragments, or excretory system antigen polypeptide binding, but also its distribution in the examined tissue. Using the present invention, those of ordinary skill will readily perceive that any of a wide variety of histological methods (such as staining procedures) can be modified in order to achieve such in situ detection.  
       [0430] Immunoassays and non-immunoassays for excretory system antigen gene products or conserved variants or peptide fragments thereof will typically comprise incubating a sample, such as a biological fluid, a tissue extract, freshly harvested cells, or lysates of cells which have been incubated in cell culture, in the presence of a detectably labeled antibody capable of binding excretory system antigen gene products or conserved variants or peptide fragments thereof, and detecting the bound antibody by any of a number of techniques well-known in the art.  
       [0431] The biological sample may be brought in contact with and immobilized onto a solid phase support or carrier such as nitrocellulose, or other solid support which is capable of immobilizing cells, cell particles or soluble proteins. The support may then be washed with suitable buffers followed by treatment with the detectably labeled anti-excretory system antigen antibody or detectable excretory system antigen polypeptide. The solid phase support may then be washed with the buffer a second time to remove unbound antibody or polypeptide. Optionally the antibody is subsequently labeled. The amount of bound label on solid support may then be detected by conventional means.  
       [0432] By “solid phase support or carrier” is intended any support capable of binding an antigen or an antibody. Well-known supports or carriers include glass, polystyrene, polypropylene, polyethylene, dextran, nylon, amylases, natural and modified celluloses, polyacrylamides, gabbros, and magnetite. The nature of the carrier can be either soluble to some extent or insoluble for the purposes of the present invention. The support material may have virtually any possible structural configuration so long as the coupled molecule is capable of binding to an antigen or antibody. Thus, the support configuration may be spherical, as in a bead, or cylindrical, as in the inside surface of a test tube, or the external surface of a rod. Alternatively, the surface may be flat such as a sheet, test strip, etc. Preferred supports include polystyrene beads. Those skilled in the art will know many other suitable carriers for binding antibody or antigen, or will be able to ascertain the same by use of routine experimentation.  
       [0433] The binding activity of a given lot of anti-excretory system antigen antibody or excretory system antigen polypeptide may be determined according to well known methods. Those skilled in the art will be able to determine operative and optimal assay conditions for each determination by employing routine experimentation.  
       [0434] In addition to assaying excretory system antigen polypeptide levels or polynucleotide levels in a biological sample obtained from an individual, excretory system antigen polypeptide or polynucleotide can also be detected in vivo by imaging. For example, in one embodiment of the invention, excretory system antigen polypeptide and/or anti-excretory system antigen antibodies are used to image excretory system diseased cells, such as neoplasms. In another embodiment, excretory system antigen polynucleotides of the invention (e.g., polynucleotides complementary to all or a portion of excretory system antigen mRNA) and/or anti-excretory system antigen antibodies (e.g., antibodies directed to any one or a combination of the epitopes of excretory system antigens, antibodies directed to a conformational epitope of excretory system antigens, antibodies directed to the full length polypeptide expressed on the cell surface of a mammalian cell) are used to image diseased or neoplastic cells of the excretory system.  
       [0435] Antibody labels or markers for in vivo imaging of excretory system antigen polypeptides include those detectable by X-radiography, NMR, MRI, CAT-scans or ESR. For X-radiography, suitable labels include radioisotopes such as barium or cesium, which emit detectable radiation but are not overtly harmful to the subject. Suitable markers for NMR and ESR include those with a detectable characteristic spin, such as deuterium, which may be incorporated into the antibody by labeling of nutrients for the relevant hybridoma. Where in vivo imaging is used to detect enhanced levels of excretory system antigen polypeptides for diagnosis in humans, it may be preferable to use human antibodies or “humanized” chimeric monoclonal antibodies. Such antibodies can be produced using techniques described herein or otherwise known in the art. For example methods for producing chimeric antibodies are known in the art. See, for review, Morrison,  Science  229:1202 (1985); Oi et al.,  BioTechniques  4:214 (1986); Cabilly et al., U.S. Pat. No. 4,816,567; Taniguchi et al., EP 171496; Morrison et al., EP 173494; Neuberger et al., WO 8601533; Robinson et al., WO 8702671; Boulianne et al.,  Nature  312:643 (1984); Neuberger et al.,  Nature  314:268 (1985).  
       [0436] Additionally, any excretory system antigen polypeptides whose presence can be detected, can be administered. For example, excretory system antigen polypeptides labeled with a radio-opaque or other appropriate compound can be administered and visualized in vivo, as discussed, above for labeled antibodies. Further such excretory system antigen polypeptides can be utilized for in vitro diagnostic procedures.  
       [0437] An excretory system antigen polypeptide-specific antibody or antibody fragment which has been labeled with an appropriate detectable imaging moiety, such as a radioisotope (for example,  131 I,  112 In,  99m Tc), a radio-opaque substance, or a material detectable by nuclear magnetic resonance, is introduced (for example, parenterally, subcutaneously or intraperitoneally) into the mammal to be examined for an excretory system disorder. It will be understood in the art that the size of the subject and the imaging system used will determine the quantity of imaging moiety needed to produce diagnostic images. In the case of a radioisotope moiety, for a human subject, the quantity of radioactivity injected will normally range from about 5 to 20 millicuries of  99m Tc. The labeled antibody or antibody fragment will then preferentially accumulate at the location of cells which contain excretory system antigen protein. In vivo tumor imaging is described in S. W. Burchiel et al., “Immunopharmacokinetics of Radiolabeled Antibodies and Their Fragments” (Chapter 13 in  Tumor Imaging: The Radiochemical Detection of Cancer,  S. W. Burchiel and B. A. Rhodes, eds., Masson Publishing Inc. (1982)).  
       [0438] With respect to antibodies, one of the ways in which the anti-excretory system antigen antibody can be detectably labeled is by linking the same to an enzyme and using the linked product in an enzyme immunoassay (EIA) (Voller, A., “The Enzyme Linked Immunosorbent Assay (ELISA)”, 1978, Diagnostic Horizons 2:1-7, Microbiological Associates Quarterly Publication, Walkersville, Md.); Voller et al.,  J. Clin. Pathol.  31:507-520 (1978); Butler, J. E.,  Meth. Enzymol.  73:482-523 (1981); Maggio, E. (ed.), 1980, Enzyme Immunoassay, CRC Press, Boca Raton, Fla.; Ishikawa, E. et al., (eds.), 1981, Enzyme Immunoassay, Kgaku Shoin, Tokyo). The enzyme which is bound to the antibody will react with an appropriate substrate, preferably a chromogenic substrate, in such a manner as to produce a chemical moiety which can be detected, for example, by spectrophotometric, fluorimetric or by visual means. Enzymes which can be used to detectably label the antibody include, but are not limited to, malate dehydrogenase, staphylococcal nuclease, delta-5-steroid isomerase, yeast alcohol dehydrogenase, alpha-glycerophosphate, dehydrogenase, triose phosphate isomerase, horseradish peroxidase, alkaline phosphatase, asparaginase, glucose oxidase, beta-galactosidase, ribonuclease, urease, catalase, glucose-6-phosphate dehydrogenase, glucoamylase and acetylcholinesterase. Additionally, the detection can be accomplished by colorimetric methods which employ a chromogenic substrate for the enzyme. Detection may also be accomplished by visual comparison of the extent of enzymatic reaction of a substrate in comparison with similarly prepared standards.  
       [0439] Detection may also be accomplished using any of a variety of other immunoassays. For example, by radioactively labeling the antibodies or antibody fragments, it is possible to detect excretory system antigens through the use of a radioimmunoassay (RIA) (see, for example, Weintraub, B., Principles of Radioimmunoassays, Seventh Training Course on Radioligand Assay Techniques, The Endocrine Society, March, 1986, which is incorporated by reference herein). The radioactive isotope can be detected by means including, but not limited to, a gamma counter, a scintillation counter, or autoradiography.  
       [0440] It is also possible to label the antibody with a fluorescent compound. When the fluorescently labeled antibody is exposed to light of the proper wavelength, its presence can then be detected due to fluorescence. Among the most commonly used fluorescent labeling compounds are fluorescein isothiocyanate, rhodamine, phycoerythrin, phycocyanin, allophycocyanin, ophthaldehyde and fluorescamine.  
       [0441] The antibody can also be detectably labeled using fluorescence emitting metals such as  152 Eu, or others of the lanthanide series. These metals can be attached to the antibody using such metal chelating groups as diethylenetriaminepentacetic acid (DTPA) or ethylenediaminetetraacetic acid (EDTA).  
       [0442] The antibody also can be detectably labeled by coupling it to a chemiluminescent compound. The presence of the chemiluminescent-tagged antibody is then determined by detecting the presence of luminescence that arises during the course of a chemical reaction. Examples of particularly useful chemiluminescent labeling compounds are luminol, isoluminol, theromatic acridinium ester, imidazole, acridinium salt and oxalate ester.  
       [0443] Likewise, a bioluminescent compound may be used to label the antibody of the present invention. Bioluminescence is a type of chemiluminescence found in biological systems in, which a catalytic protein increases the efficiency of the chemiluminescent reaction. The presence of a bioluminescent protein is determined by detecting the presence of luminescence. Important bioluminescent compounds for purposes of labeling are luciferin, luciferase and aequorin.  
       [0444] Methods for Detecting Excretory System Disease, Including Cancer  
       [0445] In general, an excretory system disease or cancer may be detected in a patient based on the presence of one or more excretory system antigen proteins of the invention and/or polynucleotides encoding such proteins in a biological sample (for example, blood, sera, urine, and/or tumor biopsies) obtained from the patient. In other words, such proteins and/or polynucleotides may be used as markers to indicate the presence or absence of an excretory system disease or disorder, including cancer. Cancers that may be diagnosed, and/or prognosed using the compositions of the invention include but are not limited to, cancer of excretory system tissues. In addition, such proteins and/or polynucleotides may be useful for the detection of other diseases and cancers, including cancers of tissues/cells corresponding to the library source disclosed in column 7 of Table 1A expressing the corresponding excretory system sequence disclosed in the same row of Table 1A. The binding agents provided herein generally permit detection of the level of antigen that binds to the agent in the biological sample. Polynucleotide primers and probes may be used to detect the level of mRNA encoding excretory system antigen polypeptides, which is also indicative of the presence or absence of a excretory system disease or disorder, including cancer. In general, excretory system antigen polypeptides should be present at a level that is at least three fold higher in diseased tissue than in normal tissue.  
       [0446] There are a variety of assay formats known to those of ordinary skill in the art for using a binding agent to detect polypeptide markers in a sample. See, e.g., Harlow and Lane, supra. In general, the presence or absence of an excretory system disease in a patient may be determined by (a) contacting a biological sample obtained from a patient with a binding agent; (b) detecting in the sample a level of polypeptide that binds to the binding agent; and (c) comparing the level of polypeptide with a predetermined cut-off value.  
       [0447] In a preferred embodiment, the assay involves the use of binding agent immobilized on a solid support to bind to and remove the excretory system antigen polypeptide of the invention from the remainder of the sample. The bound polypeptide may then be detected using a detection reagent that contains a reporter group and specifically binds to the binding agent/polypeptide complex. Such detection reagents may comprise, for example, a binding agent that specifically binds to the polypeptide or an antibody or other agent that specifically binds to the binding agent, such as an anti-immunoglobulin, protein G, protein A or a lectin. Alternatively, a competitive assay may be utilized, in which a polypeptide is labeled with a reporter group and allowed to bind to the immobilized binding agent after incubation of the binding agent with the sample. The extent to which components of the sample inhibit the binding of the labeled polypeptide to the binding agent is indicative of the reactivity of the sample with the immobilized binding agent. Suitable polypeptides for use within such assays include excretory system antigen polypeptides and portions thereof, or antibodies, to which the binding agent binds, as described above.  
       [0448] The solid support may be any material known to those of skill in the art to which excretory system antigen polypeptides of the invention may be attached. For example, the solid support may be a test well in a microtiter plate or a nitrocellulose or other suitable membrane. Alternatively, the support may be a bead or disc, such as glass fiberglass, latex or a plastic material such as polystyrene or polyvinylchloride. The support may also be a magnetic particle or a fiber optic sensor, such as those disclosed, for example, in U.S. Pat. No. 5,359,681. The binding agent may be immobilized on the solid support using a variety of techniques known to those of skill in the art, which are amply described in the patent and scientific literature. In the context of the present invention, the term “immobilization” refers to both noncovalent association, such as adsorption, and covalent attachment (which may be a direct linkage between the agent and functional groups on the support or may be a linkage by way of a cross-linking agent). Immobilization by adsorption to a well in a microtiter plate or to a membrane is preferred. In such cases, adsorption may be achieved by contacting the binding agent, in a suitable buffer, with the solid support for the suitable amount of time. The contact time varies with temperature, but is typically between about 1 hour and about 1 day. In general, contacting a well of plastic microtiter plate (such as polystyrene or polyvinylchloride) with an amount of binding agent ranging from about 10 ng to about 10 ug, and preferably about 100 ng to about 1 ug, is sufficient to immobilize an adequate amount of binding agent.  
       [0449] Covalent attachment of binding agent to a solid support may generally be achieved by first reacting the support with a bifunctional reagent that will react with both the support and a functional group, such as a hydroxyl or amino group, on the binding agent. For example, the binding agent may be covalently attached to supports having an appropriate polymer coating using benzoquinone or by condensation of an aldehyde group on the support with an amine and an active hydrogen on the binding partner (see, e.g., Pierce Immunotechnology Catalog and Handbook, 1991, at A12-A13).  
       [0450] Gene Therapy Methods  
       [0451] Also encompassed by the present invention are gene therapy methods for treating or preventing disorders, diseases and conditions. The gene therapy methods relate to the introduction of nucleic acid (DNA, RNA and antisense DNA or RNA) sequences into an animal to achieve expression of an excretory system antigen of the present invention. This method requires a polynucleotide, which codes for a polypeptide of the present invention operatively linked to a promoter and any other genetic elements necessary for the expression of the polypeptide by the target tissue. Such gene therapy and delivery techniques are known in the art, see, for example, WO90/11092, which is herein incorporated by reference.  
       [0452] Thus, for example, cells from a patient may be engineered with a polynucleotide (DNA or RNA) comprising a promoter operably linked to a polynucleotide of the present invention ex vivo, with the engineered cells then being provided to a patient to be treated with the polypeptide of the present invention. Such methods are well-known in the art. For example, see Belldegrun, A., et al., J. Natl. Cancer Inst. 85: 207-216 (1993); Ferrantini, M. et al., Cancer Research 53: 1107-1112 (1993); Ferrantini, M. et al., J. Immunology 153: 4604-4615 (1994); Kaido, T., et al., Int. J. Cancer 60: 221-229 (1995); Ogura, H., et al., Cancer Research 50: 5102-5106 (1990); Santodonato, L., et al., Human Gene Therapy 7:1-10 (1996); Santodonato, L., et al., Gene Therapy 4:1246-1255 (1997); and Zhang, J. -F. et al., Cancer Gene Therapy 3: 31-38 (1996)), which are herein incorporated by reference. In one embodiment, the cells which are engineered are arterial cells. The arterial cells may be reintroduced into the patient through direct injection to the artery, the tissues surrounding the artery, or through catheter injection.  
       [0453] As discussed in more detail below, the polynucleotide constructs can be delivered by any method that delivers injectable materials to the cells of an animal, such as, injection into the interstitial space of tissues (heart, muscle, skin, lung, liver, and the like). The polynucleotide constructs may be delivered in a pharmaceutically acceptable liquid or aqueous carrier.  
       [0454] In one embodiment, the polynucleotide of the present invention is delivered as a naked polynucleotide. The term “naked” polynucleotide, DNA or RNA refers to sequences that are free from any delivery vehicle that acts to assist, promote or facilitate entry into the cell, including viral sequences, viral particles, liposome formulations, lipofectin or precipitating agents and the like. However, the polynucleotide of the present invention can also be delivered in liposome formulations and lipofectin formulations and the like can be prepared by methods well known to those skilled in the art. Such methods are described, for example, in U.S. Pat. Nos. 5,593,972, 5,589,466, and 5,580,859, which are herein incorporated by reference.  
       [0455] The polynucleotide vector constructs used in the gene therapy method are preferably constructs that will not integrate into the host genome nor will they contain sequences that allow for replication. Appropriate vectors include pWLNEO, pSV2CAT, pOG44, pXT1 and pSG available from Stratagene; pSVK3, pBPV, pMSG and pSVL available from Pharmacia; and pEF1/V5, pcDNA3.1, and pRc/CMV2 available from Invitrogen. Other suitable vectors will be readily apparent to the skilled artisan.  
       [0456] Any strong promoter known to those skilled in the art can be used for driving the expression of the polynucleotide sequence. Suitable promoters include adenoviral promoters, such as the adenoviral major late promoter; or heterologous promoters, such as the cytomegalovirus (CMV) promoter; the respiratory syncytial virus (RSV) promoter; inducible promoters, such as the MMT promoter, the metallothionein promoter; heat shock promoters; the albumin promoter; the ApoAI promoter; human globin promoters; viral thymidine kinase promoters, such as the Herpes Simplex thymidine kinase promoter; retroviral LTRs; the b-actin promoter; and human growth hormone promoters. The promoter also may be the native promoter for the polynucleotide of the present invention.  
       [0457] Unlike other gene therapy techniques, one major advantage of introducing naked nucleic acid sequences into target cells is the transitory nature of the polynucleotide synthesis in the cells. Studies have shown that non-replicating DNA sequences can be introduced into cells to provide production of the desired polypeptide for periods of up to six months.  
       [0458] The polynucleotide construct can be delivered to the interstitial space of tissues within the animal, including of muscle, skin, brain, lung, liver, spleen, bone marrow, thymus, heart, lymph, blood, bone, cartilage, pancreas, kidney, gall bladder, stomach, intestine, testis, ovary, uterus, rectum, nervous system, eye, gland, and connective tissue. Interstitial space of the tissues comprises the intercellular, fluid, mucopolysaccharide matrix among the reticular fibers of organ tissues, elastic fibers in the walls of vessels or chambers, collagen fibers of fibrous tissues, or that same matrix within connective tissue ensheathing muscle cells or in the lacunae of bone. It is similarly the space occupied by the plasma of the circulation and the lymph fluid of the lymphatic channels. Delivery to the interstitial space of muscle tissue is preferred for the reasons discussed below. They may be conveniently delivered by injection into the tissues comprising these cells. They are preferably delivered to and expressed in persistent, non-dividing cells which are differentiated, although delivery and expression may be achieved in non-differentiated or less completely differentiated cells, such as, for example, stem cells of blood or skin fibroblasts. In vivo muscle cells are particularly competent in their ability to take up and express polynucleotides.  
       [0459] For the naked nucleic acid sequence injection, an effective dosage amount of DNA or RNA will be in the range of from about 0.05 mg/kg body weight to about 50 mg/kg body weight. Preferably the dosage will be from about 0.005 mg/kg to about 20 mg/kg and more preferably from about 0.05 mg/kg to about 5 mg/kg. Of course, as the artisan of ordinary skill will appreciate, this dosage will vary according to the tissue site of injection. The appropriate and effective dosage of nucleic acid sequence can readily be determined by those of ordinary skill in the art and may depend on the condition being treated and the route of administration.  
       [0460] The preferred route of administration is by the parenteral route of injection into the interstitial space of tissues. However, other parenteral routes may also be used, such as, inhalation of an aerosol formulation particularly for delivery to lungs or bronchial tissues, throat or mucous membranes of the nose. In addition, naked DNA constructs can be delivered to arteries during angioplasty by the catheter used in the procedure.  
       [0461] The naked polynucleotides are delivered by any method known in the art, including, but not limited to, direct needle injection at the delivery site, intravenous injection, topical administration, catheter infusion, and so-called “gene guns”. These delivery methods are known in the art.  
       [0462] The constructs may also be delivered with delivery vehicles such as viral sequences, viral particles, liposome formulations, lipofectin, precipitating agents, etc. Such methods of delivery are known in the art.  
       [0463] In certain embodiments, the polynucleotide constructs are complexed in a liposome preparation. Liposomal preparations for use in the instant invention include cationic (positively charged), anionic (negatively charged) and neutral preparations. However, cationic liposomes are particularly preferred because a tight charge complex can be formed between the cationic liposome and the polyanionic nucleic acid. Cationic liposomes have been shown to mediate intracellular delivery of plasmid DNA (Felgner et al., Proc. Natl. Acad. Sci. USA (1987) 84:7413-7416, which is herein incorporated by reference); mRNA (Malone et al., Proc. Natl. Acad. Sci. USA (1989) 86:6077-6081, which is herein incorporated by reference); and purified transcription factors (Debs et al., J. Biol. Chem. (1990) 265:10189-10192, which is herein incorporated by reference), in functional form.  
       [0464] Cationic liposomes are readily available. For example, N[1-2,3-dioleyloxy)propyl]-N,N,N-triethylammonium (DOTMA) liposomes are particularly useful and are available under the trademark Lipofectin, from GIBCO BRL, Grand Island, N.Y., (see, also, Felgner et al., Proc. Natl Acad. Sci. USA (1987) 84:7413-7416, which is herein incorporated by reference). Other commercially available liposomes include transfectace (DDAB/DOPE) and DOTAP/DOPE (Boehringer).  
       [0465] Other cationic liposomes can be prepared from readily available materials using techniques well known in the art. See, e.g. PCT Publication No. WO 90/11092 (which is herein incorporated by reference) for a description of the synthesis of DOTAP (1,2-bis(oleoyloxy)-3-(trimethylammonio)propane) liposomes. Preparation of DOTMA liposomes is explained in the literature, see, e.g., P. Felgner et al., Proc. Natl. Acad. Sci. USA 84:7413-7417, which is herein incorporated by reference. Similar methods can be used to prepare liposomes from other cationic lipid materials.  
       [0466] Similarly, anionic and neutral liposomes are readily available, such as from Avanti Polar Lipids (Birmingham, Ala.), or can be easily prepared using readily available materials. Such materials include phosphatidyl choline, cholesterol, phosphatidyl ethanolamine, dioleoylphosphatidyl choline (DOPC), dioleoylphosphatidyl glycerol (DOPG), dioleoylphoshatidyl ethanolamine (DOPE), among others. These materials can also be mixed with the DOTMA and DOTAP starting materials in appropriate ratios. Methods for making liposomes using these materials are well known in the art.  
       [0467] For example, commercially dioleoylphosphatidyl choline (DOPC), dioleoylphosphatidyl glycerol (DOPG), and dioleoylphosphatidyl ethanolamine (DOPE) can be used in various combinations to make conventional liposomes, with or without the addition of cholesterol. Thus, for example, DOPG/DOPC vesicles can be prepared by drying 50 mg each of DOPG and DOPC under a stream of nitrogen gas into a sonication vial. The sample is placed under a vacuum pump overnight and is hydrated the following day with deionized water. The sample is then sonicated for 2 hours in a capped vial, using a Heat Systems model 350 sonicator equipped with an inverted cup (bath type) probe at the maximum setting while the bath is circulated at 15EC. Alternatively, negatively charged vesicles can be prepared without sonication to produce multilamellar vesicles or by extrusion through nucleopore membranes to produce unilamellar vesicles of discrete size. Other methods are known and available to those of skill in the art.  
       [0468] The liposomes can comprise multilamellar vesicles (MLVs), small unilamellar vesicles (SUVs), or large unilamellar vesicles (LUVs), with SUVs being preferred. The various liposome-nucleic acid complexes are prepared using methods well known in the art. See, e.g., Straubinger et al., Methods of Immunology (1983), 101:512-527, which is herein incorporated by reference. For example, MLVs containing nucleic acid can be prepared by depositing a thin film of phospholipid on the walls of a glass tube and subsequently hydrating with a solution of the material to be encapsulated. SUVs are prepared by extended sonication of MLVs to produce a homogeneous population of unilamellar liposomes. The material to be entrapped is added to a suspension of preformed MLVs and then sonicated. When using liposomes containing cationic lipids, the dried lipid film is resuspended in an appropriate solution such as sterile water or an isotonic buffer solution such as 10 mM Tris/NaCl, sonicated, and then the preformed liposomes are mixed directly with the DNA. The liposome and DNA form a very stable complex due to binding of the positively charged liposomes to the cationic DNA. SUVs find use with small nucleic acid fragments. LUVs are prepared by a number of methods, well known in the art. Commonly used methods include Ca 2+ -EDTA chelation (Papahadjopoulos et al., Biochim. Biophys. Acta (1975) 394:483; Wilson et al., Cell 17:77 (1979); ether injection (Deamer, D. and Bangham, A., Biochim. Biophys. Acta 443:629 (1976); Ostro et al., Biochem. Biophys. Res. Commun. 76:836 (1977); Fraley et al., Proc. Natl. Acad. Sci. USA 76:3348 (1979)); detergent dialysis (Enoch, H. and Strittmatter, P., Proc. Natl. Acad. Sci. USA 76:145 (1979)); and reverse-phase evaporation (REV) (Fraley et al., J. Biol. Chem. 255:10431 (1980); Szoka et al., Proc. Natl. Acad. Sci. USA 75:145 (1978); Schaefer-Ridder et al., Science 215:166 (1982)), which are herein incorporated by reference.  
       [0469] Generally, the ratio of DNA to liposomes will be from about 10:1 to about 1:10. Preferably, the ration will be from about 5:1 to about 1:5. More preferably, the ration will be about 3:1 to about 1:3. Still more preferably, the ratio will be about 1:1.  
       [0470] U.S. Pat. No. 5,676,954 (which is herein incorporated by reference) reports on the injection of genetic material, complexed with cationic liposomes carriers, into mice. U.S. Pat. Nos. 4,897,355, 4,946,787, 5,049,386, 5,459,127, 5,589,466, 5,693,622, 5,580,859, 5,703,055, and international publication no. WO 94/9469 (which are herein incorporated by reference) provide cationic lipids for use in transfecting DNA into cells and mammals. U.S. Pat. Nos. 5,589,466, 5,693,622, 5,580,859, 5,703,055, and International Publication No. WO 94/9469 provide methods for delivering DNA-cationic lipid complexes to mammals.  
       [0471] In certain embodiments, cells are engineered, ex vivo or in vivo, using a retroviral particle containing RNA, which comprises a sequence encoding a polypeptide of the present invention. Retroviruses from which the retroviral plasmid vectors may be derived include, but are not limited to, Moloney Murine Leukemia Virus, spleen necrosis virus, Rous sarcoma Virus, Harvey Sarcoma Virus, avian leukosis virus, gibbon ape leukemia virus, human immunodeficiency virus, Myeloproliferative Sarcoma Virus, and mammary tumor virus.  
       [0472] The retroviral plasmid vector is employed to transduce packaging cell lines to form producer cell lines. Examples of packaging cells which may be transfected include, but are not limited to, the PE501, PA317, R-2, R-AM, PA12, T19-14X, VT-19-17-H2, RCRE, RCRIP, GP+E-86, GP+envAm12, and DAN cell lines as described in Miller, Human Gene Therapy 1:5-14 (1990), which is incorporated herein by reference in its entirety. The vector may transduce the packaging cells through any means known in the art. Such means include, but are not limited to, electroporation, the use of liposomes, and CaPO 4  precipitation. In one alternative, the retroviral plasmid vector may be encapsulated into a liposome, or coupled to a lipid, and then administered to a host.  
       [0473] The producer cell line generates infectious retroviral vector particles which include polynucleotide encoding a polypeptide of the present invention. Such retroviral vector particles then may be employed, to transduce eukaryotic cells, either in vitro or in vivo. The transduced eukaryotic cells will express a polypeptide of the present invention.  
       [0474] In certain other embodiments, cells are engineered, ex vivo or in vivo, with polynucleotide contained in an adenovirus vector. Adenovirus can be manipulated such that it encodes and expresses a polypeptide of the present invention, and at the same time is inactivated in terms of its ability to replicate in a normal lytic viral life cycle. Adenovirus expression is achieved without integration of the viral DNA into the host cell chromosome, thereby alleviating concerns about insertional mutagenesis. Furthermore, adenoviruses have been used as live enteric vaccines for many years with an excellent safety profile (Schwartz, et al., Am. Rev. Respir. Dis.109:233-238 (1974)). Finally, adenovirus mediated gene transfer has been demonstrated in a number of instances including transfer of alpha-1-antitrypsin and CFTR to the lungs of cotton rats (Rosenfeld et al., Science 252:431-434 (1991); Rosenfeld et al., Cell 68:143-155 (1991)). Furthermore, extensive studies to attempt to establish adenovirus as a causative agent in human cancer were uniformly negative (Green et al., Proc. Natl. Acad. Sci. USA 76:6606 (1979)).  
       [0475] Suitable adenoviral vectors useful in the present invention are described, for example, in Kozarsky and Wilson, Curr. Opin. Genet. Devel. 3:499-503 (1993); Rosenfeld et al., Cell 68:143-155 (1992); Engelhardt et al., Human Genet. Ther. 4:759-769 (1993); Yang et al., Nature Genet. 7:362-369 (1994); Wilson et al., Nature 365:691-692 (1993); and U.S. Pat. No. 5,652,224, which are herein incorporated by reference. For example, the adenovirus vector Ad2 is useful and can be grown in human 293 cells. These cells contain the E1 region of adenovirus and constitutively express E1a and E1b, which complement the defective adenoviruses by providing the products of the genes deleted from the vector. In addition to Ad2, other varieties of adenovirus (e.g., Ad3, Ad5, and Ad7) are also useful in the present invention.  
       [0476] Preferably, the adenoviruses used in the present invention are replication deficient. Replication deficient adenoviruses require the aid of a helper virus and/or packaging cell line to form infectious particles. The resulting virus is capable of infecting cells and can express a polynucleotide of interest, which is operably linked to a promoter, but cannot replicate in most cells. Replication deficient adenoviruses may be deleted in one or more of all or a portion of the following genes: E1a, E1b, E3, E4, E2a, or L1 through L5.  
       [0477] In certain other embodiments, the cells are engineered, ex vivo or in vivo, using an adeno-associated virus (AAV). AAVs are naturally occurring defective viruses that require helper viruses to produce infectious particles (Muzyczka, N., Curr. Topics in Microbiol. Immunol. 158:97 (1992)). It is also one of the few viruses that may integrate its DNA into non-dividing cells. Vectors containing as little as 300 base pairs of AAV can be packaged and can integrate, but space for exogenous DNA is limited to about 4.5 kb. Methods for producing and using such AAVs are known in the art. See, for example, U.S. Pat. Nos. 5,139,941, 5,173,414, 5,354,678, 5,436,146, 5,474,935, 5,478,745, and 5,589,377.  
       [0478] For example, an appropriate AAV vector for use in the present invention will include all the sequences necessary for DNA replication, encapsidation, and host-cell integration. The polynucleotide construct is inserted into the AAV vector using standard cloning methods, such as those found in Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press (1989). The recombinant AAV vector is then transfected into packaging cells which are infected with a helper virus, using any standard technique, including lipofection, electroporation, calcium phosphate precipitation, etc. Appropriate helper viruses include adenoviruses, cytomegaloviruses, vaccinia viruses, or herpes viruses. Once the packaging cells are transfected and infected, they will produce infectious AAV viral particles, which contain the polynucleotide construct. These viral particles are then used to transduce eukaryotic cells, either ex vivo or in vivo. The transduced cells will contain the polynucleotide construct integrated into its genome, and will express a polypeptide of the invention.  
       [0479] Another method of gene therapy involves operably associating heterologous control regions and endogenous excretory system antigen polynucleotide sequences (e.g., encoding an excretory system antigen polypeptide of the present invention) via homologous recombination (see, e.g., U.S. Pat. No. 5,641,670, issued Jun. 24, 1997; International Publication No. WO 96/29411, published Sep. 26, 1996; International Publication No. WO 94/12650, published Aug. 4, 1994; Koller et al., Proc. Natl. Acad. Sci. USA 86:8932-8935 (198,9); and Zijlstra et al., Nature 342:435-438 (1989), which are herein incorporated by reference. This method involves the activation of a gene which is present in the target cells, but which is not normally expressed in the cells, or is expressed at a lower level than desired.  
       [0480] Polynucleotide constructs are made, using standard techniques known in the art, which contain the promoter with targeting sequences flanking the promoter. Suitable promoters are described herein. The targeting sequence is sufficiently complementary to an endogenous sequence to permit homologous recombination of the promoter-targeting sequence with the endogenous sequence. The targeting sequence will be sufficiently near the 5′ end of the desired endogenous polynucleotide sequence so the promoter will be operably linked to the endogenous sequence upon homologous recombination.  
       [0481] The promoter and the targeting sequences can be amplified using PCR. Preferably, the amplified promoter contains distinct restriction enzyme sites on the 5′ and 3′ ends. Preferably, the 3′ end of the first targeting sequence contains the same restriction enzyme site as the 5′ end of the amplified promoter and the 5′ end of the second targeting sequence contains the same restriction site as the 3′ end of the amplified promoter. The amplified promoter and targeting sequences are digested and ligated together.  
       [0482] The promoter-targeting sequence construct is delivered to the cells, either as naked polynucleotide, or in conjunction with transfection-facilitating agents, such as liposomes, viral sequences, viral particles, whole viruses, lipofection, precipitating agents, etc., described in more detail above. The P promoter-targeting sequence can be delivered by any method, included direct needle injection, intravenous injection, topical administration, catheter infusion, particle accelerators, etc. The methods are described in more detail below.  
       [0483] The promoter-targeting sequence construct is taken up by cells. Homologous recombination between the construct and the endogenous sequence takes place, such that an endogenous sequence is placed under the control of the promoter. The promoter then drives the expression of the endogenous sequence.  
       [0484] The polynucleotide encoding a polypeptide of the present invention may contain a secretory signal sequence that facilitates secretion of the protein. Typically, the signal sequence is positioned in the coding region of the polynucleotide to be expressed towards or at the 5′ end of the coding region. The signal sequence may be homologous or heterologous to the excretory system antigen polynucleotide of interest and may be homologous or heterologous to the cells to be transfected. Additionally, the signal sequence may be chemically synthesized using methods known in the art.  
       [0485] Any mode of administration of any of the above-described polynucleotides constructs can be used so long as the mode results in the expression of one or more molecules in an amount sufficient to provide a therapeutic effect. This includes direct needle injection, systemic injection, catheter infusion, biolistic injectors, particle accelerators (i.e., “gene guns”), gelfoam sponge depots, other commercially available depot materials, osmotic pumps (e.g., Alza minipumps), oral or suppositorial solid (tablet or pill) pharmaceutical formulations, and decanting or topical applications during surgery. For example, direct injection of naked calcium phosphate-precipitated plasmid into rat liver and rat spleen or a protein-coated plasmid into the portal vein has resulted in gene expression of the foreign gene in the rat livers (Kaneda et al., Science 243:375 (1989)).  
       [0486] A preferred method of local administration is by direct injection. Preferably, a recombinant molecule of the present invention complexed with a delivery vehicle is administered by direct injection into or locally within the area of arteries. Administration of a composition locally within the area of arteries refers to injecting the composition centimeters and preferably, millimeters within arteries.  
       [0487] Another method of local administration is to contact a polynucleotide construct of the present invention in or around a surgical wound. For example, a patient can undergo surgery and the polynucleotide construct can be coated on the surface of tissue inside the wound or the construct can be injected into areas of tissue inside the wound.  
       [0488] Therapeutic compositions useful in systemic administration, include recombinant molecules of the present invention complexed to a targeted delivery vehicle of the present invention. Suitable delivery vehicles for use with systemic administration comprise liposomes comprising ligands for targeting the vehicle to a particular site. In specific embodiments, suitable delivery vehicles for use with systemic administration comprise liposomes comprising polypeptides of the invention for targeting the vehicle to a particular site.  
       [0489] referred methods of systemic administration, include intravenous injection, aerosol, oral and percutaneous (topical) delivery. Intravenous injections can be performed using methods standard in the art. Aerosol delivery can also be performed using methods standard in the art (see, for example, Stribling et al., Proc. Natl. Acad. Sci. USA 189:11277-11281, 1992, which is incorporated herein by reference). Oral delivery can be performed by complexing a polynucleotide construct of the present invention to a carrier capable of withstanding degradation by digestive enzymes in the gut of an animal. Examples of such carriers, include plastic capsules or tablets, such as those known in the art. Topical delivery can be performed by mixing a polynucleotide construct of the present invention with a lipophilic reagent (e.g., DMSO) that is capable of passing into the skin.  
       [0490] Determining an effective amount of substance to be delivered can depend upon a number of factors including, for example, the chemical structure and biological activity of the substance, the age and weight of the animal, the precise condition requiring treatment and its severity, and the route of administration. The frequency of treatments depends upon a number of factors, such as the amount of polynucleotide constructs administered per dose, as well as the health and history of the subject. The precise amount, number of doses, and timing of doses will be determined by the attending physician or veterinarian.  
       [0491] Therapeutic compositions of the present invention can be administered to any animal, preferably to mammals and birds. Preferred mammals include humans, dogs, cats, mice, rats, rabbits sheep, cattle, horses and pigs, with humans being particularly preferred.  
       [0492] Biological Activities  
       [0493] Polynucleotides or polypeptides, or agonists or antagonists of the present invention, can be used in assays to test for one or more biological activities. If these polynucleotides or polypeptides, or agonists or antagonists of the present invention, do exhibit activity in a particular assay, it is likely that these molecules may be involved in the diseases associated with the biological activity. Thus, the polynucleotides and polypeptides, and agonists or antagonists could be used to treat, prevent diagnose and/or prognose the associated disease.  
       [0494] The excretory system antigen polynucleotides and polypeptides of the invention are predicted to have predominant expression in excretory system tissues.  
       [0495] Thus, the excretory system antigens of the invention may be useful as therapeutic molecules. Each would be useful for diagnosis, detection, treatment and/or prevention of diseases or disorders of the excretory system, including but not limited to renal disorders (e.g., kidney failure, nephritis, blood vessel disorders of kidney, metabolic and congenital kidney disorders, urinary disorders of the kidney, autoimmune disorders, sclerosis and necrosis, and electrolyte imbalance, and kidney cancer), bladder disorders (e.g, urinary tract infection, bladder obstruction, urination disorders, and bladder cancer), urether disorders (e.g., obstruction of the ureter and ureter cancer), urethra disorders (e.g., obstruction of the urethra and urethra cancers) and/or those disorders as discribed under “Urinary System Disorders” below.  
       [0496] In a preferred embodiment, polynucleotides of the invention (e.g., a nucleic acid sequence of SEQ ID NO: X or the complement thereof, or the cDNA sequence contained in Clone ID NO: Z, or fragments or variants thereof) and/or polypeptides of the invention (e.g., an amino acid sequence contained in SEQ ID NO: Y, an amino acid sequence encoded by SEQ ID NO: X, or the complement threof, an amino acid sequence encoded by the cDNA sequence contained in Clone ID NO: Z and fragments or variants thereof as described herein) are useful for the diagnosis, detection, treatement, and/or prevention of diseases or disorders of the tissues/cells corresponding to the library source disclosed in column 7 of Table 1A expressing the corresponding excretory system sequence disclosed in the same row of Table 1A.  
       [0497] In certain embodiments, a polypeptide of the invention, or polynucleotides, antibodies, agonists, or antagonists corresponding to that polypeptide, may be used to diagnose and/or prognose diseases and/or disorders associated with the tissue(s) in which the polypeptide of the invention is expressed, including one, two, three, four, five, or more tissues disclosed in Table 1A, column 7 (Tissue Distribution Library Code).  
       [0498] Particularly, the excretory system antigens may be a useful therapeutic for cancer of excretory system tissues. Treatment, diagnosis, detection, and/or prevention of excretory system disorders could be carried out using an excretory system antigen or soluble form of a excretory system antigen, an excretory system antigen ligand, gene therapy, or ex vivo applications. Moreover, inhibitors of an excretory system antigen, either blocking antibodies or mutant forms, could modulate the expression of the excretory system antigen. These inhibitors may be useful to treat, diagnose, detect, and/or prevent diseases associated with the misregulation of an excretory system antigen.  
       [0499] In one embodiment, the invention provides a method for the specific delivery of compositions of the invention to cells (e.g., normal or diseased excretory system cells) by administering polypeptides of the invention (e.g., excretory system antigen polypeptides or anti-excretory system antigen antibodies) that are associated with heterologous polypeptides or nucleic acids. In one example, the invention provides a method for delivering a therapeutic protein into the targeted cell (e.g., an, aberrant excretory system cell or excretory system cancer cell). In another example, the invention provides a method for delivering a single stranded nucleic acid (e.g., antisense or ribozymes) or double stranded nucleic acid (e.g., DNA that can integrate into the cell&#39;s genome or replicate episomally and that can be transcribed) into the targeted cell.  
       [0500] In another embodiment, the invention provides a method for the specific destruction of cells (e.g., the destruction of aberrant excretory system cells, including, but not limited to, excretory system tumor cells) by administering polypeptides of the invention (e.g., excretory system antigen polypeptides or fragments thereof, or anti-excretory system antigen antibodies) in association with toxins or cytotoxic prodrugs.  
       [0501] By “toxin” is meant compounds that bind and activate endogenous cytotoxic effector systems, radioisotopes, holotoxins, modified toxins, catalytic subunits of toxins, cytotoxins (cytotoxic agents), or any molecules or enzymes not normally present in or on the surface of a cell that under defined conditions cause the cell&#39;s death. Toxins that may be used according to the methods of the invention include, but are not limited to, radioisotopes known in the art, compounds such as, for example, antibodies (or complement fixing containing portions thereof) that bind an inherent or induced endogenous cytotoxic effector system, thymidine kinase, endonuclease, RNAse, alpha toxin, ricin, abrin, Pseudomonas exotoxin A, diphtheria toxin, saporin, momordin, gelonin, pokeweed antiviral protein, alpha-sarcin and cholera toxin. “Toxin” also includes a cytostatic or cytocidal agent, a therapeutic agent or a radioactive metal ion, e.g., alpha-emitters such as, for example,  213 Bi, or other radioisotopes such as, for example,  103 Pd,  133 Xe,  131 I,  68 Ge,  57 Co,  65 Zn,  85 Sr,  32 P,  35 S,  90 Y,  153 Sm,  153 Gd,  169 Yb,  51 Cr,  54 Mn,  75 Se,  113 Sn,  90 Yttrium,  117 Tin,  186 Rhenium,  166 Holmium, and  188 Rhenium; luminescent labels, such as luminol; and fluorescent labels, such as fluorescein and rhodamine, and biotin.  
       [0502] Techniques known in the art may be applied to label antibodies of the invention. Such techniques include, but are not limited to, the use of bifunctional conjugating agents (see e.g., U.S. Pat. Nos. 5,756,065; 5,714,631; 5,696,239; 5,652,361; 5,505,931; 5,489,425; 5,435,990; 5,428,139; 5,342,604; 5,274,119; 4,994,560; and 5,808,003; the contents of each of which are hereby incorporated by reference in its entirety). A cytotoxin or cytotoxic agent includes any agent that is detrimental to cells. Examples include paclitaxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicin, doxorubicin, daunorubicin, dihydroxy anthracin dione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, and puromycin and analogs or homologs thereof. Therapeutic agents include, but are not limited to, antimetabolites (e.g., methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil decarbazine), alkylating agents (e.g., mechlorethamine, thioepa chlorambucil, melphalan, carmustine (BSNU) and lomustine (CCNU), cyclothosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C, and cis- dichlorodiamine platinum (II) (DDP) cisplatin), anthracyclines (e.g., daunorubicin (formerly daunomycin) and doxorubicin), antibiotics (e.g., dactinomycin (formerly actinomycin), bleomycin, mithramycin, and anthramycin (AMC)), and anti-mitotic agents (e.g., vincristine and vinblastine).  
       [0503] By “cytotoxic prodrug” is meant a non-toxic compound that is converted by an enzyme, normally present in the cell, into a cytotoxic compound. Cytotoxic prodrugs that may be used according to the methods of the invention include, but are not limited to, glutamyl derivatives of benzoic acid mustard alkylating agent, phosphate derivatives of etoposide or mitomycin C, cytosine arabinoside, daunorubisin, and phenoxyacetamide derivatives of doxorubicin.  
       [0504] It will be appreciated that conditions caused by a decrease in the standard or normal level of an excretory system antigen activity in an individual, particularly disorders of the excretory system, can be treated by administration of an excretory system antigen polypeptide (e.g., such as, for example, the complete excretory system antigen polypeptide, the soluble form of the extracellular domain of an excretory system antigen polypeptide, or cells expressing the complete protein) or agonist. Thus, the invention also provides a method of treatment of an individual in need of an increased level of excretory system antigen activity comprising administering to such an individual a pharmaceutical composition comprising an amount of an isolated excretory system antigen polypeptide of the invention, or agonist thereof (e.g., an agonistic anti-excretory system antigen antibody), effective to increase the excretory system antigen activity level in such an individual.  
       [0505] It will also be appreciated that conditions caused by a increase in the standard or normal level of excretory system antigen activity in an individual, particularly disorders of the excretory system, can be treated by administration of excretory system antigen polypeptides (e.g., such as, for example, the complete excretory system antigen polypeptide, the soluble form of the extracellular domain of an excretory system antigen polypeptide, or cells expressing the complete protein) or antagonist (e.g., an antagonistic excretory system antigen antibody). Thus, the invention also provides a method of treatment of an individual in need of an decreased level of excretory system antigen activity comprising administering to such an individual a pharmaceutical composition comprising an amount of an isolated excretory system antigen polypeptide of the invention, or antagonist thereof (e.g., an antagonistic anti-excretory system antigen antibody), effective to decrease the excretory system antigen activity level in such an individual.  
       [0506] More generally, polynucleotides, translation products and antibodies corresponding to this gene may be useful for the diagnosis, prognosis, prevention, and/or treatment of diseases and/or disorders associated with the following systems.  
       [0507] Urinary System Disorders  
       [0508] Polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention, may be used to treat, prevent, diagnose, and/or prognose disorders of the urinary system, including but not limited to disorders of the renal system, bladder, ureters, and urethra. Renal disorders include, but are not limited to, kidney failure, nephritis, blood vessel disorders of kidney, metabolic and congenital kidney disorders, urinary disorders of the kidney, autoimmune disorders, sclerosis and necrosis, electrolyte imbalance, and kidney cancers.  
       [0509] Kidney failure diseases include, but are not limited to, acute kidney failure, chronic kidney failure, atheroembolic renal failure, and end-stage renal disease. Inflammatory diseases of the kidney include acute glomerulonephritis, postinfectious glomerulonephritis, rapidly progressive glomerulonephritis, nephrotic syndrome, membranous glomerulonephritis, familial nephrotic syndrome, membranoproliferative glomerulonephritis I and II, mesangial proliferative glomerulonephritis, chronic glomerulonephritis, acute tubulointerstitial nephritis, chronic tubulointerstitial nephritis, acute post-streptococcal glomerulonephritis (PSGN), pyelonephritis, lupus nephritis, chronic nephritis, interstitial nephritis, and post-streptococcal glomerulonephritis.  
       [0510] Blood vessel disorders of the kidneys include, but are not limited to, kidney infarction, atheroembolic kidney disease, cortical necrosis, malignant nephrosclerosis, renal vein thrombosis, renal underperfusion, renal ischemia-reperfusion, renal artery embolism, and renal artery stenosis. Kidney disorders resulting form urinary tract problems include, but are not limited to, pyelonephritis, hydronephrosis, urolithiasis (renal lithiasis, nephrolithiasis), reflux nephropathy, urinary tract infections, urinary retention, and acute or chronic unilateral obstructive uropathy.  
       [0511] Metabolic and congenital disorders of the kidneys include, but are not limited to, renal tubular acidosis, renal glycosuria, nephrogenic diabetes insipidus, cystinuria, Fanconi&#39;s syndrome, vitamin D-resistant rickets, Hartnup disease, Bartter&#39;s syndrome, Liddle&#39;s syndrome, polycystic kidney disease, medullary cystic disease, medullary sponge kidney, Alport&#39;s syndrome, nail-patella syndrome, congenital nephrotic syndrome, CRUSH syndrome, horseshoe kidney, diabetic nephropathy, nephrogenic diabetes insipidus, analgesic nephropathy, kidney stones, and membranous nephropathy, Kidney disorders resulting from an autoimmune response include, but are not limited to, systemic lupus erythematosus (SLE), Goodpasture syndrome, IgA nephropathy, and IgM mesangial proliferative glomerulonephritis.  
       [0512] Sclerotic or necrotic disorders of the kidney include, but are not limited to, glomerulosclerosis, diabetic nephropathy, focal segmental glomerulosclerosis (FSGS), necrotizing glomerulonephritis, and renal papillary necrosis. Kidneys may also develop carcinomas, including, but not limited to, hypemephroma, nephroblastoma, renal cell cancer, transitional cell cancer, squamous cell cancer, and Wilm&#39;s tumor.  
       [0513] Kidney disorders may also result in electrolyte imbalances, including, but not limited to, nephrocalcinosis, pyuria, edema, hydronephritis, proteinuria, hyponatremia, hypernatremia, hypokalemia, hyperkalemia, hypocalcemia, hypercalcemia, hypophosphatemia, and hyperphosphatemia.  
       [0514] Bladder disorders include, but are not limited to, benign prostatic hyperplasia (BPH), interstitial cystitis (IC), prostatitis, proteinuria, urinary tract infections, urinary incontinence, urinary retention. Disorders of the ureters and urethra include, but are not limited to, acute or chronic unilateral obstructive uropathy. The bladder, ureters, and urethra may also develop carcinomas, including, but not limited to, superficial bladder canccer, invasive bladder cancer, carcinoma of the ureter, and urethra cancers.  
       [0515] Polypeptides may be administered using any method known in the art, including, but not limited to, direct needle injection at the delivery site, intravenous injection, topical administration, catheter infusion, biolistic injectors, particle accelerators, gelfoam sponge depots, other commercially available depot materials, osmotic pumps, oral or suppositorial solid pharmaceutical formulations, decanting or topical applications during surgery, aerosol delivery. Such methods are known in the art. Polypeptides may be administered as part of a Therapeutic, described in more detail below. Methods of delivering polynucleotides are described in more detail herein.  
       [0516] Immune Activity  
       [0517] Polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in treating, preventing, diagnosing and/or prognosing diseases, disorders, and/or conditions of the immune system, by, for example, activating or inhibiting the proliferation, differentiation, or mobilization (chemotaxis) of immune cells. Immune cells develop through a process called hematopoiesis, producing myeloid (platelets, red blood cells, neutrophils, and macrophages) and lymphoid (B and T lymphocytes) cells from pluripotent stem cells. The etiology of these immune diseases, disorders, and/or conditions may be genetic, somatic, such as cancer and some autoimmune diseases, acquired (e.g., by chemotherapy or toxins), or infectious. Moreover, polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention can be used as a marker or detector of a particular immune system disease or disorder.  
       [0518] In another embodiment, a polypeptide of the invention, or polynucleotides, antibodies, agonists, or antagonists corresponding to that polypeptide, may be used to treat diseases and disorders of the immune system and/or to inhibit or enhance an immune response generated by cells associated with the tissue(s) in which the polypeptide of the invention is expressed, including one, two, three, four, five, or more tissues disclosed in Table 1A, column 7 (Tissue Distribution Library Code).  
       [0519] In another embodiment, a polypeptide of the invention, or polynucleotides, antibodies, agonists, or antagonists corresponding to that polypeptide, may be used to treat diseases and disorders of the immune system and/or to inhibit or enhance an immune response generated by cells associated with the tissue(s) in which the polypeptide of the invention is expressed, including one, two, three, four, five, or more tissues disclosed in Table 1A, column 8 (Tissue Distribution Library Code).  
       [0520] Polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in treating, preventing, diagnosing, and/or prognosing immunodeficiencies, including both congenital and acquired immunodeficiencies. Examples of B cell immunodeficiencies in which immunoglobulin levels B cell function and/or B cell numbers are decreased include: X-linked agammaglobulinemia (Bruton&#39;s disease), X-linked infantile agammaglobulinemia, X-linked immunodeficiency with hyper IgM, non X-linked immunodeficiency with hyper IgM, X-linked lymphoproliferative syndrome (XLP), agammaglobulinemia including congenital and acquired agammaglobulinemia, adult onset agammaglobulinemia, late-onset agammaglobulinemia, dysgammaglobulinemia, hypogammaglobulinemia, unspecified hypogammaglobulinemia, recessive agammaglobulinemia (Swiss type), Selective IgM deficiency, selective IgA deficiency, selective IgG subclass deficiencies, IgG subclass deficiency (with or without IgA deficiency), Ig deficiency with increased IgM, IgG and IgA deficiency with increased IgM, antibody deficiency with normal or elevated Igs, Ig heavy chain deletions, kappa chain deficiency, B cell lymphoproliferative disorder (BLPD), common variable immunodeficiency (CVID), common variable immunodeficiency (CVI) (acquired), and transient hypogammaglobulinemia of infancy.  
       [0521] In specific embodiments, ataxia-telangiectasia or conditions associated with ataxia-telangiectasia are treated, prevented, diagnosed, and/or prognosing using the polypeptides or polynucleotides of the invention, and/or agonists or antagonists thereof.  
       [0522] Examples of congenital immunodeficiencies in which T cell and/or B cell function and/or number is decreased include, but are not limited to: DiGeorge anomaly, severe combined immunodeficiencies (SCID) (including, but not limited to, X-linked SCID, autosomal recessive SCID, adenosine deaminase deficiency, purine nucleoside phosphorylase (PNP) deficiency, Class II MHC deficiency (Bare lymphocyte syndrome), Wiskott-Aldrich syndrome, and ataxia telangiectasia), thymic hypoplasia, third and fourth pharyngeal pouch syndrome, 22q11.2 deletion, chronic mucocutaneous candidiasis, natural killer cell deficiency (NK), idiopathic CD4+ T-lymphocytopenia, immunodeficiency with predominant T cell defect (unspecified), and unspecified immunodeficiency of cell mediated immunity.  
       [0523] In specific embodiments, DiGeorge anomaly or conditions associated with DiGeorge anomaly are treated, prevented, diagnosed, and/or prognosed using polypeptides or polynucleotides of the invention, or antagonists or agonists thereof.  
       [0524] Other immunodeficiencies that may be treated, prevented, diagnosed, and/or prognosed using polypeptides or polynucleotides of the invention, and/or agonists or antagonists thereof, include, but are not limited to, chronic granulomatous disease, Chédiak-Higashi syndrome, myeloperoxidase deficiency, leukocyte glucose-6-phosphate dehydrogenase deficiency, X-linked lymphoproliferative syndrome (XLP), leukocyte adhesion deficiency, complement component deficiencies (including C1, C2, C3, C4, C5, C6, C7, C8 and/or C9 deficiencies), reticular dysgenesis, thymic alymphoplasia-aplasia, immunodeficiency with thymoma, severe congenital leukopenia, dysplasia with immunodeficiency, neonatal neutropenia, short limbed dwarfism, and Nezelof syndrome-combined immunodeficiency with Igs.  
       [0525] In a preferred embodiment, the immunodeficiencies and/or conditions associated with the immunodeficiencies recited above are treated, prevented, diagnosed and/or prognosed using polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention.  
       [0526] In a preferred embodiment polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention could be used as an agent to boost immunoresponsiveness among immunodeficient individuals. In specific embodiments, polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention could be used as an agent to boost immunoresponsiveness among B cell and/or T cell immunodeficient individuals.  
       [0527] The polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in treating, preventing, diagnosing and/or prognosing autoimmune disorders. Many autoimmune disorders result from inappropriate recognition of self as foreign material by immune cells. This inappropriate recognition results in an immune response leading to the destruction of the host tissue. Therefore, the administration of polynucleotides and polypeptides of the invention that can inhibit an immune response, particularly the proliferation, differentiation, or chemotaxis of T-cells, may be an effective therapy in preventing autoimmune disorders.  
       [0528] Autoimmune diseases or disorders that may be treated, prevented, diagnosed and/or prognosed by polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention include, but are not limited to, one or more of the following: systemic lupus erythematosus, rheumatoid arthritis, ankylosing spondylitis, multiple sclerosis, autoimmune thyroiditis, Hashimoto&#39;s thyroiditis, autoimmune hemolytic anemia, hemolytic anemia, thrombocytopenia, autoimmune thrombocytopenia purpura, autoimmune neonatal thrombocytopenia, idiopathic thrombocytopenia purpura, purpura (e.g., Henloch-Scoenlein purpura), autoimmunocytopenia, Goodpasture&#39;s syndrome, Pemphigus vulgaris, myasthenia gravis, Grave&#39;s disease (hyperthyroidism), and insulin-resistant diabetes mellitus.  
       [0529] Additional disorders that are likely to have an autoimmune component that may be treated, prevented, and/or diagnosed with the compositions of the invention include, but are not limited to, type II collagen-induced arthritis, antiphospholipid syndrome, dermatitis, allergic encephalomyelitis, myocarditis, relapsing polychondritis, rheumatic heart disease, neuritis, uveitis ophthalmia, polyendocrinopathies, Reiter&#39;s Disease, Stiff-Man Syndrome, autoimmune pulmonary inflammation, autism, Guillain-Barre Syndrome, insulin dependent diabetes mellitus, and autoimmune inflammatory eye disorders.  
       [0530] Additional disorders that are likely to have an autoimmune component that may be treated, prevented, diagnosed and/or prognosed with the compositions of the invention include, but are not limited to, scleroderma with anti-collagen antibodies (often characterized, e.g., by nucleolar and other nuclear antibodies), mixed connective tissue disease (often characterized, e.g., by antibodies to extractable nuclear antigens (e.g., ribonucleoprotein)), polymyositis (often characterized, e.g., by nonhistone ANA), pernicious anemia (often characterized, e.g., by antiparietal cell, microsomes, and intrinsic factor antibodies), idiopathic Addison&#39;s disease (often characterized, e.g., by humoral and cell-mediated adrenal cytotoxicity, infertility (often characterized, e.g., by antispermatozoal antibodies), glomerulonephritis (often characterized, e.g., by glomerular basement membrane antibodies or immune complexes), bullous pemphigoid (often characterized, e.g., by IgG and complement in basement membrane), Sjogren&#39;s syndrome (often characterized, e.g., by multiple tissue antibodies, and/or a specific nonhistone ANA (SS-B)), diabetes mellitus (often characterized, e.g., by cell-mediated and humoral islet cell antibodies), and adrenergic drug resistance (including adrenergic drug resistance with asthma or cystic fibrosis) (often characterized, e.g., by beta-adrenergic receptor antibodies).  
       [0531] Additional disorders that may have an autoimmune component that may be treated, prevented, diagnosed and/or prognosed with the compositions of the invention include, but are not limited to, chronic active hepatitis (often characterized, e.g., by smooth muscle antibodies), primary biliary cirrhosis (often characterized, e.g., by mitochondria antibodies), other endocrine gland failure (often characterized, e.g., by specific tissue antibodies in some cases), vitiligo (often characterized, e.g., by melanocyte antibodies), vasculitis (often characterized, e.g., by Ig and complement in vessel walls and/or low serum complement), post-MI (often characterized, e.g., by myocardial antibodies), cardiotomy syndrome (often characterized, e.g., by myocardial antibodies), urticaria (often characterized, e.g., by IgG and IgM antibodies to IgE), atopic dermatitis (often characterized, e.g., by IgG and IgM antibodies to IgE), asthma (often characterized, e.g., by IgG and IgM antibodies to IgE), and many other inflammatory, granulomatous, degenerative, and atrophic disorders.  
       [0532] In a preferred embodiment, the autoimmune diseases and disorders and/or conditions associated with the diseases and disorders recited above are treated, prevented, diagnosed and/or prognosed using for example, antagonists or agonists, polypeptides or polynucleotides, or antibodies of the present invention. In a specific preferred embodiment, rheumatoid arthritis is treated, prevented, and/or diagnosed using polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention.  
       [0533] In another specific preferred embodiment, systemic lupus erythematosus is treated, prevented, and/or diagnosed using polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention. In another specific preferred embodiment, idiopathic thrombocytopenia purpura is treated, prevented, and/or diagnosed using polynucleotides, polypeptides, antibodies, and/or agonists or agtagonists of the present invention.  
       [0534] In another specific preferred embodiment IgA nephropathy is treated, prevented, and/or diagnosed using polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention.  
       [0535] In a preferred embodiment, the autoimmune diseases and disorders and/or conditions associated with the diseases and disorders recited above are treated, prevented, diagnosed and/or prognosed using polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention.  
       [0536] In preferred embodiments, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as a immunosuppressive agent(s).  
       [0537] Polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in treating, preventing, prognosing, and/or diagnosing diseases, disorders, and/or conditions of hematopoietic cells. Polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention could be used to increase differentiation and proliferation of hematopoletic cells, including the pluripotent stem cells, in an effort to treat or prevent those diseases, disorders, and/or conditions associated with a decrease in certain (or many) types hematopoietic cells, including but not limited to, leukopenia, neutropenia, anemia, and thrombocytopenia. Alternatively, Polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention could be used to increase differentiation and proliferation of hematopoietic cells, including the pluripotent stem cells, in an effort to treat or prevent those diseases, disorders, and/or conditions associated with an increase in certain (or many) types of hematopoietic cells, including but not limited to, histiocytosis.  
       [0538] Allergic reactions and conditions, such as asthma (particularly allergic asthma) or other respiratory problems, may also be treated, prevented, diagnosed and/or prognosed using polypeptides, antibodies, or polynucleotides of the invention, and/or agonists or antagonists thereof. Moreover, these molecules can be used to treat, prevent, prognose, and/or diagnose anaphylaxis, hypersensitivity to an antigenic molecule, or blood group incompatibility.  
       [0539] Additionally, polypeptides or polynucleotides of the invention, and/or agonists or antagonists thereof, may be used to treat, prevent, diagnose and/or prognose IgE-mediated allergic reactions. Such allergic reactions include, but are not limited to, asthma, rhinitis, and eczema. In specific embodiments, polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be used to modulate IgE concentrations in vitro or in vivo.  
       [0540] Moreover, polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention have uses in the diagnosis, prognosis, prevention, and/or treatment of inflammatory conditions. For example, since polypeptides, antibodies, or polynucleotides of the invention, and/or agonists or antagonists of the invention may inhibit the activation, proliferation and/or differentiation of cells involved in an inflammatory response, these molecules can be used to prevent and/or treat chronic and acute inflammatory conditions. Such inflammatory conditions include, but are not limited to, for example, inflammation associated with infection (e.g., septic shock, sepsis, or systemic inflammatory response syndrome), ischemia-reperfusion injury, endotoxin lethality, complement-mediated hyperacute rejection, nephritis, cytokine or chemokine induced lung injury, inflammatory bowel disease, Crohn&#39;s disease, over production of cytokines (e.g., TNF or IL-1.), respiratory disorders (e.g., asthma and allergy); gastrointestinal disorders (e.g., inflammatory bowel disease); cancers (e.g., gastric, ovarian, lung, bladder, liver, and breast); CNS disorders (e.g., multiple sclerosis; ischemic brain injury and/or stroke, traumatic brain injury, neurodegenerative disorders (e.g., Parkinson&#39;s disease and Alzheimer&#39;s disease); AIDS-related dementia; and prion disease); cardiovascular disorders (e.g., atherosclerosis, myocarditis, cardiovascular disease, and cardiopulmonary bypass complications); as well as many additional diseases, conditions, and disorders that are characterized by inflammation (e.g., hepatitis, rheumatoid arthritis, gout, trauma, pancreatitis, sarcoidosis, dermatitis, renal ischemia-reperfusion injury, Grave&#39;s disease, systemic lupus erythematosus, diabetes mellitus, and allogenic transplant rejection).  
       [0541] Because inflammation is a fundamental defense mechanism, inflammatory disorders can effect virtually any tissue of the body. Accordingly, polynucleotides, polypeptides, and antibodies of the invention, as well as agonists or antagonists thereof, have uses in the treatment of tissue-specific inflamrnatory disorders, including, but not limited to, adrenalitis, alveolitis, angiocholecystitis, appendicitis, balanitis, blepharitis, bronchitis, bursitis, carditis, cellulitis, cervicitis, cholecystitis, chorditis, cochlitis, colitis, conjunctivitis, cystitis, dermatitis, diverticulitis, encephalitis, endocarditis, esophagitis, eustachitis, fibrositis, folliculitis, gastritis, gastroenteritis, gingivitis, glossitis, hepatosplenitis, keratitis, labyrinthitis, laryngitis, lymphangitis, mastitis, media otitis, meningitis, metritis, mucitis, myocarditis, myosititis, myringitis, nephritis, neuritis, orchitis, osteochondritis, otitis, pericarditis, peritendonitis, peritonitis, pharyngitis, phlebitis, poliomyelitis, prostatitis, pulpitis, retinitis, rhinitis, salpingitis, scleritis, sclerochoroiditis, scrotitis, sinusitis, spondylitis, steatitis, stomatitis, synovitis, syringitis, tendonitis, tonsillitis, urethritis, and vaginitis.  
       [0542] In specific embodiments, polypeptides, antibodies, or polynucleotides of the invention, and/or agonists or antagonists thereof, are useful to diagnose, prognose, prevent, and/or treat organ transplant rejections and graft-versus-host disease. Organ rejection occurs by host immune cell destruction of the transplanted tissue through an immune response. Similarly, an immune response is also involved in GVHD, but, in this case, the foreign transplanted immune cells destroy the host tissues. Polypeptides, antibodies, or polynucleotides of the invention, and/or agonists or antagonists thereof, that inhibit an immune response, particularly the activation, proliferation, differentiation, or chemotaxis of T-cells, may be an effective therapy in preventing organ rejection or GVHD. In specific embodiments, polypeptides, antibodies, or polynucleotides of the invention, and/or agonists or antagonists thereof, that inhibit an immune response, particularly the activation, proliferation, differentiation, or chemotaxis of T-cells, may be an effective therapy in preventing experimental allergic and hyperacute xenograft rejection.  
       [0543] In other embodiments, polypeptides, antibodies, or polynucleotides of the invention, and/or agonists or antagonists thereof, are useful to diagnose, prognose, prevent, and/or treat immune complex diseases, including, but not limited to, serum sickness, post streptococcal glomerulonephritis, polyarteritis nodosa, and immune complex-induced vasculitis.  
       [0544] Polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the invention can be used to treat, detect, and/or prevent infectious agents. For example, by increasing the immune response, particularly increasing the proliferation activation and/or differentiation of B and/or T cells, infectious diseases may be treated, detected, and/or prevented. The immune response may be increased by either enhancing an existing immune response, or by initiating a new immune response. Alternatively, polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may also directly inhibit the infectious agent (refer to section of application listing infectious agents, etc), without necessarily eliciting an immune response.  
       [0545] In another embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as a vaccine adjuvant that enhances immune responsiveness to an antigen. In a specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as an adjuvant to enhance tumor-specific immune responses.  
       [0546] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as an adjuvant to enhance anti-viral immune responses. Anti-viral immune responses that may be enhanced using the compositions of the invention as an adjuvant, include virus and virus associated diseases or symptoms described herein or otherwise known in the art. In specific embodiments, the compositions of the invention are used as an adjuvant to enhance an immune response to a virus, disease, or symptom selected from the group consisting of: AIDS, meningitis, Dengue, EBV, and hepatitis (e.g., hepatitis B). In another specific embodiment, the compositions of the invention are used as an adjuvant to enhance an immune response to a virus, disease, or symptom selected from the group consisting of: HIV/AIDS, respiratory syncytial virus, Dengue, rotavirus, Japanese B encephalitis, influenza A and B, parainfluenza, measles, cytomegalovirus, rabies, Junin, Chikungunya, Rift Valley Fever, herpes simplex, and yellow fever.  
       [0547] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as an adjuvant to enhance anti-bacterial or anti-fungal immune responses. Anti-bacterial or anti-fungal immune responses that may be enhanced using the compositions of the invention as an adjuvant, include bacteria or fungus and bacteria or fungus associated diseases or symptoms described herein or otherwise known in the art. In specific embodiments, the compositions of the invention are used as an adjuvant to enhance an immune response to a bacteria or fungus, disease, or symptom selected from the group consisting of: tetanus, Diphtheria, botulism, and meningitis type B.  
       [0548] In another specific embodiment, the compositions of the invention are used as an adjuvant to enhance an immune response to a bacteria or fungus, disease, or symptom selected from the group consisting of:  Vibrio cholerae, Mycobacterium leprae, Salmonella typhi, Salmonella paratyphi, Meisseria meningitidis, Streptococcus pneumoniae , Group B streptococcus, Shigella spp., Enterotoxigenic  Escherichia coli , Enterohemorrhagic  E. coli , and  Borrelia burgdorferi.    
       [0549] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as an adjuvant to enhance anti-parasitic immune responses. Anti-parasitic immune responses that may be enhanced using the compositions of the invention as an adjuvant, include parasite and parasite associated diseases or symptoms described herein or otherwise known in the art. In specific embodiments, the compositions of the invention are used as an adjuvant to enhance an immune response to a parasite. In another specific embodiment, the compositions of the invention are used as an adjuvant to enhance an immune response to Plasmodium (malaria) or Leishmania.  
       [0550] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention may also be employed to treat infectious diseases including silicosis, sarcoidosis, and idiopathic pulmonary fibrosis; for example, by preventing the recruitment and activation of mononuclear phagocytes.  
       [0551] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as an antigen for the generation of antibodies to inhibit or enhance immune mediated responses against polypeptides of the invention.  
       [0552] In one embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are administered to an animal (e.g., mouse, rat, rabbit, hamster, guinea pig, pigs, micro-pig, chicken, camel, goat, horse, cow, sheep, dog, cat, non-human primate, and human, most preferably human) to boost the immune system to produce increased quantities of one or more antibodies (e.g., IgG, IgA, IgM, and IgE), to induce higher affinity antibody production and immunoglobulin class switching (e.g., IgG, IgA, IgM, and IgE), and/or to increase an immune response.  
       [0553] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as a stimulator of B cell responsiveness to pathogens.  
       [0554] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as an activator of T cells.  
       [0555] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as an agent that elevates the immune status of an individual prior to their receipt of immunosuppressive therapies.  
       [0556] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as an agent to induce higher affinity antibodies.  
       [0557] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as an agent to increase serum immunoglobulin concentrations.  
       [0558] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as an agent to accelerate recovery of immunocompromised individuals.  
       [0559] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as an agent to boost immunoresponsiveness among aged populations and/or neonates.  
       [0560] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as an immune system enhancer prior to, during, or after bone marrow transplant and/or other transplants (e.g., allogeneic or xenogeneic organ transplantation). With respect to transplantation, compositions of the invention may be administered prior to, concomitant with, and/or after transplantation. In a specific embodiment, compositions of the invention are administered after transplantation, prior to the beginning of recovery of T-cell populations. In another specific embodiment, compositions of the invention are first administered after transplantation after the beginning of recovery of T cell populations, but prior to full recovery of B cell populations.  
       [0561] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as an agent to boost immunoresponsiveness among individuals having an acquired loss of B cell function. Conditions resulting in an acquired loss of B cell function that may be ameliorated or treated by administering the polypeptides, antibodies, polynucleotides and/or agonists or antagonists thereof, include, but are not limited to, HIV Infection, AIDS, bone marrow transplant, and B cell chronic lymphocytic leukemia (CLL).  
       [0562] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as an agent to boost immunoresponsiveness among individuals having a temporary immune deficiency. Conditions resulting in a temporary immune deficiency that may be ameliorated or treated by administering the polypeptides, antibodies, polynucleotides and/or agonists or antagonists thereof, include, but are not limited to, recovery from viral infections (e.g., influenza), conditions associated with malnutrition, recovery from infectious mononucleosis, or conditions associated with stress, recovery from measles, recovery from blood transfusion, and recovery from surgery.  
       [0563] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as a regulator of antigen presentation by monocytes, dendritic cells, and/or B-cells. In one embodiment, polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention enhance antigen presentation or antagonizes antigen presentation in vitro or in vivo. Moreover, in related embodiments, said enhancement or antagonism of antigen presentation may be useful as an anti-tumor treatment or to modulate the immune system.  
       [0564] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as an agent to direct an individual&#39;s immune system towards development of a humoral response (i.e. TH2) as opposed to a TH1 cellular response.  
       [0565] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as a means to induce tumor proliferation and thus make it more susceptible to anti-neoplastic agents. For example, multiple myeloma is a slowly dividing disease and is thus refractory to virtually all anti-neoplastic regimens. If these cells were forced to proliferate more rapidly their susceptibility profile would likely change.  
       [0566] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as a stimulator of B cell production in pathologies such as AIDS, chronic lymphocyte disorder and/or Common Variable Immunodificiency.  
       [0567] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as a therapy for generation and/or regeneration of lymphoid tissues following surgery, trauma or genetic defect. In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used in the pretreatment of bone marrow samples prior to transplant.  
       [0568] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as a gene-based therapy for genetically inherited disorders resulting in immuno-incompetence/immunodeficiency such as observed among SCID patients.  
       [0569] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as a means of activating monocytes/macrophages to defend against parasitic diseases that effect monocytes such as Leishmania.  
       [0570] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as a means of regulating secreted cytokines that are elicited by polypeptides of the invention.  
       [0571] In another embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used in one or more of the applications decribed herein, as they may apply to veterinary medicine.  
       [0572] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as a means of blocking various aspects of immune responses to foreign agents or self. Examples of diseases or conditions in which blocking of certain aspects of immune responses may be desired include autoimmune disorders such as lupus, and arthritis, as well as immunoresponsiveness to skin allergies, inflammation, bowel disease, injury and diseases/disorders associated with pathogens.  
       [0573] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as a therapy for preventing the B cell proliferation and Ig secretion associated with autoimmune diseases such as idiopathic thrombocytopenic purpura, systemic lupus erythematosus and multiple sclerosis.  
       [0574] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as a inhibitor of B and/or T cell migration in endothelial cells. This activity disrupts tissue architecture or cognate responses and is useful, for example in disrupting immune responses, and blocking sepsis.  
       [0575] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as a therapy for chronic hypergammaglobulinemia evident in such diseases as monoclonal gammopathy of undetermined significance (MGUS), Waldenstrom&#39;s disease, related idiopathic monoclonal gammopathies, and plasmacytpmas.  
       [0576] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention may be employed for instance to inhibit polypeptide chemotaxis and activation of macrophages and their precursors, and of neutrophils, basophils, B lymphocytes and some T-cell subsets, e.g., activated and CD8 cytotoxic T cells and natural killer cells, in certain autoimmune and chronic inflammatory and infective diseases. Examples of autoimmune diseases are described herein and include multiple sclerosis, and insulin-dependent diabetes.  
       [0577] The polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention may also be employed to treat idiopathic hypereosinophilic syndrome by, for example, preventing eosinophil production and migration.  
       [0578] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used to enhance or inhibit complement mediated cell lysis.  
       [0579] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used to enhance or inhibit antibody dependent cellular cytotoxicity.  
       [0580] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention may also be employed for treating atherosclerosis, for example, by preventing monocyte infiltration in the artery wall.  
       [0581] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention may be employed to treat adult respiratory distress syndrome (ARDS).  
       [0582] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention may be useful for stimulating wound and tissue repair, stimulating angiogenesis, and/or stimulating the repair of vascular or lymphatic diseases or disorders. Additionally, agonists and antagonists of the invention may be used to stimulate the regeneration of mucosal surfaces.  
       [0583] In a specific embodiment, polynucleotides or polypeptides, and/or agonists thereof are used to diagnose, prognose, treat, and/or prevent a disorder characterized by primary or acquired immunodeficiency, deficient serum immunoglobulin production, recurrent infections, and/or immune system dysfunction. Moreover, polynucleotides or polypeptides, and/or agonists thereof may be used to treat or prevent infections of the joints, bones, skin, and/or parotid glands, blood-borne infections (e.g., sepsis, meningitis, septic arthritis, and/or osteomyelitis), autoimmune diseases (e.g., those disclosed herein), inflammatory disorders, and malignancies, and/or any disease or disorder or condition associated with these infections, diseases, disorders and/or malignancies) including, but not limited to, CVID, other primary immune deficiencies, HIV disease, CLL, recurrent bronchitis, sinusitis, otitis media, conjunctivitis, pneumonia, hepatitis, meningitis, herpes zoster (e.g., severe herpes zoster), and/or pneumocystis carnii. Other diseases and disorders that may be prevented, diagnosed, prognosed, and/or treated with polynucleotides or polypeptides, and/or agonists of the present invention include, but are not limited to, HIV infection, HTLV-BLV infection, lymphopenia, phagocyte bactericidal dysfunction anemia, thrombocytopenia, and hemoglobinuria.  
       [0584] In another embodiment, polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention are used to treat, and/or diagnose an individual having common variable immunodeficiency disease (“CVID”; also known as “acquired agammaglobulinemia” and “acquired hypogammaglobulinemia”) or a subset of this disease.  
       [0585] In a specific embodiment, polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be used to diagnose, prognose, prevent, and/or treat cancers or neoplasms including immune cell or immune tissue-related cancers or neoplasms. Examples of cancers or neoplasms that may be prevented, diagnosed, or treated by polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention include, but are not limited to, acute myelogenous leukemia, chronic myelogenous leukemia, Hodgkin&#39;s disease, non-Hodgkin&#39;s lymphoma, acute lymphocytic anemia (ALL) Chronic lymphocyte leukemia, plasmacytomas, multiple myeloma, Burkitt&#39;s lymphoma, EBV-transformed diseases, and/or diseases and disorders described in the section entitled “Hyperproliferative Disorders” elsewhere herein.  
       [0586] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as a therapy for decreasing cellular proliferation of Large B-cell Lymphomas.  
       [0587] In another specific embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are used as a means of decreasing the involvement of B cells and Ig associated with Chronic Myelogenous Leukemia.  
       [0588] In specific embodiments, the compositions of the invention are used as an agent to boost immunoresponsiveness among B cell immunodeficient individuals, such as, for example, an individual who has undergone a partial or complete splenectomy.  
       [0589] Antagonists of the invention include, for example, binding and/or inhibitory antibodies, antisense nucleic acids, ribozymes or soluble forms of the polypeptides of the present invention (e.g., Fc fusion protein; see, e.g., Example 9). Agonists of the invention include, for example, binding or stimulatory antibodies, and soluble forms of the polypeptides (e.g., Fc fusion proteins; see, e.g., Example 9). polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention may be employed in a composition with a pharmaceutically acceptable carrier, e.g., as described herein.  
       [0590] In another embodiment, polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention are administered to an animal (including, but not limited to, those listed above, and also including transgenic animals) incapable of producing functional endogenous antibody molecules or having an otherwise compromised endogenous immune system, but which is capable of producing human immunoglobulin molecules by means of a reconstituted or partially reconstituted immune system from another animal (see, e.g., published PCT Application Nos. WO98/24893, WO/9634096, WO/9633735, and WO/9110741). Administration of polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention to such animals is useful for the generation of monoclonal antibodies against the polypeptides, antibodies, polynucleotides and/or agonists or antagonists of the present invention.  
       [0591] Blood-Related Disorders  
       [0592] The polynucleotides, polypeptides, antibodies, and/or, agonists or antagonists of the present invention may be used to modulate hemostatic (the stopping of bleeding) or thrombolytic (clot dissolving) activity. For example, by increasing hemostatic or thrombolytic activity, polynucleotides or polypeptides, and/or agonists or antagonists of the present invention could be used to treat or prevent blood coagulation diseases, disorders, and/or conditions (e.g., afibrinogenemia, factor deficiencies, hemophilia), blood platelet diseases, disorders, and/or conditions (e.g., thrombocytopenia), or wounds resulting from trauma, surgery, or other causes. Alternatively, polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention that can decrease hemostatic or thrombolytic activity could be used to inhibit or dissolve clotting. These molecules could be important in the treatment or prevention of heart attacks (infarction), strokes, or scarring.  
       [0593] In specific embodiments, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be used to prevent, diagnose, prognose, and/or treat thrombosis, arterial thrombosis, venous thrombosis, thromboembolism, pulmonary embolism, atherosclerosis, myocardial infarction, transient ischemic attack, unstable angina. In specific embodiments, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be used for the prevention of occulsion of saphenous grafts, for reducing the risk of periprocedural thrombosis as might accompany angioplasty procedures, for reducing the risk of stroke in patients with atrial fibrillation including nonrheumatic atrial fibrillation, for reducing the risk of embolism associated with mechanical heart valves and or mitral valves disease. Other uses for the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention, include, but are not limited to, the prevention of occlusions in extrcorporeal devices (e.g., intravascular canulas, vascular access shunts in hemodialysis patients, hemodialysis machines, and cardiopulmonary bypass machines).  
       [0594] In another embodiment, a polypeptide of the invention, or polynucleotides, antibodies, agonists, or antagonists corresponding to that polypeptide, may be used to prevent, diagnose, prognose, and/or treat diseases and disorders of the blood and/or blood forming organs associated with the tissue(s) in which the polypeptide of the invention is expressed, including one, two, three, four, five, or more tissues disclosed in Table 1A, column 7 (Tissue Distribution Library Code).  
       [0595] In another embodiment, a polypeptide of the invention, or polynucleotides, antibodies, agonists, or antagonists corresponding to that polypeptide, may be used to prevent, diagnose, prognose, and/or treat diseases and disorders of the blood and/or blood forming organs associated with the tissue(s) in which the polypeptide of the invention is expressed, including one, two, three, four, five, or more tissues disclosed in Table 1A, column 7 (Tissue Distribution Library Code).  
       [0596] The polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be used to modulate hematopoietic activity (the formation of blood cells). For example, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be used to increase the quantity of all or subsets of blood cells, such as, for example, erythrocytes, lymphocytes (B or T cells), myeloid cells (e.g., basophils, eosinophils, neutrophils, mast cells, macrophages) and platelets. The ability to decrease the quantity of blood cells or subsets of blood cells may be useful in the prevention,, detection, diagnosis and/or treatment of anemias and leukopenias described below. Alternatively, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be used to decrease the quantity of all or subsets of blood cells, such as, for example, erythrocytes, lymphocytes (B or T cells), myeloid cells (e.g., basophils, eosinophils, neutrophils, mast cells, macrophages) and platelets.. The ability to decrease the quantity of blood cells or subsets of blood cells may be useful in the prevention, detection, diagnosis and/or treatment of leukocytoses, such as, for example eosinophilia.  
       [0597] The, polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be used to prevent, treat, or diagnose blood dyscrasia.  
       [0598] Anemias are conditions in which the number of red blood cells or amount of hemoglobin (the protein that carries oxygen) in them is below normal. Anemia may be caused by excessive bleeding, decreased red blood cell production, or increased red blood cell destruction (hemolysis). The polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in treating, preventing, and/or diagnosing anemias. Anemias that may be treated prevented or diagnosed by the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention include iron deficiency anemia, hypochromic anemia, microcytic anemia, chlorosis, hereditary siderob;astic anemia, idiopathic acquired siderobtastic anemia, red cell aplasia, megaloblastic anemia (e.g., pernicious anemia, (vitamin B12 deficiency) and folic acid deficiency anemia), aplastic anemia, hemolytic anemias (e.g., autoimmune helolytic anemia, microangiopathic hemolytic anemia, and paroxysmal nocturnal hemoglobinuria). The polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in treating, preventing, and/or diagnosing anemias associated with diseases including but not limited to, anemias associated with systemic lupus erythematosus, cancers, lymphomas, chronic renal disease, and enlarged spleens. The polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in treating, preventing, and/or diagnosing anemias arising from drug treatments such as anemias associated with methyldopa, dapsone, and/or sulfadrugs. Additionally, rhe polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in treating, preventing, and/or diagnosing anemias associated with abnormal red blood cell architecture including but not limited to, hereditary spherocytosis, hereditary elliptocytosis, glucose-6-phosphate dehydrogenase deficiency, and sickle cell anemia.  
       [0599] The polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in treating, preventing, and/or diagnosing hemoglobin abnormalities, (e.g., those associated with sickle cell anemia, hemoglobin C disease, hemoglobin S-C disease, and hemoglobin E disease). Additionally, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in diagnosing, prognosing, preventing, and/or treating thalassemias, including, but not limited to major and minor forms of alpha-thalassemia and beta-thalassemia.  
       [0600] In another embodiment, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in diagnosing, prognosing, preventing, and/or treating bleeding disorders including, but not limited to, thrombocytopenia (e.g., idiopathic thrombocytopenic purpura, and thrombotic thrombocytopenic purpura), Von Willebrand&#39;s disease, hereditary platelet disorders (e.g., storage pool disease such as Chediak-Higashi and Hermansky-Pudlak syndromes, thromboxane A2 dysfunction, thromboasthenia, and Bernard-Soulier syndrome), hemolytic-uremic syndrome, hemophelias such as hemophelia A or Factor VII deficiency and Christmas disease or Factor IX deficiency, Hereditary Hemorhhagic Telangiectsia, also known as Rendu-Osler-Weber syndrome, allergic purpura (Henoch Schonlein purpura) and disseminated intravascular coagulation.  
       [0601] The effect of the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention on the clotting time of blood may be monitored using any of the clotting tests known in the art including, but not limited to, whole blood partial thromboplastin time (PTT), the activated partial thromboplastin time (aPTT), the activated clotting time (ACT), the recalcified activated clotting time, or the Lee-White Clotting time.  
       [0602] Several diseases and a variety of drugs can cause platelet dysfunction. Thus, in a specific embodiment, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in diagnosing, prognosing, preventing, and/or treating acquired platelet dysfunction such as platelet dysfunction accompanying kidney failure, leukemia, multiple myeloma, cirrhosis of the liver, and systemic lupus erythematosus as well as platelet dysfunction associated with drug treatments, including treatment with aspirin, ticlopidine, nonsteroidal anti-inflammatory drugs (used for arthritis, pain, and sprains), and penicillin in high doses.  
       [0603] In another embodiment, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in diagnosing, prognosing, preventing, and/or treating diseases and disorders characterized by or associated with increased or decreased numbers of white blood cells. Leukopenia occurs when the number of white blood cells decreases below normal. Leukopenias include, but are not limited to, neutropenia and Iymphocytopenia. An increase in the number of white blood cells compared to normal is known as leukocytosis. The body generates increased numbers of white blood cells during infection. Thus, leukocytosis may simply be a normnal physiological parameter that reflects infection. Alternatively, leukocytosis may be an indicator of injury or other disease such as cancer. Leokocytoses, include but are not limited to, eosinophilia, and accumulations of macrophages. In specific embodiments, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in diagnosing, prognosing, preventing, and/or treating leukopenia. In other specific embodiments, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in diagnosing, prognosing, preventing, and/or treating leukocytosis  
       [0604] Leukopenia may be a generalized decreased in all types of white blood cells, or may be a specific depletion of particular types of white blood cells. Thus, in specific embodiments, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in diagnosing, prognosing, preventing, and/or treating decreases in neutrophil numbers, known as neutropenia. Neutropenias that may be diagnosed, prognosed, prevented, and/or treated by the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention include, but are not limited to, infantile genetic agranulocytosis, familial neutropenia, cyclic neutropenia, neutropenias resulting from or associated with dietary deficiencies (e.g., vitamin B 12 deficiency or folic acid deficiency), neutropenias resulting from or associated with drug treatments (e.g., antibiotic regimens such as penicillin treatment, sulfonamide treatment, anticoagulant treatment, anticonvulsant drugs, anti-thyroid drugs, and cancer chemotherapy), and neutropenias resulting from increased neutrophil destruction that may occur in association with some bacterial or viral infections, allergic disorders, autoimmune diseases, conditions in which an individual has an enlarged spleen (e.g., Felty syndrome, malaria and sarcoidosis), and some drug treatment regimens.  
       [0605] The polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in diagnosing, prognosing, preventing, and/or treating lymphocytopenias (decreased numbers of B and/or T lymphocytes), including, but not limited lymphocytopenias resulting from or associated with stress, drug treatments (e.g., drug treatment with corticosteroids, cancer chemotherapies, and/or radiation therapies), AIDS infection and/or other diseases such as, for example, cancer, rheumatoid arthritis, systemic lupus erythematosus, chronic infections, some viral infections and/or hereditary disorders (e.g., DiGeorge syndrome, Wiskott-Aldrich Syndome, severe combined immunodeficiency, ataxia telangiectsia).  
       [0606] The polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in diagnosing, prognosing, preventing, and/or treating diseases and disorders associated with macrophage numbers and/or macrophage function including, but not limited to, Gaucher&#39;s disease, Niemann-Pick disease, Letterer-Siwe disease and Hand-Schuller-Christian disease.  
       [0607] In another embodiment, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in diagnosing, prognosing, preventing, and/or treating diseases and disorders associated with eosinophil numbers and/or eosinophil function including, but not limited to, idiopathic hypereosinophilic syndrome, eosinophilia-myalgia syndrome, and Hand-Schuller-Christian disease.  
       [0608] In yet another embodiment, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in diagnosing, prognosing, preventing, and/or treating leukemias and lymphomas including, but not limited to, acute lymphocytic (lymphpblastic) leukemia (ALL), acute myeloid (myelocytic, myelogenous, myeloblastic, or myelomonocytic) leukemia, chronic lymphocytic leukemia (e.g., B cell leukemias, T cell leukemias, Sezary syndrome, and Hairy cell leukenia), chronic myelocytic (myeloid, myelogenous, or granulocytic) leukemia, Hodgkin&#39;s lymphoma, non-hodgkin&#39;s lymphoma, Burkitt&#39;s lymphoma, and mycosis fungoides.  
       [0609] In other embodiments, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in diagnosing, prognosing, preventing, and/or treating diseases and disorders of plasma cells including, but not limited to, plasma cell dyscrasias, monoclonal gammaopathies, monoclonal gammopathies of undetermined significance, multiple myeloma, macroglobulinemia, Waldenstrom&#39;s macroglobulinemia, cryoglobulinemia, and Raynaud&#39;s phenomenon.  
       [0610] In other embodiments, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in treating, preventing, and/or diagnosing myeloproliferative disorders, including but not limited to, polycythemia vera, relative polycythemia, secondary polycythemia, myelofibrosis, acute myelofibrosis, agnogenic myelod metaplasia, thrombocythemia, (including both primary and seconday thrombocythemia) and chronic myelocytic leukemia.  
       [0611] In other embodiments, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful as a treatment prior to surgery, to increase blood cell production.  
       [0612] In other embodiments, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful as an agent to enhance the migration, phagocytosis, superoxide production, antibody dependent cellular cytotoxicity of neutrophils, eosionophils and macrophages.  
       [0613] In other embodiments, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful as an agent to increase the number of stem cells in circulation prior to stem cells pheresis. In another specific embodiment, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful as an agent to increase the number of stem cells in circulation prior to platelet pheresis.  
       [0614] In other embodiments, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful as an agent to increase cytokine production.  
       [0615] In other embodiments, the polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention may be useful in preventing, diagnosing, and/or treating primary hematopoietic disorders.  
       [0616] Hyperproliferative Disorders  
       [0617] Excretory system associated polynucleotides or polypeptides, or agonists or antagonists thereof, can be used to treat, prevent, diagnose and/or prognose hyperproliferative diseases, disorders, and/or conditions, including neoplasms.  
       [0618] In a specific embodiment, excretory system associated polynucleotides or polypeptides, or agonists or antagonists thereof, can be used to treat, prevent, and/or diagnose hyperproliferative diseases, disorders, and/or conditions of the excretory system.  
       [0619] In a preferred embodiment, excretory system associated polynucleotides or polypeptides, or agonists or antagonists thereof, can be used to treat, prevent, and/or diagnose excretory system neoplasms.  
       [0620] Excretory system associated polynucleotides or polypeptides, or agonists or antagonists of the invention, may inhibit the proliferation of the disorder through direct or indirect interactions. Alternatively, excretory system associated polynucleotides or polypeptides, or agonists or antagonists thereof, may proliferate other cells, which can inhibit the hyperproliferative disorder.  
       [0621] For example, by increasing an immune response, particularly increasing antigenic qualities of the hyperprotiferative disorder or by proliferating, differentiating, or mobilizing T-cells, hyperproliferative diseases, disorders, and/or conditions can be treated, prevented, and/or diagnosed. This immune response may be increased by either enhancing an existing immune response, or by initiating a new immune response. Alternatively, decreasing an immune response may also be a method of treating, preventing, and/or diagnosing hyperproliferative diseases, disorders, and/or conditions, such as a chemotherapeutic agent.  
       [0622] Examples of hyperproliferative diseases, disorders, and/or conditions that can be treated, prevented, and/or diagnosed by excretory system associated polynucleotides or polypeptides, or agonists or antagonists thereof, include, but are not limited to neoplasms located in the: prostate, colon, abdomen, bone, breast, digestive system, liver, pancreas, peritoneum, endocrine glands (adrenal, parathyroid, pituitary, testicles, ovary, thymus, thyroid), eye, head and neck, nervous (central and peripheral), lymphatic system, pelvic, skin, soft tissue, spleen, thoracic, and urogenital.  
       [0623] Similarly, other hyperproliferative disorders can also be treated or detected by polynucleotides or polypeptides, or agonists or antagonists of the present invention. Examples of such hyperproliferative disorders include, but are not limited to: Acute Childhood Lymphoblastic Leukemia, Acute Lymphoblastic Leukemia, Acute Lymphocytic Leukemia, Acute Myeloid Leukemia, Adrenocortical Carcinoma, Adult (Primary) Hepatocellular Cancer, Adult (Primary) Liver Cancer, Adult Acute Lymphocytic Leukemia, Adult Acute Myeloid Leukemia, Adult Hodgkin&#39;s Disease, Adult Hodgkin&#39;s Lymphoma, Adult Lymphocytic Leukemia, Adult Non-Hodgkin&#39;s Lymphoma, Adult Primary Liver Cancer, Adult Soft Tissue Sarcoma, AIDS-Related Lymphoma, AIDS-Related Malignancies, Anal Cancer, Astrocytoma, Bile Duct Cancer, Bladder Cancer, Bone Cancer, Brain Stem Glioma, Brain Tumors, Breast Cancer, Cancer of the Renal Pelvis and Ureter, Central Nervous System (Primary) Lymphoma, Central Nervous System Lymphoma, Cerebellar Astrocytoma, Cerebral Astrocytoma, Cervical Cancer, Childhood (Primary) Hepatocellular Cancer, Childhood (Primary) Liver Cancer, Childhood Acute Lymphoblastic Leukemia, Childhood Acute Myeloid Leukemia, Childhood Brain Stem Glioma, Childhood Cerebellar Astrocytoma, Childhood Cerebral Astrocytoma, Childhood Extracranial Germ Cell Tumors, Childhood Hodgkin&#39;s Disease, Childhood Hodgkin&#39;s Lymphoma, Childhood Hypothalamic and Visual Pathway Glioma, Childhood Lymphoblastic Leukemia, Childhood Medulloblastoma, Childhood Non-Hodgkin&#39;s Lymphoma, Childhood Pineal and Supratentorial Primitive Neuroectodermal Tumors, Childhood Primary Liver Cancer, Childhood Rhabdomyosarcoma, Childhood Soft Tissue Sarcoma, Childhood Visual Pathway and Hypothalamic Glioma, Chronic Lymphocytic Leukemia, Chronic Myelogenous Leukemia, Colon Cancer, Cutaneous T-Cell Lymphoma, Endocrine Pancreas Islet Cell Carcinoma, Endometrial Cancer, Ependymoma, Epithelial Cancer, Esophageal Cancer, Ewing&#39;s Sarcoma and Related Tumors, Exocrine Pancreatic Cancer, Extracranial Germ Cell Tumor, Extragonadal Germ Cell Tumor, Extrahepatic Bile Duct Cancer, Eye Cancer, Female Breast Cancer, Gaucher&#39;s Disease, Gallbladder Cancer, Gastric Cancer, Gastrointestinal Carcinoid Tumor, Gastrointestinal Tumors, Germ Cell Tumors, Gestational Trophoblastic Tumor, Hairy Cell Leukemia, Head and Neck Cancer, Hepatocellular Cancer, Hodgkin&#39;s Disease, Hodgkin&#39;s Lymphoma, Hypergammaglobulinemia, Hypopharyngeal Cancer, Intestinal Cancers, Intraocular Melanoma, Islet Cell Carcinoma, Islet Cell Pancreatic Cancer, Kaposi&#39;s Sarcoma, Kidney Cancer, Laryngeal Cancer, Lip and Oral Cavity Cancer, Liver Cancer, Lung Cancer, Lymphoproliferative Disorders, Macroglobulinemia, Male Breast Cancer, Malignant Mesothelioma, Malignant Thymoma, Medulloblastoma, Melanoma, Mesothelioma, Metastatic Occult Primary Squamous Neck Cancer, Metastatic Primary Squamous Neck Cancer, Metastatic Squamous Neck Cancer, Multiple Myeloma, Multiple Myeloma/Plasma Cell Neoplasm, Myelodysplastic Syndrome, Myelogenous Leukemia, Myeloid Leukemia, Myeloproliferative Disorders, Nasal Cavity and Paranasal Sinus Cancer, Nasopharyngeal Cancer, Neuroblastoma, Non-Hodgkin&#39;s Lymphoma During Pregnancy, Nonmelanoma Skin Cancer, Non-Small Cell Lung Cancer, Occult Primary Metastatic Squamous Neck Cancer, Oropharyngeal Cancer, Osteo-/Malignant Fibrous Sarcoma, Osteosarcoma/Malignant Fibrous Histiocytoma, Osteosarcoma/Malignant Fibrous Histiocytoma of Bone, Ovarian Epithelial Cancer, Ovarian Germ Cell Tumor, Ovarian Low Malignant Potential Tumor, Pancreatic Cancer, Paraproteinemias, Purpura, Parathyroid Cancer, Penile Cancer, Pheochromocytoma, Pituitary Tumor, Plasma Cell Neoplasm/Multiple Mycloma, Primary Central Nervous System Lymphoma, Primary Liver Cancer, Prostate Cancer, Rectal Cancer, Renal Cell Cancer, Renal Pelvis and Ureter Cancer, Retinoblastoma, Rhabdomyosarcoma, Salivary Gland Cancer, Sarcoidosis Sarcomas, Sezary Syndrome, Skin Cancer, Small Cell Lung Cancer, Small Intestine Cancer, Soft Tissue Sarcoma, Squamous Neck Cancer, Stomach Cancer, Supratentorial Primitive Neuroectodermal and Pineal Tumors, T-Cell Lymphoma, Testicular Cancer, Thymoma, Thyroid Cancer, Transitional Cell Cancer of the Renal Pelvis and Ureter, Transitional Renal Pelvis and Ureter Cancer, Trophoblastic Tumors, Ureter and Renal Pelvis Cell Cancer, Urethral Cancer, Uterine Cancer, Uterine Sarcoma, Vaginal Cancer, Visual Pathway and Hypothalamic Glioma, Vulvar Cancer, Waldenstrom&#39;s Macroglobulinemia, Wilms&#39; Tumor, and any other hyperproliferative disease, besides neoplasia, located in an organ system listed above.  
       [0624] In another preferred embodiment, polynucleotides or polypeptides, or agonists or antagonists of the present invention are used to diagnose, prognose, prevent, and/or treat premalignant conditions and to prevent progression to a neoplastic or malignant state, including but not limited to those disorders described above. Such uses are indicated in conditions known or suspected of preceding progression to neoplasia or cancer, in particular, where non-neoplastic cell growth consisting of hyperplasia, metaplasia, or most particularly, dysplasia has occurred (for review of such abnormal growth conditions, see Robbins and Angell, 1976, Basic Pathology, 2d Ed., W. B. Saunders Co., Philadelphia, pp. 68-79.)  
       [0625] Hyperplasia is a form of controlled cell proliferation, involving an increase in cell number in a tissue or organ, without significant alteration in structure or function. Hyperplastic disorders which can be diagnosed, prognosed, prevented, and/or treated with compositions of the invention (including polynucleotides, polypeptides, agonists or antagonists) include, but are not limited to, angiofollicular mediastinal lymph node hyperplasia, angiolymphoid hyperplasia with eosinophilia, atypical melanocytic hyperplasia, basal cell hyperplasia, benign giant lymph node hyperplasia, cementum hyperplasia, congenital adrenal hyperplasia, congenital sebaceous hyperplasia, cystic hyperplasia, cystic hyperplasia of the breast, denture hyperplasia, ductal hyperplasia, endometrial hyperplasia, fibromuscular hyperplasia, focal epithelial hyperplasia, gingival hyperplasia, inflammatory fibrous hyperplasia, inflammatory papillary hyperplasia, intravascular papillary endothelial hyperplasia, nodular hyperplasia of prostate, nodular regenerative hyperplasia, pseudoepitheliomatous hyperplasia, senile sebaceous hyperplasia, and verrucous hyperplasia.  
       [0626] Metaplasia is a form of controlled cell growth in which one type of adult or fully differentiated cell substitutes for another type of adult cell. Metaplastic disorders which can be diagnosed, prognosed, prevented, and/or treated with compositions of the invention (including polynucleotides, polypeptides, agonists or antagonists) include, but are not limited to, agnogenic myeloid metaplasia, apocrine metaplasia, atypical metaplasia, autoparenchymatous metaplasia, connective tissue metaplasia, epithelial metaplasia, intestinal metaplasia, metaplastic anemia, metaplastic ossification, metaplastic polyps, myeloid metaplasia, primary myeloid metaplasia, secondary myeloid metaplasia, squamous metaplasia, squamous metaplasia of amnion, and symptomatic myeloid metaplasia.  
       [0627] Dysplasia is frequently a forerunner of cancer, and is found mainly in the epithelia; it is the most disorderly form of non-neoplastic cell growth, involving a loss in individual cell uniformity and in the architectural orientation of cells. Dysplastic cells often have abnormally large, deeply stained nuclei, and exhibit pleomorphism. Dysplasia characteristically occurs where there exists chronic irritation or inflammation. Dysplastic disorders which can be diagnosed, prognosed, prevented, and/or treated with compositions of the invention (including polynucleotides, polypeptides, agonists or antagonists) include, but are not limited to, anhidrotic ectodermal dysplasia, anterofacial dysplasia, asphyxiating thoracic dysplasia, atriodigital dysplasia, bronchopulmonary dysplasia, cerebral dysplasia, cervical dysplasia, chondroectodermal dysplasia, cleidocranial dysplasia, congenital ectodermal dysplasia, craniodiaphysial dysplasia, craniocarpotarsal dysplasia, craniometaphysial dysplasia, dentin dysplasia, diaphysial dysplasia, ectodermal dysplasia, enamel dysplasia, encephalo-ophthalmic dysplasia, dysplasia epiphysialis hemimelia, dysplasia epiphysialis multiplex, dysplasia epiphysialis punctata, epithelial dysplasia, faciodigitogenital dysplasia, familial fibrous dysplasia of jaws, familial white folded dysplasia, fibromuscular dysplasia, fibrous dysplasia of bone, florid osseous dysplasia, hereditary renal-retinal dysplasia, hidrotic ectodermal dysplasia, hypohidrotic ectodermal dysplasia, lymphopenic thymic dysplasia, mammary dysplasia, mandibulofacial dysplasia, metaphysial dysplasia, Mondini dysplasia, monostotic fibrous dysplasia, mucoepithelial dysplasia, multiple epiphysial dysplasia, oculoauriculovertebral dysplasia, oculodentodigital dysplasia, oculovertebral dysplasia, odontogenic dysplasia, ophthalmomandibulomelic dysplasia, periapical cemental dysplasia, polyostotic fibrous dysplasia, pseudoachondroplastic spondyloepiphysial dysplasia, retinal dysplasia, septo-optic dysplasia, spondyloepiphysial dysplasia, and ventriculoradial dysplasia.  
       [0628] Additional pre-neoplastic disorders which can be diagnosed, prognosed, prevented, and/or treated with compositions of the invention (including polynucleotides, polypeptides, agonists or antagonists) include, but are not limited to, benign dysproliferative disorders (e.g., benign tumors, fibrocystic conditions, tissue hypertrophy, intestinal polyps, colon polyps, and esophageal dysplasia), leukoplakia, keratoses, Bowen&#39;s disease, Farmer&#39;s Skin, solar cheilitis, and solar keratosis.  
       [0629] In another embodiment, a polypeptide of the invention, or polynucleotides, antibodies, agonists, or antagonists corresponding to that polypeptide, may be used to diagnose and/or prognose hyperproliferative disorders associated with the tissue(s) in which the polypeptide of the invention is expressed, including one, two, three, four, five, or more tissues disclosed in Table 1A, column 7 (Tissue Distribution Library Code).  
       [0630] In another embodiment, a polypeptide of the invention, or polynucleotides, antibodies, agonists, oantntagonists corresponding to that polypeptide, may be used to diagnose and/or prognose disorders associated with the tissue(s) in which the polypeptide of the invention is expressed, including one, two, three, four, five, or more tissues disclosed in Table 1A, column 8 (Tissue Distribution Library Code).  
       [0631] In another embodiment, polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention conjugated to a toxin or a radioactive isotope, as described herein, may be used to treat cancers and neoplasms, including, but not limited to those described herein. In a further preferred embodiment, polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention conjugated to a toxin or a radioactive isotope, as described herein, may be used to treat acute myelogenous leukemia.  
       [0632] Additionally, polynucleotides, polypeptides, and/or agonists or antagonists of the invention may affect apoptosis, and therefore, would be useful in treating a number of diseases associated with increased cell survival or the inhibition of apoptosis. For example, diseases associated with increased cell survival or the inhibition of apoptosis that could be diagnosed, prognosed, prevented, and/or treated by polynucleotides, polypeptides, and/or agonists or antagonists of the invention, include cancers (such as follicular lymphomas, carcinomas with p53 mutations, and hormone-dependent tumors, including, but not limited to colon cancer, cardiac tumors, pancreatic cancer, melanoma, retinoblastoma, glioblastoma, lung cancer, intestinal cancer, testicular cancer, stomach cancer, neuroblastoma, myxoma, myoma, lymphoma, endothelioma, osteoblastoma, osteoclastoma, osteosarcoma, chondrosarcoma, adenoma, breast cancer, prostate cancer, Kaposi&#39;s sarcoma and ovarian cancer); autoimmune disorders such as, multiple sclerosis, Sjogren&#39;s syndrome, Hashimoto&#39;s thyroiditis, biliary cirrhosis, Behcet&#39;s disease, Crohn&#39;s disease, polymyositis, systemic lupus erythematosus and immune-related glomerulonephritis and rheumatoid arthritis) and viral infections (such as herpes viruses, pox viruses and adenoviruses), inflammation, graft v. host disease, acute graft rejection, and chronic graft rejection.  
       [0633] In preferred embodiments, polynucleotides, polypeptides, and/or agonists or antagonists of the invention are used to inhibit growth, progression, and/or metastasis of cancers, in particular those listed above.  
       [0634] Additional diseases or conditions associated with increased cell survival that could be diagnosed, prognosed, prevented, and/or treated by polynucleotides, polypeptides, and/or agonists or antagonists of the invention, include, but are not limited to, progression, and/or metastases of malignancies and related disorders such as leukemia (including acute leukemias (e.g., acute lymphocytic leukemia, acute myelocytic leukemia (including myeloblastic, promyelocytic, myelomonocytic, monocytic, and erythroleukemia)) and chronic leukemias (e.g., chronic myelocytic (granulocytic) leukemia and chronic lymphocytic leukemia)), polycythemia vera, lymphomas (e.g., Hodgkin&#39;s disease and non-Hodgkin&#39;s disease), multiple myeloma, Waldenstrom&#39;s macroglobulinemia, heavy chain disease, and solid tumors including, but not limited to, sarcomas and carcinomas such as fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing&#39;s tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm&#39;s tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, emangioblastoma, acoustic neuroma, oligodendroglioma, menangioma, melanoma, neuroblastoma, and retinoblastoma.  
       [0635] Diseases associated with increased apoptosis that could be diagnosed, prognosed, prevented, and/or treated by polynucleotides, polypeptides, and/or agonists or antagonists of the invention, include AIDS; neurodegenerative disorders (such as Alzheimer&#39;s disease, Parkinson&#39;s disease, amyotrophic lateral sclerosis, retinitis pigmentosa, cerebellar degeneration and brain tumor or prior associated disease); autoimmune disorders (such as, multiple sclerosis, Sjogren&#39;s syndrome, Hashimoto&#39;s thyroiditis, biliary cirrhosis, Behcet&#39;s disease, Crohn&#39;s disease, polymyositis, systemic lupus erythematosus and immune-related glomerulonephritis and rheumatoid arthritis) myelodysplastic syndromes (such as aplastic anemia), graft v. host disease, ischemic injury (such as that caused by myocardial infarction, stroke and reperfusion injury), liver injury (e.g., hepatitis related liver injury, ischemia/reperfusion injury, cholestosis (bile duct injury) and liver cancer); toxin-induced liver disease (such as that caused by alcohol), septic shock, cachexia and anorexia.  
       [0636] Hyperproliferative diseases and/or disorders that could be diagnosed, prognosed, prevented, and/or treated by polynucleotides, polypeptides, and/or agonists or antagonists of the invention, include, but are not limited to, neoplasms located in the liver, abdomen, bone, breast, digestive system, pancreas, peritoneum, endocrine glands (adrenal, parathyroid, pituitary, testicles, ovary, thymus, thyroid), eye, head and neck, nervous system (central and peripheral), lymphatic system, pelvis, skin, soft tissue, spleen, thorax, and urogenital tract.  
       [0637] Similarly, other hyperproliferative disorders can also be diagnosed, prognosed, prevented, and/or treated by polynucleotides, polypeptides, and/or agonists or antagonists of the invention. Examples of such hyperproliferative disorders include, but are not limited to: hypergammaglobulinemia, lymphoproliferative disorders, paraproteinemias, purpura, sarcoidosis, Sezary Syndrome, Waldenstron&#39;s macroglobulinemia, Gaucher&#39;s Disease, histiocytosis, and any other hyperproliferative disease, besides neoplasia, located in an organ system listed above.  
       [0638] One preferred embodiment utilizes polynucleotides of the present invention to inhibit aberrant cellular division, by gene therapy using the present invention, and/or protein fusions or fragments thereof.  
       [0639] Thus, the present invention provides a method for treating cell proliferative diseases, disorders, and/or conditions by inserting into an abnormally proliferating cell a polynucleotide of the present invention, wherein said polynucleotide represses said cell proliferation, disease, disorder, and/or condition.  
       [0640] In a preferred embodiment, the present invention provides a method for treating cell proliferative diseases, disorders and/or conditions of the excretory system by inserting into a cell, a polynucleotide of the present invention, wherein said polynucleotide represses said cell proliferation, disease and/or disorder.  
       [0641] Another embodiment of the present invention provides a method of treating cell-proliferative diseases, disorders, and/or conditions in individuals comprising administration of one or more active gene copies of the present invention to an abnormally proliferating cell or cells. In a preferred embodiment, polynucleotides of the present invention is a DNA construct comprising a recombinant expression vector effective in expressing a DNA sequence encoding said polynucleotides. In another preferred embodiment of the present invention, the DNA construct encoding the polynucleotides of the present invention is inserted into cells to be treated utilizing a retrovirus, or more preferably an adenoviral vector (see, e.g., G J. Nabel, et. al., PNAS 96: 324-326 (1999), which is hereby incorporated by reference). In a most preferred embodiment, the viral vector is defective and will not transform non-proliferating cells, only proliferating cells. Moreover, in a preferred embodiment, the polynucleotides of the present invention inserted into proliferating cells either alone, or in combination with or fused to other polynucleotides, can then be modulated via an external stimulus (i.e., magnetic, specific small molecule, chemical, or drug administration, etc.), which acts upon the promoter upstream of said polynucleotides to induce expression of the encoded protein product. As such the beneficial therapeutic affect of the present invention may be expressly modulated (i.e., to increase, decrease, or inhibit expression of the present invention) based upon said external stimulus.  
       [0642] Polynucleotides of the present invention may be useful in repressing expression of oncogenic genes or antigens. By “repressing expression of the oncogenic genes” is intended the suppression of the transcription of the gene, the degradation of the gene transcript (pre-message RNA), the inhibition of splicing, the destruction of the messenger RNA, the prevention of the post-translational modifications of the protein, the destruction of the protein, or the inhibition of the normal function of the protein.  
       [0643] For local administration to abnormally proliferating cells, polynucleotides of the present invention may be administered by any method known to those of skill in the art including, but not limited to transfection, electroporation, microinjection of cells, or in vehicles such as liposomes, lipofectin, or as naked polynucleotides, or any other method described throughout the specification. The polynucleotide of the present invention may be delivered by known gene delivery systems such as, but not limited to, retroviral vectors (Gilboa, J. Virology 44:845 (1982); Hocke, Nature 320:275 (1986); Wilson, et al., Proc. Natl. Acad. Sci. U.S.A. 85:3014), vaccinia virus system (Chakrabarty et al., Mol. Cell Biol. 5:3403 (1985) or other efficient DNA delivery systems (Yates et al., Nature 313:812 (1985)) known to those skilled in the art. These references are exemplary only and are hereby incorporated by reference. In order to specifically deliver or transfect cells which are abnormally proliferating and spare non-dividing cells, it is preferable to utilize a retrovirus, or adenoviral (as described in the art and elsewhere herein) delivery system known to those of skill in the art. Since host DNA replication is required for retroviral DNA to integrate and the retrovirus will be unable to self replicate due to the lack of the retrovirus genes needed for its life cycle. Utilizing such a retroviral delivery system for polynucleotides of the present invention will target said gene and constructs to abnormally proliferating cells and will spare the non-dividing normal cells.  
       [0644] The polynucleotides of the present invention may be delivered directly to cell proliferative disorder/disease sites in internal organs, body cavities and the like by use of imaging devices used to guide an injecting needle directly to the disease site. The polynucleotides of the present invention may also be administered to disease sites at the time of surgical intervention.  
       [0645] By “cell proliferative disease” is meant any human or animal disease or disorder, affecting any one or any combination of organs, cavities, or body parts, which is characterized by single or multiple local abnormal proliferations of cells, groups of cells, or tissues, whether benign or malignant.  
       [0646] Any amount of the polynucleotides of the present invention may be administered as long as it has a biologically inhibiting effect on the proliferation of the treated cells. Moreover, it is possible to administer more than one of the polynucleotide of the present invention simultaneously to the same site. By “biologically inhibiting” is meant partial or total growth inhibition as well as decreases in the rate of proliferation or growth of the cells. The biologically inhibitory dose may be determined by assessing the effects of the polynucleotides of the present invention on target malignant or abnormally proliferating cell growth in tissue culture, tumor growth in animals and cell cultures, or any other method known to one of ordinary skill in the art.  
       [0647] The present invention is further directed to antibody-based therapies which involve administering of anti-polypeptides and anti-polynucleotide antibodies to a mammalian, preferably human, patient for treating one or more of the described diseases, disorders, and/or conditions. Methods for producing anti-polypeptides and anti-polynucleotide antibodies polyclonal and monoclonal antibodies are described in detail elsewhere herein. Such antibodies may be provided in pharmaceutically acceptable compositions as known in the art or as described herein.  
       [0648] A summary of the ways in which the antibodies of the present invention may be used therapeutically includes binding polynucleotides or polypeptides of the present invention locally or systemically in the body or by direct cytotoxicity of the antibody, e.g., as mediated by complement (CDC) or by effector cells (ADCC). Some of these approaches are described in more detail below. Armed with the teachings provided herein, one of ordinary skill in the art will know how to use the antibodies of the present invention for diagnostic, monitoring or therapeutic purposes without undue experimentation.  
       [0649] In particular, the antibodies, fragments and derivatives of the present invention are useful for treating a subject having or developing cell proliferative and/or differentiation diseases, disorders, and/or conditions as described herein. Such treatment comprises administering a single or multiple doses of the antibody, or a fragment, derivative, or a conjugate thereof.  
       [0650] The antibodies of this invention may be advantageously utilized in combination with other monoclonal or chimeric antibodies, or with lymphokines or hematopoietic growth factors, for example, which serve to increase the number or activity of effector cells which interact with the antibodies.  
       [0651] It is preferred to use high affinity and/or potent in vivo inhibiting and/or neutralizing antibodies against polypeptides or polynucleotides of the present invention, fragments or regions thereof, for both immunoassays directed to and therapy of diseases, disorders, and/or conditions related to polynucleotides or polypeptides, including fragments thereof, of the present invention. Such antibodies, fragments, or regions, will preferably have an affinity for polynucleotides or polypeptides, including fragments thereof. Preferred binding affinities include those with a dissociation constant or Kd less than 5×10 −6 M, 10 −6 M, 5×10 −7 M, 10 −7 M, 5×10 −8 M, 10 −8 M, 5×10 −9 M, 10 −9 M, 5×10 −10 M, 10 −10 M, 5×10 −11 M, 10 −11 M, 5×10 −12 M, 10 −12 M, 5×10 −13 M, 10 −13 M, 5×10 −14 M, 10 −14 M, 5×10 −115 M, and 10 −15 M.  
       [0652] Moreover, excretory system antigen polypeptides of the present invention or fragments thereof, are useful in inhibiting the angiogenesis of proliferative cells or tissues, either alone, as a protein fusion, or in combination with other polypeptides directly or indirectly, as described elsewhere herein. In a most preferred embodiment, said anti-angiogenesis effect may be achieved indirectly, for example, through the inhibition of hematopoietic, tumor-specific cells, such as tumor-associated macrophages (see, e.g., Joseph I B, et al. J Natl Cancer Inst, 90(21):1648-53 (1998), which is hereby incorporated by reference). Antibodies directed to polypeptides or polynucleotides of the present invention may also result in inhibition of angiogenesis directly, or indirectly (see, e.g., Witte L, et al., Cancer Metastasis Rev. 17(2):155-61 (1998), which is hereby incorporated by reference)).  
       [0653] Polypeptides, including protein fusions, of the present invention, or fragments thereof may be useful in inhibiting proliferative cells or tissues through the induction of apoptosis. Said polypeptides may act either directly, or indirectly to induce apoptosis of proliferative cells and tissues, for example in the activation of a death-domain receptor, such as tumor necrosis factor (TNF) receptor-1, CD95 (Fas/APO-1), TNF-receptor-related apoptosis-mediated protein (TRAMP) and TNF-related apoptosis-inducing ligand (TRAIL) receptor-1 and -2 (see, e.g., Schulze-Osthoff K, et.al., Eur J Biochem 254(3):439-59 (1998), which is hereby incorporated by reference). Moreover, in another preferred embodiment of the present invention, said polypeptides may induce apoptosis through other mechanisms, such as in the activation of other proteins which will activate apoptosis, or through stimulating the expression of said proteins, either alone or in combination with small molecule drugs or adjuvants, such as apoptonin, galectins, thioredoxins, antuinflammatory proteins (See for example, Mutat. Res. 400(1-2):447-55 (1998), Med Hypotheses.50(5):423-33 (1998), Chem. Biol. Interact. Apr 24;111-112:23-34(1998), J. Mo. Med. 76(6):402-12 (1998), Int. J. Tissue React. 20(1):3-15 (1998), which are all hereby incorporated by reference).  
       [0654] Polypeptides, including protein fusions to, or fragments thereof, of the present invention are useful in inhibiting the metastasis of proliferative cells or tissues. Inhibition may occur as a direct result of administering polypeptides, or antibodies directed to said polypeptides as described elsewhere herein, or indirectly, such as activating the expression of proteins known to inhibit metastasis, for example alpha 4 integrins, (See, e.g., Curr Top Microbiol Immunol 1998;231:125-41, which is hereby incorporated by reference). Such therapeutic affects of the present invention may be achieved either alone, or in combination with small molecule drugs or adjuvants.  
       [0655] In another embodiment, the invention provides a method of delivering compositions containing the polypeptides of the invention (e.g., compositions containing polypeptides or anti-excretory system antigen polypeptide antibodies associated with heterologous polypeptides, heterologous nucleic acids, toxins, or prodrugs) to targeted cells expressing the polypeptide of the present invention. excretory system antigen polypeptides or anti-excretory system antigen polypeptide antibodies of the invention may be associated with heterologous polypeptides, heterologous nucleic acids, toxins, or prodrugs via hydrophobic, hydrophilic, ionic and/or covalent interactions.  
       [0656] Polypeptides, protein fusions to, or fragments thereof, of the present invention are useful in enhancing the immunogenicity and/or antigenicity of proliferating cells or tissues, either directly, such as would occur if the polypeptides of the present invention ‘vaccinated’ the immune response to respond to proliferative antigens and immunogens, or indirectly, such as in activating the expression of proteins known to enhance the immune response (e.g. chemokines), to said antigens and immunogens.  
       [0657] Cardiovascular Disorders  
       [0658] Polynucleotides or polypeptides, or agonists or antagonists of the present invention, may be used to treat, prevent, diagnose, and/or prognose cardiovascular disorders, including, but not limited to, peripheral artery disease, such as limb ischemia.  
       [0659] Cardiovascular disorders include cardiovascular abnormalities, such as arterio-arterial fistula, arteriovenous fistula, cerebral arteriovenous malformations, congenital heart defects, pulmonary atresia, and Scimitar Syndrome. Congenital heart defects include aortic coarctation, cor triatriatum, coronary vessel anomalies, crisscross heart, dextrocardia, patent ductus arteriosus, Ebstein&#39;s anomaly, Eisenmenger complex, hypoplastic left heart syndrome, levocardia, tetralogy of fallot, transposition of great vessels, double outlet right ventricle, tricuspid atresia, persistent truncus arteriosus, total anomalous pulmonary venous connection, hypoplastic left heart syndrome, and heart septal defects, such as aortopulmonary septal defect, endocardial cushion defects, Lutembacher&#39;s Syndrome, atrioventricular canal defect, trilogy of Fallot, ventricular heart septal defects.  
       [0660] Cardiovascular disorders also include heart disease, such as arrhythmias, carcinoid heart disease, high cardiac output, low cardiac output, cardiac tamponade, endocarditis (including bacterial), heart aneurysm, cardiac arrest, sudden cardiac death, congestive heart failure, congestive cardiomyopathy, paroxysmal dyspnea, cardiac edema, heart hypertrophy, congestive cardiomyopathy, left ventricular hypertrophy, right ventricular hypertrophy, post-infarction heart rupture, ventricular septal rupture, heart valve diseases, myocardial diseases, myocardial ischemia, pericardial effusion, pericarditis (including constrictive and tuberculous), pneumopericardium, postpericardiotomy syndrome, pulmonary heart disease, rheumatic heart disease, ventricular dysfunction, hyperemia, cardiovascular pregnancy complications, Scimitar Syndrome, diastolic dysfunction, enlarged heart, heart block, J-curve phenomenon, rheumatic heart disease, Marfan syndrome, cardiovascular syphilis, and cardiovascular tuberculosis.  
       [0661] Arrhythmias include sinus arrhythmia, atrial fibrillation, atrial flutter, bradycardia, extrasystole, Adams-Stokes Syndrome, bundle-branch block, sinoatrial block, long QT syndrome, parasystole, Lown-Ganong-Levine Syndrome, Mahaim-type pre-excitation syndrome, Wolff-Parkinson-White syndrome, sick sinus syndrome, tachycardias, and ventricular fibrillation. Tachycardias include paroxysmal tachycardia, supraventricular tachycardia, accelerated idioventricular rhythm, atrioventricular nodal reentry tachycardia, ectopic atrial tachycardia, ectopic junctional tachycardia, sinoatrial nodal reentry tachycardia, sinus tachycardia, Torsades de Pointes, and ventricular tachycardia.  
       [0662] Heart valve disease include aortic valve insufficiency, aortic valve stenosis, heart murmurs, aortic valve prolapse, mitral valve prolapse, tricuspid valve prolapse, mitral valve insufficiency, mitral valve stenosis, pulmonary atresia, pulmonary valve insufficiency, pulmonary valve stenosis, tricuspid atresia, tricuspid valve insufficiency, tricuspid valve stenosis, and bicuspid aortic valve.  
       [0663] Myocardial diseases include alcoholic cardiomyopathy, congestive cardiomyopathy, hypertrophic cardiomyopathy, aortic subvalvular stenosis, pulmonary subvalvular stenosis, restrictive cardiomyopathy, Chagas cardiomyopathy, endocardial fibroelastosis, endomyocardial fibrosis, Kearns Syndrome, Barth syndrome, myocardial reperfilsion injury, and myocarditis.  
       [0664] Myocardial ischemias include coronary disease, such as angina pectoris, Prinzmetal&#39;s angina, unstable angina, coronary aneurysm, coronary arteriosclerosis, coronary thrombosis, coronary vasospasm, myocardial infarction and myocardial stunning.  
       [0665] Cardiovascular diseases also include vascular diseases such as aneurysms, angiodysplasia, angiomatosis, bacillary angiomatosis, Hippel-Lindau Disease, Klippel-Trenaunay-Weber Syndrome, Sturge-Weber Syndrome, angioneurotic edema, aortic diseases, Takayasu&#39;s Arteritis, aortitis, Leriche&#39;s Syndrome, arterial occlusive diseases, arteritis, enarteritis, polyarteritis nodosa, cerebrovascular disorders, diabetic angiopathies, diabetic retinopathy, embolisms, thrombosis, erythromelalgia, hemorrhoids, hepatic veno-occlusive disease, hypertension, hypotension (shock), ischemia, peripheral vascular diseases, phlebitis, superficial phlebitis, pulmonary veno-occlusive disease, chronic obstructive pulmonary disease, Buerger&#39;s disease, Raynaud&#39;s disease, CREST syndrome, retinal vein occlusion, Scimitar syndrome, superior vena cava syndrome, telangiectasia, atacia telangiectasia, hereditary hemorrhagic telangiectasia, deep vein thrombosis, varicocele, varicose veins, varicose ulcer, vasculitis, and venous insufficiency.  
       [0666] Aneurysms include dissecting aneurysms, false aneurysms, infected aneurysms, ruptured aneurysms, aortic aneurysms, cerebral aneurysms, coronary aneurysms, heart aneurysms, and iliac aneurysms.  
       [0667] Arterial occlusive diseases include arteriosclerosis, arteriolosclerosis, atherosclerosis, intermittent claudication, carotid stenosis, fibromuscular dysplasias, mesenteric vascular occlusion, Moyamoya disease, renal artery obstruction, retinal artery occlusion, and thromboanguitis obliterans.  
       [0668] Cerebrovascular disorders include carotid artery diseases, cerebral amyloid angiopathy, cerebral aneurysm, cerebral anoxia, cerebral arteriosclerosis, cerebral arteriovenous malformation, cerebral artery diseases, cerebral embolism and thrombosis, carotid artery thrombosis, sinus thrombosis, Wallenberg&#39;s syndrome, cerebral hemorrhage, epidural hematoma, subdural hematoma, subaraxhnoid hemorrhage, cerebral infarction, cerebral ischemia (including transient), subclavian steal syndrome, periventricular leukomalacia, vascular headache, cluster headache, migraine, and vertebrobasilar insufficiency.  
       [0669] Embolisms include air embolisms, amniotic fluid embolisms, cholesterol embolisms, blue toe syndrome, fat embolisms, pulmonary embolisms, and thromoboembolisms. Thrombosis include coronary thrombosis, hepatic vein thrombosis, deep vein thrombosis, retinal vein occlusion, carotid artery thrombosis, sinus thrombosis, Wallenberg&#39;s syndrome, and thrombophlebitis.  
       [0670] Ischemia includes cerebral ischemia, ischemic colitis, silent ischemia, compartment syndromes, anterior compartment syndrome, myocardial ischemia, reperfusion injuries, and peripheral limb ischemia. Vasculitis includes aortitis, arteritis, Behcet&#39;s Syndrome, Churg-Strauss Syndrome, mucocutaneous lymph node syndrome, thromboangittis obliterans, hypersensitivity vasculitis, Schoenlein-Henoch purpura, allergic cutaneous vasculitis, and Wegener&#39;s granulomatosis.  
       [0671] Cardiovascular diseases can also occur due to electrolyte imbalances that include, but are not limited to hyponatremia, hypernatremia, hypokalemia, hyperkalemia, hypocalcemia, hypercalcemia, hypophosphatemia, and hyperphophatemia. Neoplasm and/or cancers of the cardiovascular system include, but are not limited to, myxomas, fibromas, and rhabdomyomas.  
       [0672] Polypeptides may be administered using any method known in the art, including, but not limited to, direct needle injection at the delivery site, intravenous injection, topical administration, catheter infusion, biolistic injectors, particle accelerators, gelfoam sponge depots, other commercially available depot materials, osmotic pumps, oral or suppositorial solid pharmaceutical formulations, decanting or topical applications during surgery, aerosol delivery. Such methods are known in the art. Polypeptides may be administered as part of a Therapeutic, described in more detail below. Methods of delivering polynucleotides are described in more detail herein.  
       [0673] Respiratory Disorders  
       [0674] Polynucleotides or polypeptides, or agonists or antagonists of the present invention may be used to treat, prevent, diagnose, and/or prognose diseases and/or disorders of the respiratory system.  
       [0675] Diseases and disorders of the respiratory system include, but are not limited to, nasal vestibulitis, nonallergic rhinitis (e.g., acute rhinitis, chronic rhinitis, atrophic rhinitis, vasomotor rhinitis), nasal polyps, and sinusitis, juvenile angiofibromas, cancer of the nose and juvenile papillomas, vocal cord polyps, nodules (singer&#39;s nodules), contact ulcers, vocal cord paralysis, laryngoceles, pharyngitis (e.g., viral and bacterial), tonsillitis, tonsillar cellulitis, parapharyngeal abscess, laryngitis, laryngoceles, and throat cancers (e.g., cancer of the nasopharynx, tonsil cancer, larynx cancer), lung cancer (e.g., squamous cell carcinoma, small cell (oat cell) carcinoma, large cell carcinoma, and adenocarcinoma), allergic disorders (eosinophilic pneumonia, hypersensitivity pneumonitis (e.g., extrinsic allergic alveolitis, allergic interstitial pneumonitis, organic dust pneumoconiosis, allergic bronchopulmonary aspergillosis, asthma, Wegener&#39;s granulomatosis (granulomatous vasculitis), Goodpasture&#39;s syndrome)), pneumonia (e.g., bacterial pneumonia (e.g.,  Streptococcus pneumoniae  (pneumoncoccal pneumonia),  Staphylococcus aureus  (staphylococcal pneumonia), Gram-negative bacterial pneumonia (caused by, e.g., Klebsiella and Pseudomas spp.),  Mycoplasma pneumoniae  pneumonia,  Hemophilus influenzae  pneumonia,  Legionella pneumophila  (Legionnaires&#39; disease), and  Chlamydia psittaci  (Psittacosis)), and viral pneumonia (e.g., influenza, chickenpox (varicella).  
       [0676] Additional diseases and disorders of the respiratory system include, but are not limited to bronchiolitis, polio (poliomyelitis), croup, respiratory syncytial viral infection, mumps, erythema infectiosum (fifth disease), roseola infantum, progressive rubella panencephalitis, german measles, and subacute sclerosing panencephalitis), fungal pneumonia (e.g., Histoplasmosis, Coccidioidomycosis, Blastomycosis, fungal infections in people with severely suppressed immune systems (e.g., cryptococcosis, caused by  Cryptococcus neoformans ; aspergillosis, caused by Aspergillus spp.; candidiasis, caused by Candida; and mucormycosis)),  Pneumocystis carinii  (pneumocystis pneumonia), atypical pneumonias (e.g., Mycoplasma and Chlamydia spp.), opportunistic infection pneumonia, nosocomial pneumonia, chemical pneumonitis, and aspiration pneumonia, pleural disorders (e.g., pleurisy, pleural effusion, and pneumothorax (e.g., simple spontaneous pneumothorax, complicated spontaneous pneumothorax, tension pneumothorax)), obstructive airway diseases (e.g., asthma, chronic obstructive pulmonary disease (COPD), emphysema, chronic or acute bronchitis), occupational lung diseases (e.g., silicosis, black lung (coal workers&#39; pneumoconiosis), asbestosis, berylliosis, occupational asthsma, byssinosis, and benign pneumoconioses), Infiltrative Lung Disease (e.g., pulmonary fibrosis (e.g., fibrosing alveolitis, usual interstitial pneumonia), idiopathic pulmonary fibrosis, desquamative interstitial pneumonia, lymphoid interstitial pneumonia, histiocytosis X (e.g., Letterer-Siwe disease, Hand-Schüiller-Christian disease, eosinophilic granuloma), idiopathic pulmonary hemosiderosis, sarcoidosis and pulmonary alveolar proteinosis), Acute respiratory distress syndrome (also called, e.g., adult respiratory distress syndrome), edema, pulmonary embolism, bronchitis (e.g., viral, bacterial), bronchiectasis, atelectasis, lung abscess (caused by, e.g.,  Staphylococcus aureus  or  Legionella pneumophila ), and cystic fibrosis.  
       [0677] Anti-Angiotenesis Activity  
       [0678] The naturally occurring balance between endogenous stimulators and inhibitors of angiogenesis is one in which inhibitory influences predominate. Rastinejad et al.,  Cell  56:345-355 (1989). In those rare instances in which neovascularization occurs under normal physiological conditions, such as wound healing, organ regeneration, embryonic development, and female reproductive processes, angiogenesis is stringently regulated and spatially and temporally delimited. Under conditions of pathological angiogenesis such as that characterizing solid tumor growth, these regulatory controls fail. Unregulated angiogenesis becomes pathologic and sustains progression of many neoplastic and non-neoplastic diseases. A number of serious diseases are dominated by abnormal neovascularization including solid tumor growth and metastases, arthritis, some types of eye disorders, and psoriasis. See, e.g., reviews by Moses et al.,  Biotech.  9:630-634 (1991); Folkman et al.,  N. Engl. J Med.,  333:1757-1763 (1995); Auerbach et al.,  J. Microvasc. Res.  29:401-411 (1985); Folkman, Advances in Cancer Research, eds. Klein and Weinhouse, Academic Press, New York, pp. 175-203 (1985); Patz,  Am. J. Opthalmol.  94:715-743 (1982); and Folkman et al., Science 221:719-725 (1983). In a number of pathological conditions, the process of angiogenesis contributes to the disease state. For example, significant data have accumulated which suggest that the growth of solid tumors is dependent on angiogenesis. Folkman and Klagsbrun,  Science  235:442-447 (1987).  
       [0679] The present invention provides for treatment of diseases or disorders associated with neovascularization by administration of the polynucleotides and/or polypeptides of the invention, as well as agonists or antagonists of the present invention. Malignant and metastatic conditions which can be treated with the polynucleotides and polypeptides, or agonists or antagonists of the invention include, but are not limited to, malignancies, solid tumors, and cancers described herein and otherwise known in the art (for a review of such disorders, see Fishman et al., Medicine, 2d Ed., J. B. Lippincott Co., Philadelphia (1985)). Thus, the present invention provides a method of treating an angiogenesis-related disease and/or disorder, comprising administration to an individual in need thereof a therapeutically effective amount of a polynucleotide, polypeptide, antagonist and/or agonist of the invention. For example, polynucleotides, polypeptides, antagonists and/or agonists may be utilized in a variety of additional methods in order to therapeutically treat a cancer or tumor. Cancers which may be treated with polynucleotides, polypeptides, antagonists and/or agonists include, but are not limited to solid tumors, including prostate, lung, breast, ovarian, stomach, pancreas, larynx, esophagus, testes, liver, parotid, biliary tract, colon, rectum, cervix, uterus, endometrium, kidney, bladder, thyroid cancer; primary tumors and metastases; melanomas; glioblastoma; Kaposi&#39;s sarcoma; leiomyosarcoma; non-small cell lung cancer; colorectal cancer; advanced malignancies; and blood born tumors such as leukemias. For example, polynucleotides, polypeptides, antagonists and/or agonists may be delivered topically, in order to treat cancers such as skin cancer, head and neck tumors, breast tumors, and Kaposi&#39;s sarcoma.  
       [0680] Within yet other aspects, polynucleotides, polypeptides, antagonists and/or agonists may be utilized to treat superficial forms of bladder cancer by, for example, intravesical administration. Polynucleotides, polypeptides, antagonists and/or agonists may be delivered directly into the tumor, or near the tumor site, via injection or a catheter. Of course, as the artisan of ordinary skill will appreciate, the appropriate mode of administration will vary according to the cancer to be treated. Other modes of delivery are discussed herein.  
       [0681] Polynucleotides, polypeptides, antagonists and/or agonists may be useful in treating other disorders, besides cancers, which involve angiogenesis. These disorders include, but are not limited to: benign tumors, for example hemangiomas, acoustic neuromas, neurofibromas, trachomas, and pyogenic granulomas; artheroscleric plaques; ocular angiogenic diseases, for example, diabetic retinopathy, retinopathy of prematurity, macular degeneration, corneal graft rejection, neovascular glaucoma, retrolental fibroplasia, rubeosis, retinoblastoma, uvietis and Pterygia (abnormal blood vessel growth) of the eye; rheumatoid arthritis; psoriasis; delayed wound healing; endometriosis; vasculogenesis; granulations; hypertrophic scars (keloids); nonunion fractures; scleroderma; trachoma; vascular adhesions; myocardial angiogenesis; coronary collaterals; cerebral collaterals; arteriovenous malformations; ischemic limb angiogenesis; Osler-Webber Syndrome; plaque neovascularization; telangiectasia; hemophiliac joints; angiofibroma; fibromuscular dysplasia; wound granulation; Crohn&#39;s disease; and atherosclerosis.  
       [0682] For example, within one aspect of the present invention methods are provided for treating hypertrophic scars and keloids, comprising the step of administering a polynucleotide, polypeptide, antagonist and/or agonist of the invention to a hypertrophic scar or keloid.  
       [0683] Within one embodiment of the present invention polynucleotides, polypeptides, antagonists and/or agonists of the invention are directly injected into a hypertrophic scar or keloid, in order to prevent the progression of these lesions. This therapy is of particular value in the prophylactic treatment of conditions which are known to result in the development of hypertrophic scars and keloids (e.g., burns), and is preferably initiated after the proliferative phase has had time to progress (approximately 14 days after the initial injury), but before hypertrophic scar or keloid development. As noted above, the present invention also provides methods for treating neovascular diseases of the eye, including for example, corneal neovascularization, neovascular glaucoma, proliferative diabetic retinopathy, retrolental fibroplasia and macular degeneration.  
       [0684] Moreover, ocular disorders associated with neovascularization which can be treated with the polynucleotides and polypeptides of the present invention (including agonists and/or antagonists) include, but are not limited to: neovascular glaucoma, diabetic retinopathy, retinoblastoma, retrolental fibroplasia, uveitis, retinopathy of prematurity macular degeneration, corneal graft neovascularization, as well as other eye inflammatory diseases, ocular tumors and diseases associated with choroidal or iris neovascularization. See, e.g., reviews by Waltman et al.,  Am. J. Ophthal.  85:704-710 (1978) and Gartner et al.,  Surv. Ophthal.  22:291-312 (1978).  
       [0685] Thus, within one aspect of the present invention methods are provided for treating neovascular diseases of the eye such as corneal neovascularization (including corneal graft neovascularization), comprising the step of administering to a patient a therapeutically effective amount of a compound (as described above) to the cornea, such that the formation of blood vessels is inhibited. Briefly, the cornea is a tissue, which normally lacks blood vessels. In certain pathological conditions however, capillaries may extend into the cornea from the pericorneal vascular plexus of the limbus. When the cornea becomes vascularized, it also becomes clouded, resulting in a decline in the patient&#39;s visual acuity. Visual loss may become complete if the cornea completely opacitates. A wide variety of disorders can result in corneal neovascularization, including for example, corneal infections (e.g., trachoma, herpes simplex keratitis, leishmaniasis and onchocerciasis), immunological processes (e.g., graft rejection and Stevens-Johnson&#39;s syndrome), alkali burns, trauma, inflammation (of any cause), toxic and nutritional deficiency states, and as a complication of wearing contact lenses.  
       [0686] Within particularly preferred embodiments of the invention, may be prepared for topical administration in saline (combined with any of the preservatives and antimicrobial agents commonly used in ocular preparations), and administered in eyedrop form. The solution or suspension may be prepared in its pure form and administered several times daily. Alternatively, anti-angiogenic compositions, prepared as described above, may also be administered directly to the cornea. Within preferred embodiments, the anti-angiogenic composition is prepared with a muco-adhesive polymer, which binds to cornea. Within further embodiments, the anti-angiogenic factors or anti-angiogenic compositions may be utilized as an adjunct to conventional steroid therapy. Topical therapy may also be useful prophylactically in comeal lesions which are known to have a high probability of inducing an angiogenic response (such as chemical bums). In these instances the treatment, likely in combination with steroids, may be instituted immediately to help prevent subsequent complications.  
       [0687] Within other embodiments, the compounds described above may be injected directly into the corneal stroma by an ophthalmologist under microscopic guidance. The preferred site of injection may vary with the morphology of the individual lesion, but the goal of the administration would be to place the composition at the advancing front of the vasculature (i.e., interspersed between the blood vessels and the normal cornea). In most cases this would involve perilimbic comeal injection to “protect” the cornea from the advancing blood vessels. This method may also be utilized shortly after a comeal insult in order to prophylactically prevent corneal neovascularization. In this situation, the material could be injected in the perilimbic cornea interspersed between the corneal lesion and its undesired potential limbic blood supply. Such methods may also be utilized in a similar fashion to prevent capillary invasion of transplanted corneas. In a sustained-release form, injections might only be required 2-3 times per year. A steroid could also be added to the injection solution to reduce inflammation resulting from the injection itself.  
       [0688] Within another aspect of the present invention, methods are provided for treating neovascular glaucoma, comprising the step of administering to a patient a therapeutically effective amount of a polynucleotide, polypeptide, antagonist and/or agonist to the eye, such that the formation of blood vessels is inhibited. In one embodiment, the compound may be administered topically to the eye in order to treat early forms of neovascular glaucoma. Within other embodiments, the compound may be implanted by injection into the region of the anterior chamber angle. Within other embodiments, the compound may also be placed in any location such that the compound is continuously released into the aqueous humor. Within another aspect of the present invention, methods are provided for treating proliferative diabetic retinopathy, comprising the step of administering to a patient a therapeutically effective amount of a polynucleotide, polypeptide, antagonist and/or agonist to the eyes, such that the formation of blood vessels is inhibited.  
       [0689] Within particularly preferred embodiments of the invention, proliferative diabetic retinopathy may be treated by injection into the aqueous humor or the vitreous, in order to increase the local concentration of the polynucleotide, polypeptide, antagonist and/or agonist in the retina. Preferably, this treatment should be initiated prior to the acquisition of severe disease requiring photocoagulation.  
       [0690] Within another aspect of the present invention, methods are provided for treating retrolental fibroplasia, comprising the step of administering to a patient a therapeutically effective amount of a polynucleotide, polypeptide, antagonist and/or agonist to the eye, such that the formation of blood vessels is inhibited. The compound may be administered topically, via intravitreous injection and/or via intraocular implants.  
       [0691] Additionally, disorders which can be treated with the polynucleotides, polypeptides, agonists and/or agonists include, but are not limited to, hemangioma, arthritis, psoriasis, angiofibroma, atherosclerotic plaques, delayed wound healing, granulations, hemophilic joints, hypertrophic scars, nonunion fractures, Osler-Weber syndrome, pyogenic granuloma, scleroderma, trachoma, and vascular adhesions.  
       [0692] Moreover, disorders and/or states, which can be treated, prevented, diagnosed and/or prognosed with the polynucleotides, polypeptides, agonists and/or agonists of the invention include, but are not limited to, solid tumors, blood born tumors such as leukemias, tumor metastasis, Kaposi&#39;s sarcoma, benign tumors, for example hemangiomas, acoustic neuromas, neurofibromas, trachomas, and pyogenic granulomas, rheumatoid arthritis, psoriasis, ocular angiogenic diseases, for example, diabetic retinopathy, retinopathy of prematurity, macular degeneration, corneal graft rejection, neovascular glaucoma, retrolental fibroplasia, rubeosis, retinoblastoma, and uvietis, delayed wound healing, endometriosis, vascluogenesis, granulations, hypertrophic scars (keloids), nonunion fractures, scleroderma, trachoma, vascular adhesions, myocardial angiogenesis, coronary collaterals, cerebral collaterals, arteriovenous malformations, ischemic limb angiogenesis, Osler-Webber Syndrome, plaque neovascularization, telangiectasia, hemophiliac joints, angiofibroma fibromuscular dysplasia, wound granulation, Crohn&#39;s disease, atherosclerosis, birth control agent by preventing vascularization required for embryo implantation controlling menstruation, diseases that have angiogenesis as a pathologic consequence such as cat scratch disease ( Rochele minalia quintosa ), ulcers ( Helicobacter pylori ), Bartonellosis and bacillary angiomatosis.  
       [0693] In one aspect of the birth control method, an amount of the compound sufficient to block embryo implantation is administered before or after intercourse and fertilization have occurred, thus providing an effective method of birth control, possibly a “morning after” method. Polynucleotides, polypeptides, agonists and/or agonists may also be used in controlling menstruation or administered as either a peritoneal lavage fluid or for peritoneal implantation in the treatment of endometriosis.  
       [0694] Polynucleotides, polypeptides, agonists and/or agonists of the present invention may be incorporated into surgical sutures in order to prevent stitch granulomas.  
       [0695] Polynucleotides, polypeptides, agonists and/or agonists may be utilized in a wide variety of surgical procedures. For example, within one aspect of the present invention a compositions (in the form of, for example, a spray or film) may be utilized to coat or spray an area prior to removal of a tumor, in order to isolate normal surrounding tissues from malignant tissue, and/or to prevent the spread of disease to surrounding tissues. Within other aspects of the present invention, compositions (e.g., in the form of a spray) may be delivered via endoscopic procedures in order to coat tumors, or inhibit angiogenesis in a desired locale. Within yet other aspects of the present invention, surgical meshes, which have been coated with anti-angiogenic compositions of the present invention may be utilized in any procedure wherein a surgical mesh might be utilized. For example, within one embodiment of the invention a surgical mesh laden with an anti-angiogenic composition may be utilized during abdominal cancer resection surgery (e.g., subsequent to colon resection) in order to provide support to the structure, and to release an amount of the anti-angiogenic factor.  
       [0696] Within further aspects of the present invention, methods are provided for treating tumor excision sites, comprising administering a polynucleotide, polypeptide, agonist and/or agonist to the resection margins of a tumor subsequent to excision, such that the local recurrence of cancer and the formation of new blood vessels at the site is inhibited. Within one embodiment of the invention, the anti-angiogenic compound is administered directly to the tumor excision site (e.g., applied by swabbing, brushing or otherwise coating the resection margins of the tumor with the anti-angiogenic compound). Alternatively, the anti-angiogenic compounds may be incorporated into known surgical pastes prior to administration. Within particularly preferred embodiments of the invention, the anti-angiogenic compounds are applied after hepatic resections for malignancy, and after neurosurgical operations.  
       [0697] Within one aspect of the present invention, polynucleotides, polypeptides, agonists and/or agonists may be administered to the resection margin of a wide variety of tumors, including for example, breast, colon, brain and hepatic tumors. For example, within one embodiment of the invention, anti-angiogenic compounds may be administered to the site of a neurological tumor subsequent to excision, such that the formation of new blood vessels at the site are inhibited.  
       [0698] The polynucleotides, polypeptides, agonists and/or agonists of the present invention may also be administered along with other anti-angiogenic factors. Representative examples of other anti-angiogenic factors include: Anti-Invasive Factor, retinoic acid and derivatives thereof, paclitaxel, Suramin, Tissue Inhibitor of Metalloproteinase-1, Tissue Inhibitor of Metalloproteinase-2, Plasminogen Activator Inhibitor-1, Plasminogen Activator Inhibitor-2, and various forms of the lighter “d group” transition metals.  
       [0699] Lighter “d group” transition metals include, for example, vanadium, molybdenum, tungsten, titanium, niobium, and tantalum species. Such transition metal species may form transition metal complexes. Suitable complexes of the above-mentioned transition metal species include oxo transition metal complexes.  
       [0700] Representative examples of vanadium complexes include oxo vanadium complexes such as vanadate and vanadyl complexes. Suitable vanadate complexes include metavanadate and orthovanadate complexes such as, for example, ammonium metavanadate, sodium metavanadate, and sodium orthovanadate. Suitable vanadyl complexes include, for example, vanadyl acetylacetonate and vanadyl sulfate including vanadyl sulfate hydrates such as vanadyl sulfate mono- and trihydrates.  
       [0701] Representative examples of tungsten and molybdenum complexes also include oxo complexes. Suitable oxo tungsten complexes include tungstate and tungsten oxide complexes. Suitable tungstate complexes include ammonium tungstate, calcium tungstate, sodium tungstate dihydrate, and tungstic acid. Suitable tungsten oxides include tungsten (IV) oxide and tungsten (VI) oxide. Suitable oxo molybdenum complexes include molybdate, molybdenum oxide, and molybdenyl complexes. Suitable molybdate complexes include ammonium molybdate and its hydrates, sodium molybdate and its hydrates, and potassium molybdate and its hydrates. Suitable molybdenum oxides include molybdenum (VI) oxide, molybdenum (VI) oxide, and molybdic acid. Suitable molybdenyl complexes include, for example, molybdenyl acetylacetonate. Other suitable tungsten and molybdenum complexes include hydroxo derivatives derived from, for example, glycerol, tartaric acid, and sugars.  
       [0702] A wide variety of other anti-angiogenic factors may also be utilized within the context of the present invention. Representative examples include platelet factor 4; protamine sulphate; sulphated chitin derivatives (prepared from queen crab shells), (Murata et al., Cancer Res. 51:22-26 (1991)); Sulphated Polysaccharide Peptidoglycan Complex (SP-PG) (the function of this compound may be enhanced by the presence of steroids such as estrogen, and tamoxifen citrate); Staurosporine; modulators of matrix metabolism, including for example, proline analogs, cishydroxyproline, d,L-3,4-dehydroproline, Thiaproline, alpha,alpha-dipyridyl, aminopropionitrile fumarate; 4-propyl-5-(4-pyridinyl)-2(3H)-oxazolone; Methotrexate; Mitoxantrone; Heparin; Interferons; 2 Macroglobulin-serum; ChIMP-3 (Pavloff et al., J. Bio. Chem. 267:17321-17326 (1992)); Chymostatin (Tomkinson et al., Biochem J. 286:475-480 (1992)); Cyclodextrin Tetradecasulfate; Eponemycin; Camptothecin; Fumagillin (Ingber et al., Nature 348:555-557 (1990)); Gold Sodium Thiomalate (“GST”; Matsubara and Ziff, J. Clin. Invest. 79:1440-1446 (1987)); anticollagenase-serum; alpha2-antiplasmin (Holmes et al., J. Biol. Chem. 262(4):1659-1664 (1987)); Bisantrene (National Cancer Institute); Lobenzarit disodium (N-(2)-carboxyphenyl-4-chloroanthronilic acid disodium or “CCA”; Takeuchi et al., Agents Actions 36:312-316, 1992); Thalidomide; Angostatic steroid; AGM-1470; carboxynaminolmidazole; and metalloproteinase inhibitors such as BB94.  
       [0703] Musculoskeletal System Disorders  
       [0704] Polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention, may be used to treat, prevent, diagnose, and/or prognose disorders of the musculoskeletal system, including but not limited to, disorders of the bone, joints, ligaments, tendons, bursa, muscle, and/or neoplasms and cancers associated with musculoskeletal tissue.  
       [0705] Diseases or disorders of the bone include, but are not limited to, Albers-Schönberg disease, bowlegs, heel spurs, Köhler&#39;s bone disease, knock-knees,. Legg-Calvé-Perthes disease, Marfan&#39;s syndrome, mucopolysaccharidoses, Osgood-Schiatter disease, osteochondroses, osteochondrodysplasia, osteomyelitis, osteopetroses, osteoporosis (postmenopausal, senile, and juvenile), Paget&#39;s disease, Scheuermann&#39;s disease, scoliosis, Sever&#39;s disease, and patellofemoral stress syndrome.  
       [0706] Joint diseases or disorders include, but are not limited to, ankylosing spondylitis, Behcet&#39;s syndrome, CREST syndrome, Ehlers-Danlos syndrome, infectious arthritis, discoid lupus erythematosus, systemic lupus erythematosus, Lyme disease, osteoarthritis, psoriatic arthritis, relapsing polychondrites, Reiter&#39;s syndrome, rheumatoid arthritis (adult and juvenile), scleroderma, and Still&#39;s disease.  
       [0707] Diseases or disorders affecting ligaments, tendons, or bursa include, but are not limited to, ankle sprain, bursitis, posterior Achilles tendon bursitis (Haglund&#39;s deformity), anterior Achilles tendon bursitis (Albert&#39;s disease), tendinitis, tenosynovitis, poplieus tendinitis, Achilles tendinitis, medial or lateral epicondylitis, rotator cuff tendinitis, spasmodic torticollis, and fibromyalgia syndrome.  
       [0708] Muscle diseases or disorders include, but are not limited to, Becker&#39;s muscular dystrophy, Duchenne&#39;s muscular dystrophy, Landouzy-Dejerine muscular dystrophy, Leyden-Möbius muscular dystrophy, Erb&#39;s muscular dystrophy, Charcot&#39;s joints, dermatomyositis, gout, pseudogout, glycogen storage diseases, Pompe&#39;s disease, mitochondrial myopathy;, periodic paralysis, polymyalgia rheumatica, polymyositis, Steinert&#39;s disease, Thomsen&#39;s disease, anterolateral and posteromedial shin splints, posterior femoral muscle strain, and fibromyositis.  
       [0709] Musculoskeletal tissue may also develop cancers and/or neoplasms that include, but are not limited to, osteochondroma, benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, giant cell tumor, multiple myeloma, osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing&#39;s tumor, and malignant lymphoma of bone.  
       [0710] Neural Activity and Neuroloical Diseases  
       [0711] The polynucleotides, polypeptides and agonists or antagonists of the invention may be used for the diagnosis and/or treatment of diseases, disorders, damage or injury of the brain and/or nervous system. Nervous system disorders that can be treated with the compositions of the invention (e.g., polypeptides, polynucleotides, and/or agonists or antagonists), include, but are not limited to, nervous system injuries, and diseases or disorders which result in either a disconnection of axons, a diminution or degeneration of neurons, or demyelination. Nervous system lesions which may be treated in a patient (including human and non-human mammalian patients) according to the methods of the invention, include but are not limited to, the following lesions of either the central (including spinal cord, brain) or peripheral nervous systems: (1) ischemic lesions, in which a lack of oxygen in a portion of the nervous system results in neuronal injury or death, including cerebral infarction or ischemia, or spinal cord infarction or ischemia; (2) traumatic lesions, including lesions caused by physical injury or associated with surgery, for example, lesions which sever a portion of the nervous system, or compression injuries; (3) malignant lesions, in which a portion of the nervous system is destroyed or injured by malignant tissue which is either a nervous system associated malignancy or a malignancy derived from non-nervous system tissue; (4) infectious lesions, in which a portion of the nervous system is destroyed or injured as a result of infection, for example, by an abscess or associated with infection by human immunodeficiency virus, herpes zoster, or herpes simplex virus or with Lyme disease, tuberculosis, or syphilis; (5) degenerative lesions, in which a portion of the nervous system is destroyed or injured as a result of a degenerative process including but not limited to, degeneration associated with Parkinson&#39;s disease, Alzheimer&#39;s disease, Huntington&#39;s chorea, or amyotrophic lateral sclerosis (ALS); (6) lesions associated with nutritional diseases or disorders, in which a portion of the nervous system is destroyed or injured by a nutritional disorder or disorder of metabolism including, but not limited to, vitamin B12 deficiency, folic acid deficiency, Wernicke disease, tobacco-alcohol amblyopia, Marchiafava-Bignami disease (primary degeneration of the corpus callosum), and alcoholic cerebellar degeneration; (7) neurological lesions associated with systemic diseases including, but not limited to, diabetes (diabetic neuropathy, Bell&#39;s palsy), systemic lupus erythematosus, carcinoma, or sarcoidosis; (8) lesions caused by toxic substances including alcohol, lead, or particular neurotoxins; and (9) demyelinated lesions in which a portion of the nervous system is destroyed or injured by a demyelinating disease including, but not limited to, multiple sclerosis, human immunodeficiency virus-associated myelopathy, transverse myelopathy or various etiologies, progressive multifocal leukoencephalopathy, and central pontine myelinolysis.  
       [0712] In one embodiment, the polypeptides, polynucleotides, or agonists or antagonists of the invention are used to protect neural cells from the damaging effects of hypoxia. In a further preferred embodiment, the polypeptides, polynucleotides, or agonists or antagonists of the invention are used to protect neural cells from the damaging effects of cerebral hypoxia. According to this embodiment, the compositions of the invention are used to treat or prevent neural cell injury associated with cerebral hypoxia. In one non-exclusive aspect of this embodiment, the polypeptides, polynucleotides, or agonists or antagonists of the invention, are used to treat or prevent neural cell injury associated with cerebral ischemia. In another non-exclusive aspect of this embodiment, the polypeptides, polynucleotides, or agonists or antagonists of the invention are used to treat or prevent neural cell injury associated with cerebral infarction.  
       [0713] In another preferred embodiment, the polypeptides, polynucleotides, or agonists or antagonists of the invention are used to treat or prevent neural cell injury associated with a stroke. In a specific embodiment, the polypeptides, polynucleotides, or agonists or antagonists of the invention are used to treat or prevent cerebral neural cell injury associated with a stroke.  
       [0714] In another preferred embodiment, the polypeptides, polynucleotides, or agonists or antagonists of the invention are used to treat or prevent neural cell injury associated with a heart attack. In a specific embodiment, the polypeptides, polynucleotides, or agonists or antagonists of the invention are used to treat or prevent cerebral neural cell injury associated with a heart attack.  
       [0715] The compositions of the invention which are useful for treating or preventing a nervous system disorder may be selected by testing for biological activity in promoting the survival or differentiation of neurons. For example, and not by way of limitation, compositions of the invention which elicit any of the following effects may be useful according to the invention: (1) increased survival time of neurons in culture either in the presence or absence of hypoxia or hypoxic conditions; (2) increased sprouting of neurons in culture or in vivo; (3) increased production of a neuron-associated molecule in culture or in vivo, e.g., choline acetyltransferase or acetylcholinesterase with respect to motor neurons; or (4) decreased symptoms of neuron dysfunction in vivo. Such effects may be measured by any method known in the art. In preferred, non-limiting embodiments, increased survival of neurons may routinely be measured using a method set forth herein or otherwise known in the art, such as, for example, in Zhang et al.,  Proc Natl Acad Sci USA  97:3637-42 (2000) or in Arakawa et al.,  J. Neurosci.,  10:3507-15 (1990); increased sprouting of neurons may be detected by methods known in the art, such as, for example, the methods set forth in Pestronk et al.,  Exp. Neurol.,  70:65-82 (1980), or Brown et al.,  Ann. Rev. Neurosci.,  4:17-42 (1981); increased production of neuron-associated molecules may be measured by bioassay, enzymatic assay, antibody binding, Northern blot assay, etc., using techniques known in the art and depending on the molecule to be measured; and motor neuron dysfunction may be measured by assessing the physical manifestation of motor neuron disorder, e.g., weakness, motor neuron conduction velocity, or functional disability.  
       [0716] In specific embodiments, motor neuron disorders that may be treated according to the invention include, but are not limited to, disorders such as infarction, infection, exposure to toxin, trauma, surgical damage, degenerative disease or malignancy that may affect motor neurons as well as other components of the nervous system, as well as disorders that selectively affect neurons such as amyotrophic lateral sclerosis, and including, but not limited to, progressive spinal muscular atrophy, progressive bulbar palsy, primary lateral sclerosis, infantile and Juvenile muscular atrophy, progressive bulbar paralysis of childhood (Fazio-Londe syndrome), poliomyelitis and the post polio syndrome, and Hereditary Motorsensory Neuropathy (Charcot-Marie-Tooth Disease).  
       [0717] Further, polypeptides or polynucleotides of the invention may play a role in neuronal survival; synapse formation; conductance; neural differentiation, etc. Thus, compositions of the invention (including polynucleotides, polypeptides, and agonists or antagonists) may be used to diagnose and/or treat or prevent diseases or disorders associated with these roles, including, but not limited to, learning and/or cognition disorders. The compositions of the invention may also be useful in the treatment or prevention of neurodegenerative disease states and/or behavioural disorders. Such neurodegenerative disease states and/or behavioral disorders include, but are not limited to, Alzheimer&#39;s Disease, Parkinson&#39;s Disease, Huntington&#39;s Disease, Tourette Syndrome, schizophrenia, mania, dementia, paranoia, obsessive compulsive disorder, panic disorder, learning disabilities, ALS, psychoses, autism, and altered behaviors, including disorders in feeding, sleep patterns, balance, and perception. In addition, compositions of the invention may also play a role in the treatment, prevention and/or detection of developmental disorders associated with the developing embryo, or sexually-linked disorders.  
       [0718] Additionally, polypeptides, polynucleotides and/or agonists or antagonists of the invention, may be useful in protecting neural cells from diseases, damage, disorders, or injury, associated with cerebrovascular disorders including, but not limited to, carotid artery diseases (e.g., carotid artery thrombosis, carotid stenosis, or Moyamoya Disease), cerebral amyloid angiopathy, cerebral aneurysm, cerebral anoxia, cerebral arteriosclerosis, cerebral arteriovenous malformations, cerebral artery diseases, cerebral embolism and thrombosis (e.g., carotid artery thrombosis, sinus thrombosis, or Wallenberg&#39;s Syndrome), cerebral hemorrhage (e.g., epidural or subdural hematoma, or subarachnoid hemorrhage), cerebral infarction, cerebral ischemia (e.g., transient cerebral ischemia, Subclavian Steal Syndrome, or vertebrobasilar insufficiency), vascular dementia (e.g., multi-infarct), leukomalacia, periventricular, and vascular headache (e.g., cluster headache or migraines).  
       [0719] In accordance with yet a further aspect of the present invention, there is provided a process for utilizing polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, for therapeutic purposes, for example, to stimulate neurological cell proliferation and/or differentiation. Therefore, polynucleotides, polypeptides, agonists and/or antagonists of the invention may be used to treat and/or detect neurologic diseases. Moreover, polynucleotides or polypeptides, or agonists or antagonists of the invention, can be used as a marker or detector of a particular nervous system disease or disorder.  
       [0720] Examples of neurologic diseases which can be treated or detected with polynucleotides, polypeptides, agonists, and/or antagonists of the present invention include brain diseases, such as metabolic brain diseases which includes phenylketonuria such as maternal phenylketonuria, pyruvate carboxylase deficiency, pyruvate dehydrogenase complex deficiency, Wernicke&#39;s Encephalopathy, brain edema, brain neoplasms such as cerebellar neoplasms which include infratentorial neoplasms, cerebral ventricle neoplasms such as choroid plexus neoplasms, hypothalamic neoplasms, supratentorial neoplasms, canavan disease, cerebellar diseases such as cerebellar ataxia which include spinocerebellar degeneration such as ataxia telangiectasia, cerebellar dyssynergia, Friederich&#39;s Ataxia, Machado-Joseph Disease, olivopontocerebellar atrophy, cerebellar neoplasms such as infratentorial neoplasms, diffuse cerebral sclerosis such as encephalitis periaxialis, globoid cell leukodystrophy, metachromatic leukodystrophy and subacute sclerosing panencephalitis.  
       [0721] Additional neurologic diseases which can be treated or detected with polynucleotides, polypeptides, agonists, and/or antagonists of the present invention include cerebrovascular disorders (such as carotid artery diseases which include carotid artery thrombosis, carotid stenosis and Moyamoya Disease), cerebral amyloid angiopathy, cerebral aneurysm, cerebral anoxia, cerebral arteriosclerosis, cerebral arteriovenous malformations, cerebral artery diseases, cerebral embolism and thrombosis such as carotid artery thrombosis, sinus thrombosis and Wallenberg&#39;s Syndrome, cerebral hemorrhage such as epidural hematoma, subdural hematoma and subarachnoid hemorrhage, cerebral infarction, cerebral ischemia such as transient cerebral ischemia, Subclavian Steal Syndrome and vertebrobasilar insufficiency, vascular dementia such as multi-infarct dementia, periventricular leukomalacia, vascular headache such as cluster headache and migraine.  
       [0722] Additional neurologic diseases which can be treated or detected with polynucleotides, polypeptides, agonists, and/or antagonists of the present invention include dementia such as AIDS Dementia Complex, presenile dementia such as Alzheimer&#39;s Disease and Creutzfeldt-Jakob Syndrome, senile dementia such as Alzheimer&#39;s Disease and progressive supranuclear palsy, vascular dementia such as multi-infarct dementia, encephalitis which include encephalitis periaxialis, viral encephalitis such as epidemic encephalitis, Japanese Encephalitis, St. Louis Encephalitis, tick-borne encephalitis and West Nile Fever, acute disseminated encephalomyelitis, meningoencephalitis such as uveomeningoencephalitic syndrome, Postencephalitic Parkinson Disease and subacute sclerosing panencephalitis, encephalomalacia such as periventricular leukomalacia, epilepsy such as generalized epilepsy which includes infantile spasms, absence epilepsy, myoclonic epilepsy which includes MERRF Syndrome, tonic-clonic epilepsy, partial epilepsy such as complex partial epilepsy, frontal lobe epilepsy and temporal lobe epilepsy, post-traumatic epilepsy, status epilepticus such as Epilepsia Partialis Continua, and Hallervorden-Spatz Syndrome.  
       [0723] Additional neurologic diseases which can be treated or detected with polynucleotides, polypeptides, agonists, and/or antagonists of the present invention include hydrocephalus such as Dandy-Walker Syndrome and normal pressure hydrocephalus, hypothalamic diseases such as hypothalamic neoplasms, cerebral malaria, narcolepsy which includes cataplexy, bulbar poliomyelitis, cerebri pseudotumor, Rett Syndrome, Reye&#39;s Syndrome, thalamic diseases, cerebral toxoplasmosis, intracranial tuberculoma and Zellweger Syndrome, central nervous system infections such as AIDS Dementia Complex, Brain Abscess, subdural empyema, encephalomyelitis such as Equine Encephalomyelitis, Venezuelan Equine Encephalomyelitis, Necrotizing Hemorrhagic Encephalomyelitis, Visna, and cerebral malaria.  
       [0724] Additional neurologic diseases which can be treated or detected with polynucleotides, polypeptides, agonists, and/or antagonists of the present invention include meningitis such as arachnoiditis, aseptic meningtitis such as viral meningtitis which includes lymphocytic choriomeningitis, Bacterial meningtitis which includes Haemophilus Meningtitis, Listeria Meningtitis, Meningococcal Meningtitis such as Waterhouse-Friderichsen Syndrome, Pneumococcal Meningtitis and meningeal tuberculosis, fungal meningitis such as Cryptococcal Meningtitis, subdural effusion, meningoencephalitis such as uvemeningoencephalitic syndrome, myelitis such as transverse myelitis, neurosyphilis such as tabes dorsalis, poliomyelitis which includes bulbar poliomyelitis and postpoliomyelitis syndrome, prion diseases (such as Creutzfeldt-Jakob Syndrome, Bovine Spongiform Encephalopathy, Gerstmann-Straussler Syndrome, Kuru, Scrapie), and cerebral toxoplasmosis.  
       [0725] Additional neurologic diseases which can be treated or detected with polynucleotides, polypeptides, agonists, and/or antagonists of the present invention include central nervous system neoplasms such as brain neoplasms that include cerebellar neoplasms such as infratentorial neoplasms, cerebral ventricle neoplasms such as choroid plexus neoplasms, hypothalamic neoplasms and supratentorial neoplasms, meningeal neoplasms, spinal cord neoplasms which include epidural neoplasms, demyelinating diseases such as Canavan Diseases, diffuse cerebral sceloris which includes adrenoleukodystrophy, encephalitis periaxialis, globoid cell leukodystrophy, diffuse cerebral sclerosis such as metachromatic leukodystrophy, allergic encephalomyelitis, necrotizing hemorrhagic encephalomyelitis, progressive multifocal leukoencephalopathy, multiple sclerosis, central pontine myelinolysis, transverse myelitis, neuromyelitis optica, Scrapie, Swayback, Chronic Fatigue Syndrome, Visna, High Pressure Nervous Syndrome, Meningism, spinal cord diseases such as amyotonia congenita, amyotrophic lateral sclerosis, spinal muscular atrophy such as Werdnig-Hoffmann Disease, spinal cord compression, spinal cord neoplasms such as epidural neoplasms, syringomyelia, Tabes Dorsalis, Stiff-Man Syndrome, mental retardation such as Angelman Syndrome, Cri-du-Chat Syndrome, De Lange&#39;s Syndrome, Down Syndrome, Gangliosidoses such as gangliosidoses G(M1), Sandhoff Disease, Tay-Sachs Disease, Hartnup Disease, homocystinuria, Laurence-Moon-Biedl Syndrome, Lesch-Nyhan Syndrome, Maple Syrup Urine Disease, mucolipidosis such as fucosidosis, neuronal ceroid-lipofuscinosis, oculocerebrorenal syndrome, phenylketonuria such as maternal phenylketonuria, Prader-Willi Syndrome, Rett Syndrome, Rubinstein-Taybi Syndrome, Tuberous Sclerosis, WAGR Syndrome, nervous system abnormalities such as holoprosencephaly, neural tube defects such as anencephaly which includes hydrangencephaly, Arnold-Chairi Deformity, encephalocele, meningocele, meningomyelocele, spinal dysraphism such as spina bifida cystica and spina bifida occulta.  
       [0726] Additional neurologic diseases which can be treated or detected with polynucleotides, polypeptides, agonists, and/or antagonists of the present invention include hereditary motor and sensory neuropathies which include Charcot-Marie Disease, Hereditary optic atrophy, Refsum&#39;s Disease, hereditary spastic paraplegia, Werdnig-Hoffmann Disease, Hereditary Sensory and Autonomic Neuropathies such as Congenital Analgesia and Familial Dysautonomia, Neurologic manifestations (such as agnosia that include Gerstmann&#39;s Syndrome, Amnesia such as retrograde amnesia, apraxia, neurogenic bladder, cataplexy, communicative disorders such as hearing disorders that includes deafness, partial hearing loss, loudness recruitment and tinnitus, language disorders such as aphasia which include agraphia, anomia, broca aphasia, and Wernicke Aphasia, Dyslexia such as Acquired Dyslexia, language development disorders, speech disorders such as aphasia which includes anomia, broca aphasia and Wernicke Aphasia, articulation disorders, communicative disorders such as speech disorders which include dysarthria, echolalia, mutism and stuttering, voice disorders such as aphonia and hoarseness, decerebrate state, delirium, fasciculation, hallucinations, meningism, movement disorders such as angelman syndrome, ataxia, athetosis, chorea, dystonia, hypokinesia, muscle hypotonia, myoclonus, tic, torticollis and tremor, muscle hypertonia such as muscle rigidity such as stiff-man syndrome, muscle spasticity, paralysis such as facial paralysis which includes Herpes Zoster Oticus, Gastroparesis, Hemiplegia, ophthalmoplegia such as diplopia, Duane&#39;s Syndrome, Horner&#39;s Syndrome, Chronic progressive external ophthalmoplegia such as Kearns Syndrome, Bulbar Paralysis, Tropical Spastic Paraparesis, Paraplegia such as Brown-Sequard Syndrome, quadriplegia, respiratory paralysis and vocal cord paralysis, paresis, phantom limb, taste disorders such as ageusia and dysgeusia, vision disorders such as amblyopia, blindness, color vision defects, diplopia, hemianopsia, scotoma and subnormal vision, sleep disorders such as hypersomnia which includes Kleine-Levin Syndrome, insomnia, and somnambulism, spasm such as trismus, unconsciousness such as coma, persistent vegetative state and syncope and vertigo, neuromuscular diseases such as amyotonia congenita, amyotrophic lateral sclerosis, Lambert-Eaton Myasthenic Syndrome, motor neuron disease, muscular atrophy such as spinal muscular atrophy, Charcot-Marie Disease and Werdnig-Hoffmann Disease, Postpoliomyelitis Syndrome, Muscular Dystrophy, Myasthenia Gravis, Myotonia Atrophica, Myotonia Confenita, Nemaline Myopathy, Familial Periodic Paralysis, Multiplex Paramyloclonus, Tropical Spastic Paraparesis and Stiff-Man Syndrome, peripheral nervous system diseases such as acrodynia, amyloid neuropathies, autonomic nervous system diseases such as Adie&#39;s Syndrome, Barre-Lieou Syndrome, Familial Dysautonomia, Homer&#39;s Syndrome, Reflex Sympathetic Dystrophy and Shy-Drager Syndrome, Cranial Nerve Diseases such as Acoustic Nerve Diseases such as Acoustic Neuroma which includes Neurofibromatosis 2, Facial Nerve Diseases such as Facial Neuralgia,Melkersson-Rosenthal Syndrome, ocular motility disorders which includes amblyopia, nystagmus, oculomotor nerve paralysis, ophthalmoplegia such as Duane&#39;s Syndrome, Horner&#39;s Syndrome, Chronic Progressive External Ophthalmoplegia which includes Kearns Syndrome, Strabismus such as Esotropia and Exotropia, Oculomotor Nerve Paralysis, Optic Nerve Diseases such as Optic Atrophy which includes Hereditary Optic Atrophy, Optic Disk Drusen, Optic Neuritis such as Neuromyelitis Optica, Papilledema, Trigeminal Neuralgia, Vocal Cord Paralysis, Demyelinating Diseases such as Neuromyelitis Optica and Swayback, and Diabetic neuropathies such as diabetic foot.  
       [0727] Additional neurologic diseases which can be treated or detected with polynucleotides, polypeptides, agonists, and/or antagonists of the present invention include nerve compression syndromes such as carpal tunnel syndrome, tarsal tunnel syndrome, thoracic outlet syndrome such as cervical rib syndrome, ulnar nerve compression syndrome, neuralgia such as causalgia, cervico-brachial neuralgia, facial neuralgia and trigeminal neuralgia, neuritis such as experimental allergic neuritis, optic neuritis, polyneuritis, polyradiculoneuritis and radiculities such as polyradiculitis, hereditary motor and sensory neuropathies such as Charcot-Marie Disease, Hereditary Optic Atrophy, Refsum&#39;s Disease, Hereditary Spastic Paraplegia and Werdnig-Hoffmann Disease, Hereditary Sensory and Autonomic Neuropathies which include Congenital Analgesia and Familial Dysautonomia, POEMS Syndrome, Sciatica, Gustatory Sweating and Tetany).  
       [0728] Endocrine Disorders  
       [0729] Polynucleotides or polypeptides, or agonists or antagonists of the present invention, may be used to treat, prevent, diagnose, and/or prognose disorders and/or diseases related to hormone imbalance, and/or disorders or diseases of the endocrine system.  
       [0730] Hormones secreted by the glands of the endocrine system control physical growth, sexual function, metabolism, and other functions. Disorders may be classified in two ways: disturbances in the production of hormones, and the inability of tissues to respond to hormones. The etiology of these hormone imbalance or endocrine system diseases, disorders or conditions may be genetic, somatic, such as cancer and some autoimmune diseases, acquired (e.g., by chemotherapy, injury or toxins), or infectious. Moreover, polynucleotides, polypeptides, antibodies, and/or agonists or antagonists of the present invention can be used as a marker or detector of a particular disease or disorder related to the endocrine system and/or hormone imbalance.  
       [0731] Endocrine system and/or hormone imbalance and/or diseases encompass disorders of uterine motility including, but not limited to: complications with pregnancy and labor (e.g., pre-term labor, post-term pregnancy, spontaneous abortion, and slow or stopped labor); and disorders and/or diseases of the menstrual cycle (e.g., dysmenorrhea and endometriosis).  
       [0732] Endocrine system and/or hormone imbalance disorders and/or diseases include disorders and/or diseases of the pancreas, such as, for example, diabetes mellitus, diabetes insipidus, congenital pancreatic agenesis, pheochromocytoma—islet cell tumor syndrome; disorders and/or diseases of the adrenal glands such as, for example, Addison&#39;s Disease, corticosteroid deficiency, virilizing disease, hirsutism, Cushing&#39;s Syndrome, hyperaldosteronism, pheochromocytoma; disorders and/or diseases of the pituitary gland, such as, for example, hyperpituitarism, hypopituitarism, pituitary dwarfism, pituitary adenoma, panhypopituitarism, acromegaly, gigantism; disorders and/or diseases of the thyroid, including but not limited to, hyperthyroidism, hypothyroidism, Plummer&#39;s disease, Graves&#39; disease (toxic diffuse goiter), toxic nodular goiter, thyroiditis (Hashimoto&#39;s thyroiditis, subacute granulomatous thyroiditis, and silent lymphocytic thyroiditis), Pendred&#39;s syndrome, myxedema, cretinism, thyrotoxicosis, thyroid hormone coupling defect, thymic aplasia, Hurthle cell tumours of the thyroid, thyroid cancer, thyroid carcinoma, Medullary thyroid carcinoma; disorders and/or diseases of the parathyroid, such as, for example, hyperparathyroidism, hypoparathyroidism; disorders and/or diseases of the hypothalamus.  
       [0733] In addition, endocrine system and/or hormone imbalance disorders and/or diseases may also include disorders and/or diseases of the testes or ovaries, including cancer. Other disorders and/or diseases of the testes or ovaries further include, for example, ovarian cancer, polycystic ovary syndrome, Klinefelter&#39;s syndrome, vanishing testes syndrome (bilateral anorchia), congenital absence of Leydig&#39;s cells, cryptorchidism, Noonan&#39;s syndrome, myotonic dystrophy, capillary haemangioma of the testis (benign), neoplasias of the testis and neo-testis.  
       [0734] Moreover, endocrine system and/or hormone imbalance disorders and/or diseases may also include disorders and/or diseases such as, for example, polyglandular deficiency syndromes, pheochromocytoma, neuroblastoma, multiple Endocrine neoplasia, and disorders and/or cancers of endocrine tissues.  
       [0735] In certain embodiments, a polypeptide of the invention, or polynucleotides, antibodies, agonists, or antagonists corresponding to that polypeptide, may be used to diagnose and/or prognose endocrine diseases and/or disorders associated with the tissue(s) in which the polypeptide of the invention is expressed, including one, two, three, four, five, or more tissues disclosed in Table 1A, column 7 (Tissue Distribution Library Code).  
       [0736] Gastrointestinal Disorders  
       [0737] Polynucleotides or polypeptides, or agonists or antagonists of the present invention, may be used to treat, prevent, diagnose, and/or prognose gastrointestinal disorders, including inflammatory diseases and/or conditions, infections, cancers (e.g., intestinal neoplasms (carcinoid tumor of the small intestine, non-Hodgkin&#39;s lymphoma of the small intestine, small bowl lymphoma)), and ulcers, such as peptic ulcers.  
       [0738] Gastrointestinal disorders include dysphagia, odynophagia, inflammation of the esophagus, peptic esophagitis, gastric reflux, submucosal fibrosis and stricturing, Mallory-Weiss lesions, leiomyomas, lipomas, epidermal cancers, adeoncarcinomas, gastric retention disorders, gastroenteritis, gastric atrophy, gastric/stomach cancers, polyps of the stomach, autoimmune disorders such as pernicious anemia, pyloric stenosis, gastritis (bacterial, viral, eosinophilic, stress-induced, chronic erosive, atrophic, plasma cell, and Menetrier&#39;s), and peritoneal diseases (e.g., chyloperioneum, hemoperitoneum, mesenteric cyst, mesenteric lymphadenitis, mesenteric vascular occlusion, panniculitis, neoplasms, peritonitis, pneumoperitoneum, bubphrenic abscess).  
       [0739] Gastrointestinal disorders also include disorders associated with the small intestine, such as malabsorption syndromes, distension, irritable bowel syndrome, sugar intolerance, celiac disease, duodenal ulcers, duodenitis, tropical sprue, Whipple&#39;s disease, intestinal lymphangiectasia, Crohn&#39;s disease, appendicitis, obstructions of the ileum, Meckel&#39;s diverticulum, multiple diverticula, failure of complete rotation of the small and large intestine, lymphoma, and bacterial and parasitic diseases (such as Traveler&#39;s diarrhea, typhoid and paratyphoid, cholera, infection by Roundworms ( Ascariasis lumbricoides ), Hookworms ( Ancylostoma duodenale ), Threadwonns ( Enterobius vermicularis ), Tapeworms ( Taenia saginata, Echinococcus granulosus , Diphyllobothrium spp., and  T. solium ).  
       [0740] Liver diseases and/or disorders include intrahepatic cholestasis (alagille syndrome, binary liver cirrhosis), fatty liver (alcoholic fatty liver, reye syndrome), hepatic vein thrombosis, hepatolentricular degeneration, hepatomegaly, hepatopulmonary syndrome, hepatorenal syndrome, portal hypertension (esophageal and gastric varices), liver abscess (amebic liver abscess), liver cirrhosis (alcoholic, biliary and experimental), alcoholic liver diseases (fatty liver, hepatitis, cirrhosis), parasitic (hepatic echinococcosis, fascioliasis, amebic liver abscess), jaundice (hemolytic, hepatocellular, and cholestatic), cholestasis, portal hypertension, liver enlargement, ascites, hepatitis (alcoholic hepatitis, animal hepatitis, chronic hepatitis (autoimmune, hepatitis B, hepatitis C, hepatitis D, drug induced), toxic hepatitis, viral human hepatitis (hepatitis A, hepatitis B, hepatitis C, hepatitis D, hepatitis E), Wilson&#39;s disease, granulomatous hepatitis, secondary biliary cirrhosis, hepatic encephalopathy, portal hypertension, varices, hepatic encephalopathy, primary biliary cirrhosis, primary sclerosing cholangitis, hepatocellular adenoma, hemangiomas, bile stones, liver failure (hepatic encephalopathy, acute liver failure), and liver neoplasms (angiomyolipoma, calcified liver metastases, cystic liver metastases, epithelial tumors, fibrolamellar hepatocarcinoma, focal nodular hyperplasia, hepatic adenoma, hepatobiliary cystadenoma, hepatoblastoma, hepatocellular carcinoma, hepatoma, liver cancer, liver hemangioendothelioma, mesenchymal hamartoma, mesenchymal tumors of liver, nodular regenerative hyperplasia, benign liver tumors (Hepatic cysts [Simple cysts, Polycystic liver disease, Hepatobiliary cystadenoma, Choledochal cyst], Mesenchymal tumors [Mesenchymal hamartoma, Infantile hemangioendothelioma, Hemangioma, Peliosis hepatis, Lipomas, Inflammatory pseudotumor, Miscellaneous], Epithelial tumors [Bile duct epithelium (Bile duct hamartoma, Bile duct adenoma), Hepatocyte (Adenoma, Focal nodular hyperplasia, Nodular regenerative hyperplasia)], malignant liver tumors [hepatocellular, hepatoblastoma, hepatocellular carcinoma, cholangiocellular, cholangiocarcinoma, cystadenocarcinoma, tumors of blood vessels, angiosarcoma, Karposi&#39;s sarcoma, hemangioendothelioma, other tumors, embryonal sarcoma, fibrosarcoma, leiomyosarcoma, rhabdomyosarcoma, carcinosarcoma, teratoma, carcinoid, squamous carcinoma, primary lymphoma]), peliosis hepatis, erythrohepatic porphyria, hepatic porphyria (acute intermittent porphyria, porphyria cutanea tarda), Zellweger syndrome).  
       [0741] Pancreatic diseases and/or disorders include acute pancreatitis, chronic pancreatitis (acute necrotizing pancreatitis, alcoholic pancreatitis), neoplasms (adenocarcinoma of the pancreas, cystadenocarcinoma, insulinoma, gastrinoma, and glucagonoma, cystic neoplasms, islet-cell tumors, pancreoblastoma), and other pancreatic diseases (e.g., cystic fibrosis, cyst (pancreatic pseudocyst, pancreatic fistula, insufficiency)).  
       [0742] Gallbladder diseases include gallstones (cholelithiasis and choledocholithiasis), postcholecystectomy syndrome, diverticulosis of the gallbladder, acute cholecystitis, chronic cholecystitis, bile duct tumors, and mucocele.  
       [0743] Diseases and/or disorders of the large intestine include antibiotic-associated colitis, diverticulitis, ulcerative colitis, acquired megacolon, abscesses, fungal and bacterial infections, anorectal disorders (e.g., fissures, hemorrhoids), colonic diseases (colitis, colonic neoplasms [colon cancer, adenomatous colon polyps (e.g., villous adenoma), colon carcinoma, colorectal cancer], colonic diverticulitis, colonic diverticulosis, megacolon [Hirschsprung disease, toxic megacolon]; sigmoid diseases [proctocolitis, sigmoin neoplasms]), constipation, Crohn&#39;s disease, diarrhea (infantile diarrhea, dysentery), duodenal diseases (duodenal neoplasms, duodenal obstruction, duodenal ulcer, duodenitis), enteritis (enterocolitis), HIV enteropathy, ileal diseases (ileal neoplasms, ileitis), immunoproliferative small intestinal disease, inflammatory bowel disease (ulcerative colitis, Crohn&#39;s disease), intestinal atresia, parasitic diseases (anisakiasis, balantidiasis, blastocystis infections, cryptosporidiosis, dientamoebiasis, amebic dysentery, giardiasis), intestinal fistula (rectal fistula), intestinal neoplasms (cecal neoplasms, colonic neoplasms, duodenal neoplasms, ileal neoplasms, intestinal polyps, jejunal neoplasms, rectal neoplasms), intestinal obstruction (afferent loop syndrome, duodenal obstruction, impacted feces, intestinal pseudo-obstruction [cecal volvulus], intussusception), intestinal perforation, intestinal polyps (colonic polyps, gardner syndrome, peutz-jeghers syndrome), jejunal diseases (ejunal neoplasms), malabsorption syndromes (blind loop syndrome, celiac disease, lactose intolerance, short bowl syndrome, tropical sprue, whipple&#39;s disease), mesenteric vascular occlusion, pneumatosis cystoides intestinalis, protein-losing enteropathies (intestinal lymphagiectasis), rectal diseases (anus diseases, fecal incontinence, hemorrhoids, proctitis, rectal fistula, rectal prolapse, rectocele), peptic ulcer (duodenal ulcer, peptic esophagitis, hemorrhage, perforation, stomach ulcer, Zollinger-Ellison syndrome), postgastrectomy syndromes (dumping syndrome), stomach diseases (e.g., achlorhydria, duodenogastric reflux (bile reflux), gastric antral vascular ectasia, gastric fistula, gastric outlet obstruction, gastritis (atrophic or hypertrophic), gastroparesis, stomach dilatation, stomach diverticulum, stomach neoplasms (gastric cancer, gastric polyps, gastric adenocarcinoma, hyperplastic gastric polyp), stomach rupture, stomach ulcer, stomach volvulus), tuberculosis, visceroptosis, vomiting (e.g., hematemesis, hyperemesis gravidarum, postoperative nausea and vomiting) and hemorrhagic colitis.  
       [0744] Further diseases and/or disorders of the gastrointestinal system include biliary tract diseases, such as, gastroschisis, fistula (e.g., biliary fistula, esophageal fistula, gastric fistula, intestinal fistula, pancreatic fistula), neoplasms (e.g., biliary tract neoplasms, esophageal neoplasms, such as adenocarcinoma of the esophagus, esophageal squamous cell carcinoma, gastrointestinal neoplasms, pancreatic neoplasms, such as adenocarcinoma of the pancreas, mucinous cystic neoplasm of the pancreas, pancreatic cystic neoplasms, pancreatoblastoma, and peritoneal neoplasms), esophageal disease (e.g., bullous diseases, candidiasis, glycogenic acanthosis, ulceration, barrett esophagus varices, atresia, cyst, diverticulum (e.g., Zenker&#39;s diverticulum), fistula (e.g., tracheoesophageal fistula), motility disorders (e.g., CREST syndrome, deglutition disorders, achalasia, spasm, gastroesophageal reflux), neoplasms, perforation (e.g., Boerhaave syndrome, Mallory-Weiss syndrome), stenosis, esophagitis, diaphragmatic hernia (e.g., hiatal hernia); gastrointestinal diseases, such as, gastroenteritis (e.g., cholera morbus, norwalk virus infection), hemorrhage (e.g., hematemesis, melena, peptic ulcer hemorrhage), stomach neoplasms (gastric cancer, gastric polyps, gastric adenocarcinoma, stomach cancer)), hernia (e.g., congenital diaphragmatic hernia, femoral hernia, inguinal hernia, obturator hernia, umbilical hernia, ventral hernia), and intestinal diseases (e.g., cecal diseases (appendicitis, cecal neoplasms)).  
       [0745] Reproductive System Disorders  
       [0746] The polynucleotides or polypeptides, or agonists or antagonists of the invention may be used for the diagnosis, treatment, or prevention of diseases and/or disorders of the reproductive system. Reproductive system disorders that can be treated by the compositions of the invention, include, but are not limited to, reproductive system injuries, infections, neoplastic disorders, congenital defects, and diseases or disorders which result in infertility, complications with pregnancy, labor, or parturition, and postpartum difficulties.  
       [0747] Reproductive system disorders and/or diseases include diseases and/or disorders of the testes, including, but not limited to, testicular atrophy, testicular feminization, cryptorchism (unilateral and bilateral), anorchia, ectopic testis, epididymitis and orchitis (typically resulting from infections such as, for example, gonorrhea, mumps, tuberculosis, and syphilis), testicular torsion, vasitis nodosa, germ cell tumors (e.g., seminomas, embryonal cell carcinomas, teratocarcinomas, choriocarcinomas, yolk sac tumors, and teratomas), stromal tumors (e.g., Leydig cell tumors), hydrocele, hematocele, varicocele, spermatocele, inguinal hernia, and disorders of sperm production (e.g., immotile cilia syndrome, aspermia, asthenozoospermia, azoospermia, oligospermia, and teratozoospermia).  
       [0748] Reproductive system disorders also include, but are not limited to, disorders of the prostate gland, such as acute non-bacterial prostatitis, chronic non-bacterial prostatitis, acute bacterial prostatitis, chronic bacterial prostatitis, prostatodystonia, prostatosis, granulomatous prostatitis, malacoplakia, benign prostatic hypertrophy or hyperplasia, and prostate neoplastic disorders, including adenocarcinomas, transitional cell carcinomas, ductal carcinomas, and squamous cell carcinomas.  
       [0749] Additionally, the compositions of the invention may be useful in the diagnosis, treatment, and/or prevention of disorders or diseases of the penis and urethra, including, but not limited to, inflammatory disorders, such as balanoposthitis, balanitis xerotica obliterans, phimosis, paraphimosis, syphilis, herpes simplex virus, gonorrhea, non-gonococcal urethritis, chlamydia, mycoplasma, trichomonas, HIV, AIDS, Reiter&#39;s syndrome, condyloma acuminatum, condyloma latum, and pearly penile papules; urethral abnormalities, such as hypospadias, epispadias, and phimosis; premalignant lesions, including Erythroplasia of Queyrat, Bowen&#39;s disease, Bowenoid paplosis, giant condyloma of Buscke-Lowenstein, and varrucous carcinoma; penile cancers, including squamous cell carcinomas, carcinoma in situ, verrucous carcinoma, and disseminated penile carcinoma; urethral neoplastic disorders, including penile urethral carcinoma, bulbomembranous urethral carcinoma, and prostatic urethral carcinoma; and erectile disorders, such as priapism, Peyronie&#39;s disease, erectile dysfunction, and impotence.  
       [0750] Moreover, diseases and/or disorders of the vas deferens include, but are not limited to, vasculititis and CBAVD (congenital bilateral absence of the vas deferens); additionally, the polynucleotides, polypeptides, and agonists or antagonists of the present invention may be used in the diagnosis, treatment, and/or prevention of diseases and/or disorders of the seminal vesicles, including but not limited to, hydatid disease, congenital chloride diarrhea, and polycystic kidney disease.  
       [0751] Other disorders and/or diseases of the male reproductive system that may be diagnosed, treated, and/or prevented with the compositions of the invention include, but are not limited to, Klinefelter&#39;s syndrome, Young&#39;s syndrome, premature ejaculation, diabetes mellitus, cystic fibrosis, Kartagener&#39;s syndrome, high fever, multiple sclerosis, and gynecomastia.  
       [0752] Further, the polynucleotides, polypeptides, and agonists or antagonists of the present invention may be used in the diagnosis, treatment, and/or prevention of diseases and/or disorders of the vagina and vulva, including, but not limited to, bacterial vaginosis, candida vaginitis, herpes simplex virus, chancroid, granuloma inguinale, lymphogranuloma venereum, scabies, human papillomavirus, vaginal trauma, vulvar trauma, adenosis, chlamydia vaginitis, gonorrhea, trichomonas vaginitis, condyloma acuminatum, syphilis, molluscum contagiosum, atrophic vaginitis, Paget&#39;s disease, lichen sclerosus, lichen planus, vulvodynia, toxic shock syndrome, vaginismus, vulvovaginitis, vulvar vestibulitis, and neoplastic disorders, such as squamous cell hyperplasia, clear cell carcinoma, basal cell carcinoma, melanomas, cancer of Bartholin&#39;s gland, and vulvar intraepithelial neoplasia.  
       [0753] Disorders and/or diseases of the uterus that may be diagnosed, treated, and/or prevented with the compositions of the invention include, but are not limited to, dysmenorrhea, retroverted uterus, endometriosis, fibroids, adenomyosis, anovulatory bleeding, amenorrhea, Cushing&#39;s syndrome, hydatidiform moles, Asherman&#39;s syndrome, premature menopause, precocious puberty, uterine polyps, dysfunctional uterine bleeding (e.g., due to aberrant hormonal signals), and neoplastic disorders, such as adenocarcinomas, keiomyosarcomas, and sarcomas. Additionally, the polypeptides, polynucleotides, or agonists or antagonists of the invention may be useful as a marker or detector of, as well as in the diagnosis, treatment, and/or prevention of congenital uterine abnormalities, such as bicornuate uterus, septate uterus, simple unicornuate uterus, unicornuate uterus with a noncavitary rudimentary horn, unicornuate uterus with a non-communicating cavitary rudimentary horn, unicornuate uterus with a communicating cavitary horn, arcuate uterus, uterine didelfus, and T-shaped uterus.  
       [0754] Ovarian diseases and/or disorders that may be diagnosed, treated, and/or prevented with the compositions of the invention include, but are not limited to, anovulation, polycystic ovary syndrome (Stein-Leventhal syndrome), ovarian cysts, ovarian hypofunction, ovarian insensitivity to gonadotropins, ovarian overproduction of androgens, right ovarian vein syndrome, amenorrhea, hirutism, and ovarian cancer (including, but not limited to, primary and secondary cancerous growth, Sertoli-Leydig tumors, endometriod carcinoma of the ovary, ovarian papillary serous adenocarcinoma, ovarian mucinous adenocarcinoma, and Ovarian Krukenberg tumors).  
       [0755] Cervical diseases and/or disorders that may be diagnosed, treated, and/or prevented with the compositions of the invention include, but are not limited to, cervicitis, chronic cervicitis, mucopurulent cervicitis, cervical dysplasia, cervical polyps, Nabothian cysts, cervical erosion, cervical incompetence, and cervical neoplasms (including, for example, cervical carcinoma, squamous metaplasia, squamous cell carcinoma, adenosquamous cell neoplasia, and columnar cell neoplasia).  
       [0756] Additionally, diseases and/or disorders of the reproductive system that may be diagnosed, treated, and/or prevented with the compositions of the invention include, but are not limited to, disorders and/or diseases of pregnancy, including miscarriage and stillbirth, such as early abortion, late abortion, spontaneous abortion, induced abortion, therapeutic abortion, threatened abortion, missed abortion, incomplete abortion, complete abortion, habitual abortion, missed abortion, and septic abortion; ectopic pregnancy, anemia, Rh incompatibility, vaginal bleeding during pregnancy, gestational diabetes, intrauterine growth retardation, polyhydramnios, HELLP syndrome, abruptio placentae, placenta previa, hyperemesis, preeclampsia, eclampsia, herpes gestationis, and urticaria of pregnancy. Additionally, the polynucleotides, polypeptides, and agonists or antagonists of the present invention may be used in the diagnosis, treatment, and/or prevention of diseases that can complicate pregnancy, including heart disease, heart failure, rheumatic heart disease, congenital heart disease, mitral valve prolapse, high blood pressure, anemia, kidney disease, infectious disease (e.g., rubella, cytomegalovirus, toxoplasmosis, infectious hepatitis, chlamydia, HIV, AIDS, and genital herpes), diabetes mellitus, Graves&#39; disease, thyroiditis, hypothyroidism, Hashimoto&#39;s thyroiditis, chronic active hepatitis, cirrhosis of the liver, primary biliary cirrhosis, asthma, systemic lupus eryematosis, rheumatoid arthritis, myasthenia gravis, idiopathic thrombocytopenic purpura, appendicitis, ovarian cysts, gallbladder disorders,and obstruction of the intestine.  
       [0757] Complications associated with labor and parturition that may be diagnosed, treated, and/or prevented with the compositions of the invention include, but are not limited to, premature rupture of the membranes, pre-term labor, post-term pregnancy, postmaturity, labor that progresses too slowly, fetal distress (e.g., abnormal heart rate (fetal or matemal), breathing problems, and abnormal fetal position), shoulder dystocia, prolapsed umbilical cord, amniotic fluid embolism, and aberrant uterine bleeding.  
       [0758] Further, diseases and/or disorders of the postdelivery period, that may be diagnosed, treated, and/or prevented with the compositions of the invention, include, but are not limited to, endometritis, myometritis, parametritis, peritonitis, pelvic thrombophlebitis, pulmonary embolism, endotoxemia, pyelonephritis, saphenous thrombophlebitis, mastitis, cystitis, postpartum hemorrhage, and inverted uterus.  
       [0759] Other disorders and/or diseases of the female reproductive system that may be diagnosed, treated, and/or prevented by the polynucleotides, polypeptides, and agonists or antagonists of the present invention include, but are not limited to, Turner&#39;s syndrome, pseudohermaphroditism, premenstrual syndrome, pelvic inflammatory disease, pelvic congestion (vascular engorgement), frigidity, anorgasmia, dyspareunia, ruptured fallopian tube, and Mittelschmerz.  
       [0760] Developmental and Inherited Disorders  
       [0761] Polynuceotides or polypeptides, or agonists or antagonists of the present invention may be used to treat, prevent, diagnose, and/or prognose diseases associated with mixed fetal tissues, including, but not limited to, developmental and inherited disorders or defects of the nervous system, musculoskelelal system, execretory system, cardiovascular system, hematopoietic system, gastrointestinal system, reproductive system, and respiratory system. Compositions of the present invention may also be used to treat, prevent, diagnose, and/or prognose developmental and inherited disorders or defects associated with, but not limited to, skin, hair, visual, and auditory tissues, metabolism. Additionally, the compositions of the invention may be useful in the diagnosis, treatment, and/or prevention of disorders or diseases associated with, but not limited to, chromosomal or genetic abnormalities and hyperproliferation or neoplasia.  
       [0762] Disorders or defects of the nervous system associated with developmental or inherited abnormalities that may be diagnosed, treated, and/or prevented with the compostions of the invention include, but are not limited to, adrenoleukodystrophy, agenesis of corpus callosum, Alexander disease, anencephaly, Angelman syndrome, Arnold-Chiari deformity, Batten disease, Canavan disease, cephalic disorders, Charcot-Marie-Tooth disease, encephalocele, Friedreich&#39;s ataxia, Gaucher&#39;s disease, Gorlin syndrome, Hallervorden-Spatz disease, hereditary spastic paraplegia, Huntington disease, hydranencephaly, hydrocephalus, Joubert syndrome, Lesch-Nyhan syndrome, leukodystrophy, Menkes disease, microcephaly, Niemann-Pick Type C1, neurofibromatosis, porencephaly, progeria, proteus syndrome, Refsum disease, spina bifida, Sturge-Weber syndrome, Tay-Sachs disease, tuberous sclerosis, and von Hippel-Lindau disease.  
       [0763] Developmental and inherited disorders resulting in disorders or defects of the musculoskeletal system that may be diagnosed, treated, and/or prevented with the compositions of the invention include, but are not limited to, achondroplasia, atlanto-occipital fusion, arthrogryposis mulitplex congenita, autosomal recessive muscular dystrophy, Becker&#39;s muscular dystrophy, cerebral palsy, choanal atresia, cleft lip, cleft palate, clubfoot, congenital amputation, congenital dislocation of the hip, congenital torticollis, congenital scoliosis, dopa-repsonsive dystonia, Duchenne muscular dystrophy, early-onset generalized dystonia, femoral torsion, Gorlin syndrome, hypophosphatasia, Klippel-Feil syndrome, knee dislocation, myoclonic dystonia, myotonic dystrophy, nail-patella syndrome, osteogenesis imperfecta, paroxysmal dystonia, progeria, prune-belly syndrome, rapid-onset dystonia parkinsonism, scolosis, syndactyly, Treacher Collins&#39; syndrome, velocardiofacial syndrome, and X-linked dystonia-parkinsonism.  
       [0764] Developmental or hereditary disorders or defects of the excretory system that may be diagnosed, treated, and/or prevented with the compositions of the invention include, but are not limited to, Alport&#39;s syndrome, Bartter&#39;s syndrome, bladder diverticula, bladder exstrophy, cystinuria, epispadias, Fanconi&#39;s syndrome, Hartnup disease, horseshoe kidney, hypospadias, kidney agenesis, kidney ectopia, kidney malrotation, Liddle&#39;s syndrome, medullary cystic disease, medullary sponge, multicystic kidney, kidney polycystic kidney disease, nail-patella syndrome, Potter&#39;s syndrome, urinary tract flow obstruction, vitamin D-resistant rickets, and Wilm&#39;s tumor.  
       [0765] Cardiovascular disorders or defects of developmental or hereditary origin that may be diagnosed, treated, and/or prevented with the compositions of the inventtion include, but are not limited to, aortic valve stenosis, atrial septal defects, artioventricular (A-V) canal defect, bicuspid aortic valve, coarctation or the aorta, dextrocardia, Ebstein&#39;s anomaly, Eisenmenger&#39;s complex, hypoplastic left heart syndrome, Marfan syndrome, patent ductus arteriosus, progeria, pulmonary atresia, pulmonary valve stenosis, subaortic stenosis, tetralogy of fallot, total anomalous pulmonary venous (P-V) connection, transposition of the great arteries, tricuspid atresia, truncus arteriosus, ventricular septal defects. Developmental or inherited disorders resulting in disorders involving the hematopoietic system that may be diagnosed, treated, and/or prevented with the compositions of the invention include, but not limited to, Bernard-Soulier syndrome, Chédiak-Higashi syndrome, hemophilia, Hermansky-Pudlak syndrome, sickle cell anemia, storage pool disease, thromboxane A2 dysfunction, thrombasthenia, and von Willebrand&#39;s disease.  
       [0766] The compositions of the invention may also be used to diagnose, treat, and/or prevent developmental and inherited disorders resulting in disorders or defects of the gastrointestinal system, including, but not limited to, anal atresia, biliary atresia, esophageal atresia, diaphragmatic hernia, Hirschsprung&#39;s disease, Meckel&#39;s diverticulum, oligohydramnios, omphalocele, polyhydramnios, porphyria, situs inversus viscera. Developmental or inherited disorders resulting in metabolic disorders that may be diagnosed, treated, and/or prevented with the compositions of the invention include, but are not limited to, alpha-1 antitrypsin deficiency, cystic fibrosis, hemochromatosis, lysosomal storage disease, phenylketonuria, Wilson&#39;s disease, and Zellweger syndrome.  
       [0767] Disorders of the reproductive system that are developmentally or hereditary related that may also be diagnosed, treated, and/or prevented with the compositions of the invention include, but are not limited to, androgen insensitivity syndrome, ambiguous genitalia, autosomal sex reversal, congenital adreneal hyperplasia, gonadoblastoma, ovarian germ cell cancer, pseudohermphroditism, true hermaphroditism, undescended testis, XX male syndrome, and XY female type gonadal dysgenesis. The compositions of the invention may also be used to diagnose, treat, and/or prevent developmental or inherited respiratory defects including, but not limited to, askin tumor, azygos lobe, congenital diaphragmatic hernia, congenital lobar emphysema, cystic adenomatoid malformation, lobar emphysema, hyaline membrane disease, and pectus excavatum.  
       [0768] Developmental or inherited disorders may also result from chromosomal or genetic aberration that may be diagnosed, treated, and/or prevented with the compositions of the invention including, but not limited to, 4p- syndrome, cri du chat syndrome, Digeorge syndrome, Down&#39;s syndrome, Edward&#39;s syndrome, fragile X syndrome, Klinefelter&#39;s syndrome, Patau&#39;s syndrome, Prader-Willi syndrome, progeria, Turner&#39;s syndrome, triple X syndrome, and XYY syndrome. Other developmental disorders that can be diagnosed, treated, and/or prevented with the compositions of the invention, include, but are not limited to, fetal alcohol syndrome, and can be caused by environmental factors surrounding the developing fetus.  
       [0769] The compositions of the invention may further be able to be used to diagnose, treat, and/or prevent errors in development or a genetic disposition that may result in hyperproliferative disorders or neoplasms, including, but not limited to, acute childhood lymphoblastic leukemia, askin tumor, Beckwith-Wiedemann syndrome, childhood acute myeloid leukemia, childhood brain stem glioma, childhood cerebellar astrocytoma, childhood extracranial germ cell tumors childhood (primary), gonadoblastoma, hepatocellular cancer, childhood Hodgkin&#39;s disease, childhood Hodgkin&#39;s lymphoma, childhood hypothalamic and visual pathway glioma, childhood (primary) liver cancer, childhood lymphoblastic leukemia, childhood medulloblastoma, childhood non-Hodgkin&#39;s lymphoma, childhood pineal and supratentorial primitive neuroectodermal tumors, childhood primary liver cancer, childhood rhabdomyosarcoma, childhood soft tissue sarcoma, Gorlin syndrome, familial multiple endrocrine neoplasia type I, neuroblastoma, ovarian germ cell cancer, pheochromocytoma, retinoblastoma, and Wilm&#39;s tumor.  
       [0770] Polypeptides may be administered using any method known in the art, including, but not limited to, direct needle injection at the delivery site, intravenous injection, topical administration, catheter infusion, biolistic injectors, particle accelerators, gelfoam sponge depots, other commercially available depot materials, osmotic pumps, oral or suppositorial solid pharmaceutical formulations, decanting or topical applications during surgery, aerosol delivery. Such methods are known in the art. Polypeptides may be administered as part of a Therapeutic, described in more detail below. Methods of delivering polynucleotides are described in more detail herein.  
       [0771] Diseases at the Cellular Level  
       [0772] Diseases associated with increased cell survival or the inhibition of apoptosis that could be treated, prevented, diagnosed and/or prognosed using polynucleotides or polypeptides, as well as antagonists or agonists of the present invention, include cancers (such as follicular lymphomas, carcinomas with p53 mutations, and hormone-dependent tumors, including, but not limited to colon cancer, cardiac tumors, pancreatic cancer, melanoma, retinoblastoma, glioblastoma, lung cancer, intestinal cancer, testicular cancer, stomach cancer, neuroblastoma, myxoma, myoma, lymphoma, endothelioma, osteoblastoma, osteoclastoma, osteosarcoma, chondrosarcoma, adenoma, breast cancer, prostate cancer, Kaposi&#39;s sarcoma and ovarian cancer); autoimmune disorders (such as, multiple sclerosis, Sjogren&#39;s syndrome, Hashimoto&#39;s thyroiditis, biliary cirrhosis, Behcet&#39;s disease, Crohn&#39;s disease, polymyositis, systemic lupus erythematosus and immune-related glomerulonephritis and rheumatoid arthritis) and viral infections (such as herpes viruses, pox viruses and adenoviruses), inflammation, graft v. host disease, acute graft rejection, and chronic graft rejection.  
       [0773] In preferred embodiments, polynucleotides, polypeptides, and/or antagonists of the invention are used to inhibit growth, progression, and/or metastasis of cancers, in particular those [listed above] involving excretory system tissues.  
       [0774] Additional diseases or conditions associated with increased cell survival that could be treated or detected by polynucleotides or polypeptides, or agonists or antagonists of the present invention include, but are not limited to, progression, and/or metastases of malignancies and related disorders such as leukemia (including acute leukemias (e.g., acute lymphocytic leukemia, acute myelocytic leukemia (including myeloblastic, promyelocytic, myelomonocytic, monocytic, and erythroleukemia)) and chronic leukemias (e.g., chronic myelocytic (granulocytic) leukemia and chronic lymphocytic leukemia)), polycythemia vera, lymphomas (e.g., Hodgkin&#39;s disease and non-Hodgkin&#39;s disease), multiple myeloma, Waldenstrom&#39;s macroglobulinemia, heavy chain disease, and solid tumors including, but not limited to, sarcomas and carcinomas such as fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing&#39;s tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm&#39;s tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, menangioma, melanoma, neuroblastoma, and retinoblastoma.  
       [0775] Diseases associated with increased apoptosis that could be treated, prevented, diagnosted, and/or prognosed using polynucleotides or potypeptides, as well as agonists or antagonists of the present invention, include, but are not limited to, AIDS; neurodegenerative disorders (such as Alzheimer&#39;s disease, Parkinson&#39;s disease, Amyotrophic lateral sclerosis, Retinitis pigmentosa, Cerebellar degeneration and brain tumor or prior associated disease); autoimmune disorders (such as, multiple sclerosis, Sjogren&#39;s syndrome, Hashimoto&#39;s thyroiditis, biliary cirrhosis, Behcet&#39;s disease, Crohn&#39;s disease, polymyositis, systemic lupus erythematosus and immune-related glomerulonephritis and rheumatoid arthritis) myelodysplastic syndromes (such as aplastic anemia), graft v. host disease, ischemic injury (such as that caused by myocardial infarction, stroke and reperfusion injury), liver injury (e.g., hepatitis related liver injury, ischemia/reperfusion injury, cholestosis (bile duct injury) and liver cancer); toxin-induced liver disease (such as that caused by alcohol), septic shock, cachexia and anorexia.  
       [0776] Wound Healing and Epithelial Cell Proliferation  
       [0777] In accordance with yet a further aspect of the present invention, there is provided a process for utilizing polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, for therapeutic purposes, for example, to stimulate epithelial cell proliferation and basal keratinocytes for the purpose of wound healing, and to stimulate hair follicle production and healing of dermal wounds. Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, may be clinically useful in stimulating wound healing including surgical wounds, excisional wounds, deep wounds involving damage of the dermis and epidermis, eye tissue wounds, dental tissue wounds, oral cavity wounds, diabetic ulcers, dermal ulcers, cubitus ulcers, arterial ulcers, venous stasis ulcers, burns resulting from heat exposure or chemicals, and other abnormal wound healing conditions such as uremia, malnutrition, vitamin deficiencies and complications associated with systemic treatment with steroids, radiation therapy and antineoplastic drugs and antimetabolites. Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, could be used to promote dermal reestablishment subsequent to dermal loss.  
       [0778] Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, could be used to increase the adherence of skin grafts to a wound bed and to stimulate re-epithelialization from the wound bed. The following are types of grafts that polynucleotides or polypeptides, agonists or antagonists of the present invention, could be used to increase adherence to a wound bed: autografts, artificial skin, allografts, autodermic graft, autoepdermic grafts, avacular grafts, Blair-Brown grafts, bone graft, brephoplastic grafts, cutis graft, delayed graft, dermic graft, epider-mic graft, fascia graft, full thickness graft, heterologous graft, xenograft, homologous graft, hyperplastic graft, lamellar graft, mesh graft, mucosal graft, Ollier-Thiersch graft, omenpal graft, patch graft, pedicle graft, penetrating graft, split skin graft, thick split graft. Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, can be used to promote skin strength and to improve the appearance of aged skin.  
       [0779] It is believed that polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, will also produce changes in hepatocyte proliferation, and epithelial cell proliferation in the lung, breast, pancreas, stomach, small intestine, and large intestine. Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, could promote proliferation of epithelial cells such as sebocytes, hair follicles, hepatocytes, type II pneumocytes, mucin-producing goblet cells, and other epithelial cells and their progenitors contained within the skin, lung, liver, and gastrointestinal tract. Polynucleotides or polypeptides, agonists or antagonists of the present invention, may promote proliferation of endothelial cells, keratinocytes, and basal keratinocytes.  
       [0780] Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, could also be used to reduce the side effects of gut toxicity that result from radiation, chemotherapy treatments or viral infections. Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, may have a cytoprotective effect on the small intestine mucosa. Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, may also stimulate healing of mucositis (mouth ulcers) that result from chemotherapy and viral infections.  
       [0781] Polynucleotides&#39;or polypeptides, as well as agonists or antagonists of the present invention, could further be used in full regeneration of skin in full and partial thickness skin defects, including burns, (i.e., repopulation of hair follicles, sweat glands, and sebaceous glands), treatment of other skin defects such as psoriasis. Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, could be used to treat epidermolysis bullosa, a defect in adherence of the epidermis to the underlying dermis which results in frequent, open and painful blisters by accelerating reepithelialization of these lesions. Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, could also be used to treat gastric and doudenal ulcers&#39;and help heal by scar formation of the mucosal lining and regeneration of glandular mucosa and duodenal mucosal lining more rapidly. Inflammatory bowel diseases, such as Crohn&#39;s disease and ulcerative colitis, are diseases, which result in destruction of the mucosal surface of the small or large intestine, respectively. Thus, polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, could be used to promote the resurfacing of the mucosal surface to aid more rapid healing and to prevent progression of inflammatory bowel disease. Treatment with polynucleotides or polypeptides, agonists or antagonists of the present invention, is expected to have a significant effect on the production of mucus throughout the gastrointestinal tract and could be used to protect the intestinal mucosa from injurious substances that are ingested or following surgery. Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, could be used to treat diseases associate with the under expression.  
       [0782] Moreover, polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, could be used to prevent and heal damage to the lungs due to various pathological states. Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, could stimulate proliferation and differentiation and promote the repair of alveoli and brochiolar epithelium to prevent or treat acute or chronic lung damage. For example, emphysema, which results in the progressive loss of aveoli, and inhalation injuries, i.e., resulting from smoke inhalation and bums, that cause necrosis of the bronchiolar epithelium and alveoli could be effectively treated using polynucleotides or polypeptides, agonists or antagonists of the present invention. Also, polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, could be used to stimulate the proliferation of and differentiation of type II pneumocytes, which may help treat or prevent disease such as hyaline membrane diseases, such as infant respiratory distress syndrome and bronchopulmonary displasia, in premature infants.  
       [0783] Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, could stimulate the proliferation and differentiation of hepatocytes and, thus, could be used to alleviate or treat liver diseases and pathologies such as fulminant liver failure caused by cirrhosis, liver damage caused by viral hepatitis and toxic substances (i.e., acetaminophen, carbon tetraholoride and other hepatotoxins known in the art).  
       [0784] In addition, polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, could be used treat or prevent the onset of diabetes mellitus. In patients with newly diagnosed Types I and II diabetes, where some islet cell function remains, polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, could be used to maintain the islet function so as to alleviate, delay or prevent permanent manifestation of the disease. Also, polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, could be used as an auxiliary in islet cell transplantation to improve or promote islet cell function.  
       [0785] Infectious Disease  
       [0786] Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention can be used to treat or detect infectious agents. For example, by increasing the immune response, particularly increasing the proliferation and differentiation of B and/or T cells, infectious diseases may be treated. The immune response may be increased by either enhancing an existing immune response, or by initiating a new immune response. Alternatively, polynucleotides or polypeptides, as well as agonists or antagonists of the present invention may also directly inhibit the infectious agent, without necessarily eliciting an immune response.  
       [0787] Viruses are one example of an infectious agent that can cause disease or symptoms that can be treated or detected by a polynucleotide or polypeptide and/or agonist or antagonist of the present invention. Examples of viruses, include, but are not limited to Examples of viruses, include, but are not limited to the following DNA and RNA viruses and viral families: Arbovirus, Adenoviridae, Arenaviridae, Arterivirus, Birnaviridae, Bunyaviridae, Caliciviridae, Circoviridae, Coronaviridae, Dengue, EBV, HIV, Flaviviridae, Hepadnaviridae (Hepatitis), Herpesviridae (such as, Cytomegalovirus, Herpes Simplex, Herpes Zoster), Mononegavirus (e.g., Paramyxoviridae, Morbillivirus, Rhabdoviridae), Orthomyxoviridae (e.g., Influenza A, Influenza B, and parainfluenza), Papiloma virus, Papovaviridae, Parvoviridae, Picornaviridae, Poxviridae (such as Smallpox or Vaccinia), Reoviridae (e.g., Rotavirus), Retroviridae (HTLV-I, HTLV-II, Lentivirus), and Togaviridae (e.g., Rubivirus). Viruses falling within these families can cause a variety of diseases or symptoms, including, but not limited to: arthritis, bronchiollitis, respiratory syncytial virus, encephalitis, eye infections (e.g., conjunctivitis, keratitis), chronic fatigue syndrome, hepatitis (A, B, C, E, Chronic Active, Delta), Japanese B encephalitis, Junin, Chikungunya, Rift Valley fever, yellow fever, meningitis, opportunistic infections (e.g., AIDS), pneumonia, Burkitt&#39;s Lymphoma, chickenpox, hemorrhagic fever, Measles, Mumps, Parainfluenza, Rabies, the common cold, Polio, leukemia, Rubella, sexually transmitted diseases, skin diseases (e.g., Kaposi&#39;s, warts), and viremia. polynucleotides or polypeptides, or agonists or antagonists of the invention, can be used to treat or detect any of these symptoms or diseases. In specific embodiments, polynucleotides, polypeptides, or agonists or antagonists of the invention are used to treat: meningitis, Dengue, EBV, and/or hepatitis (e.g., hepatitis B). In an additional specific embodiment polynucleotides, polypeptides, or agonists or antagonists of the invention are used to treat patients nonresponsive to one or more other commercially available hepatitis vaccines. In a further specific embodiment polynucleotides, polypeptides, or agonists or antagonists of the invention are used to treat AIDS.  
       [0788] Similarly, bacterial or fungal agents that can cause disease or symptoms and that can be treated or detected by a polynucleotide or polypeptide and/or agonist or antagonist of the present invention include, but not limited to, include, but not limited to, the following Gram-Negative and Gram-positive bacteria and bacterial families and fungi: Actinomycetales (e.g., Corynebacterium, Mycobacterium, Norcardia),  Cryptococcus neoformans , Aspergillosis, Bacillaceae (e.g., Anthrax, Clostridium), Bacteroidaceae, Blastomycosis, Bordetella, Borrelia (e.g.,  Borrelia burgdorferi , Brucellosis, Candidiasis, Campylobacter, Coccidioidomycosis, Cryptococcosis, Dermatocycoses,  E. coli  (e.g., Enterotoxigenic  E. coli  and Enterohemorrhagic  E. coli ), Enterobacteriaceae (Klebsiella, Salmonella (e.g.,  Salmonella typhi , and  Salmonella paratyphi ), Serratia, Yersinia), Erysipelothrix, Helicobacter, Legionellosis, Leptospirosis, Listeria, Mycoplasmatales,  Mycobacterium leprae, Vibrio cholerae , Neisseriaceae (e.g., Acinetobacter, Gonorrhea, Menigococcal),  Meisseria meningitidis , Pasteurellacea Infections (e.g., Actinobacillus, Heamophilus (e.g., Heamophilus influenza type B), Pasteurella), Pseudomonas, Rickettsiaceae, Chlamydiaceae, Treponema spp., Leptospira spp., Shigella spp., Staphylococcal, Meningiococcal, Pneumococcal and Streptococcal (e.g., Streptococcus pneumoniae and Group B Streptococcus). These bacterial or fungal families can cause the following diseases or symptoms, including, but not limited to: bacteremia, endocarditis, eye infections (conjunctivitis, tuberculosis, uveitis), gingivitis, opportunistic infections (e.g., AIDS related infections), paronychia, prosthesis-related infections, Reiter&#39;s Disease, respiratory tract infections, such as Whooping Cough or Empyema, sepsis, Lyme Disease, Cat-Scratch Disease, Dysentery, Paratyphoid Fever, food poisoning, Typhoid, pneumonia, Gonorrhea, meningitis (e.g., mengitis types A and B), Chlamydia, Syphilis, Diphtheria, Leprosy, Paratuberculosis, Tuberculosis, Lupus, Botulism, gangrene, tetanus, impetigo, Rheumatic Fever, Scarlet Fever, sexually transmitted diseases, skin diseases (e.g., cellulitis, dermatocycoses), toxemia, urinary tract infections, wound infections. Polynucleotides or polypeptides, agonists or antagonists of the invention, can be used to treat or detect any of these symptoms or diseases. In specific embodiments, Ppolynucleotides, polypeptides, agonists or antagonists of the invention are used to treat: tetanus, Diptheria, botulism, and/or meningitis type B.  
       [0789] Moreover, parasitic agents causing disease or symptoms that can be treated or detected by a polynucleotide or polypeptide and/or agonist or antagonist of the present invention include, but not limited to, the following families or class: Amebiasis, Babesiosis, Coccidiosis, Cryptosporidiosis, Dientamoebiasis, Dourine, Ectoparasitic, Giardiasis, Helminthiasis, Leishmaniasis, Theileriasis, Toxoplasmosis, Trypanosomiasis, and Trichomonas and Sporozoans (e.g., Plasmodium virax, Plasmodium falciparium, Plasmodium malariae and Plasmodium ovate). These parasites can cause a variety of diseases or symptoms, including, but not limited to: Scabies, Trombiculiasis, eye infections, intestinal disease (e.g., dysentery, giardiasis), liver disease, lung disease, opportunistic infections (e.g., AIDS related), malaria, pregnancy complications, and toxoplasmosis. polynucleotides or polypeptides, or agonists or antagonists of the invention, can be used to treat or detect any ,of these symptoms or diseases.  
       [0790] Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention of the present invention could either be by administering an effective amount of a polypeptide to the patient, or by removing cells from the patient, supplying the cells with a polynucleotide of the present invention, and returning the engineered cells to the patient (ex vivo therapy). Moreover, the polypeptide or polynucleotide of the present invention can be used as an antigen in a vaccine to raise an immune response against infectious disease.  
       [0791] Regeneration  
       [0792] Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention can be used to differentiate, proliferate, and attract cells, leading to the regeneration of tissues. (See, Science 276:59-87 (1997).) The regeneration of tissues could be used to repair, replace, or protect tissue damaged by congenital defects, trauma (wounds, burns, incisions, or ulcers), age, disease (e.g. osteoporosis, osteocarthritis, periodontal disease, liver failure), surgery, including cosmetic plastic surgery, fibrosis, reperfusion injury, or systemic cytokine damage.  
       [0793] Tissues that could be regenerated using the present invention include organs (e.g., pancreas, liver, intestine, kidney, skin, endothelium), muscle (smooth, skeletal or cardiac), vasculature (including vascular and lymphatics), nervous, hematopoietic, and skeletal (bone, cartilage, tendon, and ligament) tissue. Preferably, regeneration occurs without or decreased scarring. Regeneration also may include angiogenesis.  
       [0794] Moreover, polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, may increase regeneration of tissues difficult to heal. For example, increased tendon/ligament regeneration would quicken recovery time after damage. Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention could also be used prophylactically in an effort to avoid damage. Specific diseases that could be treated include of tendinitis, carpal tunnel syndrome, and other tendon or ligament defects. A further example of tissue regeneration of non-healing wounds includes pressure ulcers, ulcers associated with vascular insufficiency, surgical, and traumatic wounds.  
       [0795] Similarly, nerve and brain tissue could also be regenerated by using polynucleotides or polypeptides, as well as agonists or antagonists of the present invention, to proliferate and differentiate nerve cells. Diseases that could be treated using this method include central and peripheral nervous system diseases, neuropathies, or mechanical and traumatic disorders (e.g., spinal cord disorders, head trauma, cerebrovascular disease, and stoke). Specifically, diseases associated with peripheral nerve injuries, peripheral neuropathy (e.g., resulting from chemotherapy or other medical therapies), localized neuropathies, and central nervous system diseases (e.g., Alzheimer&#39;s disease, Parkinson&#39;s disease, Huntington&#39;s disease, amyotrophic lateral sclerosis, and Shy-Drager syndrome), could all be treated using the polynucleotides or polypeptides, as well as agonists or antagonists of the present invention.  
       [0796] Chemotaxis  
       [0797] Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention may have chemotaxis activity. A chemotaxic molecule attracts or mobilizes cells (e.g., monocytes, fibroblasts, neutrophils, T-cells, mast cells, eosinophils, epithelial and/or endothelial cells) to a particular site in the body, such as inflammation, infection, or site of hyperproliferation. The mobilized cells can then fight off and/or heal the particular trauma or abnormality.  
       [0798] Polynucleotides or polypeptides, as well as agonists or antagonists of the present invention may increase chemotaxic activity of particular cells. These chemotactic molecules can then be used to treat inflammation, infection, hyperproliferative disorders, or any immune system disorder by increasing the number of cells targeted to a particular location in the body. For example, chemotaxic molecules can be used to treat wounds and other trauma to tissues by attracting immune cells to the injured location. Chemotactic molecules of the present invention can also attract fibroblasts, which can be used to treat wounds.  
       [0799] It is also contemplated that polynucleotides or polypeptides, as well as agonists or antagonists of the present invention may inhibit chemotactic activity. These molecules could also be used to treat disorders. Thus, polynucleotides or polypeptides, as well as agonists or antagonists of the present invention could be used as an inhibitor of chemotaxis.  
       [0800] Binding Activity  
       [0801] A polypeptide of the present invention may be used to screen for molecules that bind to the polypeptide or for molecules to which the polypeptide binds. The binding of the polypeptide and the molecule may activate (agonist), increase, inhibit (antagonist), or decrease activity of the polypeptide or the molecule bound. Examples of such molecules include antibodies, oligonucleotides, proteins (e.g., receptors),or small molecules.  
       [0802] Preferably, the molecule is closely related to the natural ligand of the polypeptide, e.g., a fragment of the ligand, or a natural substrate, a ligand, a structural or functional mimetic. (See, Coligan et al., Current Protocols in Immunology 1(2):Chapter 5 (1991).) Similarly, the molecule can be closely related to the natural receptor to which the polypeptide binds, or at least, a fragment of the receptor capable of being bound by the polypeptide (e.g., active site). In either case, the molecule can be rationally designed using known techniques.  
       [0803] Preferably, the screening for these molecules involves producing appropriate cells, which express the polypeptide. Preferred cells include cells from mammals, yeast, Drosophila, or  E. coli . Cells expressing the polypeptide (or cell membrane containing the expressed polypeptide) are then preferably contacted with a test compound potentially containing the molecule to observe binding, stimulation, or inhibition of activity of either the polypeptide or the molecule.  
       [0804] The assay may simply test binding of a candidate compound to the polypeptide, wherein binding is detected by a label, or in an assay involving competition with a labeled competitor. Further, the assay may test whether the candidate compound results in a signal generated by binding to the polypeptide.  
       [0805] Alternatively, the assay can be carried out using cell-free preparations, polypeptide/molecule affixed to a solid support, chemical libraries, or natural product mixtures. The assay may also simply comprise the steps of mixing a candidate compound with a solution containing a polypeptide, measuring polypeptide/molecule activity or binding, and comparing the polypeptide/molecule activity or binding to a standard.  
       [0806] Preferably, an ELISA assay can measure polypeptide level or activity in a sample (e.g., biological sample) using a monoclonal or polyclonal antibody. The antibody can measure polypeptide level or activity by either binding, directly or indirectly, to the polypeptide or by competing with the polypeptide for a substrate.  
       [0807] Additionally, the receptor to which the polypeptide of the present invention binds can be identified by numerous methods known to those of skill in the art, for example, ligand panning and FACS sorting (Coligan, et al., Current Protocols in Immun., 1(2), Chapter 5, (1991)). For example, expression cloning is employed wherein polyadenylated RNA is prepared from a cell responsive to the polypeptides, for example, NIH3T3 cells which are known to contain multiple receptors for the FGF family proteins, and SC-3 cells, and a cDNA library created from this RNA is divided into pools and used to transfect COS cells or other cells that are not responsive to the polypeptides. Transfected cells which are grown on glass slides are exposed to the polypeptide of the present invention, after they have been labeled. The polypeptides can be labeled by a variety of means including iodination or inclusion of a recognition site for a site-specific protein kinase.  
       [0808] Following fixation and incubation, the slides are subjected to auto-radiographic analysis. Positive pools are identified and sub-pools are prepared and re-transfected using an iterative sub-pooling and re-screening process, eventually yielding single clones that encode the putative receptor.  
       [0809] As an alternative approach for receptor identification, the labeled polypeptides can be photoaffinity linked with cell membrane or extract preparations that express the receptor molecule. Cross-linked material is resolved by PAGE analysis and exposed to X-ray film. The labeled complex containing the receptors of the polypeptides can be excised, resolved into peptide fragments, and subjected to protein microsequencing. The amino acid sequence obtained from microsequencing would be used to design a set of degenerate oligonucieotide probes to screen a cDNA library to identify the genes encoding the putative receptors.  
       [0810] Moreover, the techniques of gene-shuffling, motif-shuffling, exon-shuffling, and/or codon-shuffling (collectively referred to as “DNA shuffling”) may be employed to modulate the activities of the polypeptide of the present invention thereby effectively generating agonists and antagonists of the polypeptide of the present invention. See generally, U.S. Pat. Nos. 5,605,793, 5,811,238, 5,830,721, 5,834,252, and 5,837,458, and Patten, P. A., et al., Curr. Opinion Biotechnol. 8:724-33 (1997); Harayama, S. Trends Biotechnol. 16(2):76-82 (1998); Hansson L. O., et al., J. Mol. Biol. 287:265-76 (1999); and Lorenzo, M. M. and Blasco, R. Biotechniques 24(2):308-13 (1998); each of these patents and publications are hereby incorporated by reference). In one embodiment, alteration of polynucleotides and corresponding polypeptides may be achieved by DNA shuffling. DNA shuffling involves the assembly of two or more DNA segments into a desired molecule by homologous, or site-specific, recombination. In another embodiment, polynucleotides and corresponding polypeptides may be altered by being subjected to random mutagenesis by error-prone PCR, random nucleotide insertion or other methods prior to recombination. In another embodiment, one or more components, motifs, sections, parts, domains, fragments, etc., of the polypeptide of the present invention may be recombined with one or more components, motifs, sections, parts, domains, fragments, etc. of one or more heterotogous molecules. In preferred embodiments, the heterologous molecules are family members. In further preferred embodiments, the heterologous molecule is a growth factor such as, for example, platelet-derived growth factor (PDGF), insulin-like growth factor (IGF-I), transforming growth factor (TGF)-alpha, epidermal growth factor (EGF), fibroblast growth factor (FGF), TGF-beta, bone morphogenetic protein (BMP)-2, BMP-4, BMP-5, BMP-6, BMP-7, activins A and B, decapentaplegic(dpp), 60A, OP-2, dorsalin, growth differentiation factors (GDFs), nodal, MIS, inhibin-alpha, TGF-betal, TGF-beta2, TGF-beta3, TGF-beta5, and glial-derived neurotrophic factor (GDNF).  
       [0811] Other preferred fragments are biologically active fragments of the polypeptide of the present invention. Biologically active fragments are those exhibiting activity similar, but not necessarily identical, to an activity of the polypeptide of the present invention. The biological activity of the fragments may include an improved desired activity, or a decreased undesirable activity.  
       [0812] Additionally, this invention provides a method of screening compounds to identify those which modulate the action of the polypeptide of the present invention. An example of such an assay comprises combining a mammalian fibroblast cell, a the polypeptide of the present invention, the compound to be screened and  3 [H] thymidine under cell culture conditions where the fibroblast cell would normally proliferate. A control assay may be performed in the absence of the compound to be screened and compared to the amount of fibroblast proliferation in the presence of the compound to determine if the compound stimulates proliferation by determining the uptake of  3 [H] thymidine in each case. The amount of fibroblast cell proliferation is measured by liquid scintillation chromatography which measures the incorporation of  3 [H] thymidine. Both agonist and antagonist compounds may be identified by this procedure.  
       [0813] In another method, a mammalian cell or membrane preparation expressing a receptor for a polypeptide of the present invention is incubated with a labeled polypeptide of the present invention in the presence of the compound. The ability of the compound to enhance or block this interaction could then be measured. Alternatively, the response of a known second messenger system following interaction of a compound to be screened and the receptor is measured and the ability of the compound to bind to the receptor and elicit a second messenger response is measured to determine if the compound is a potential agonist or antagonist. Such second messenger systems include but are not limited to, cAMP guanylate cyclase, ion channels or phosphoinositide hydrolysis.  
       [0814] All of these above assays can be used as diagnostic or prognostic markers. The molecules discovered using these assays can be used to treat disease or to bring about a particular result in a patient (e.g., blood vessel growth) by activating or inhibiting the polypeptide/molecule. Moreover, the assays can discover agents, which may inhibit or enhance the production of the polypeptides of the invention from suitably manipulated cells or tissues.  
       [0815] Therefore, the invention includes a method of identifying compounds which bind to a polypeptide of the invention comprising the steps of: (a) incubating a candidate binding compound with a polypeptide of the present invention; and (b) determining if binding has occurred. Moreover, the invention includes a method of identifying agonists/antagonists comprising the steps of: (a) incubating a candidate compound with a polypeptide of the present invention, (b) assaying a biological activity, and (b) determining if a biological activity of the polypeptide has been altered.  
       [0816] Targeted Delivery  
       [0817] In another embodiment, the invention provides a method of delivering compositions to targeted cells expressing a receptor for a polypeptide of the invention, or cells expressing a cell bound form of a polypeptide of the invention.  
       [0818] As discussed herein, polypeptides or antibodies of the invention may be associated with heterologous polypeptides, heterologous nucleic acids, toxins, or prodrugs via hydrophobic, hydrophilic, ionic and/or covalent interactions. In one embodiment, the invention provides a method for the specific delivery of compositions of the invention to cells by administering polypeptides of the invention (including antibodies) that are associated with heterologous polypeptides or nucleic acids. In one example, the invention provides a method for delivering a therapeutic protein into the targeted cell. In another example, the invention provides a method for delivering a single stranded nucleic acid (e.g., antisense or ribozymes) or double stranded nucleic acid (e.g., DNA that can integrate into the cell&#39;s genome or replicate episomally and that can be transcribed) into the targeted cell.  
       [0819] In another embodiment, the invention provides a method for the specific destruction of cells (e.g., the destruction of tumor cells) by administering polypeptides of the invention (e.g., polypeptides of the invention or antibodies of the invention) in association with toxins or cytotoxic prodrugs.  
       [0820] By “toxin” is meant compounds that bind and activate endogenous cytotoxic effector systems, radioisotopes, holotoxins, modified toxins, catalytic subunits of toxins, or any molecules or enzymes not normnally present in or on the surface of a cell that under defined conditions cause the cell&#39;s death. Toxins that may be used according to the methods of the invention include, but are not limited to, radioisotopes known in the art, compounds such as, for example, antibodies (or complement fixing containing portions thereof) that bind an inherent or induced endogenous cytotoxic effector system, thymidine kinase, endonuclease, RNAse, alpha toxin, ricin, abrin, Pseudomonas exotoxin A, diphtheria toxin, saporin, momordin, gelonin, pokeweed antiviral protein, alpha-sarcin and cholera toxin. By “cytotoxic prodrug” is meant a non-toxic compound that is converted by an enzyme, normally present in the cell, into a cytotoxic compound. Cytotoxic prodrugs that may be used according to the methods of the invention include, but are not limited to, glutamyl derivatives of benzoic acid mustard alkylating agent, phosphate derivatives of etoposide or mitomycin C, cytosine arabinoside, daunorubisin, and phenoxyacetamide derivatives of doxorubicin.  
       [0821] Drug Screening  
       [0822] Further contemplated is the use of the polypeptides of the present invention, or the polynucleotides encoding these polypeptides, to screen for molecules, which modify the activities of the polypeptides of the present invention. Such a method would include contacting the polypeptide of the present invention with a selected compound(s) suspected of having antagonist or agonist activity, and assaying the activity of these polypeptides following binding.  
       [0823] This invention is particularly useful for screening therapeutic compounds by using the polypeptides of the present invention, or binding fragments thereof, in any of a variety of drug screening techniques. The polypeptide or fragment employed in such a test may be affixed to a solid support, expressed on a cell surface, free in solution, or located intracellularly. One method of drug screening utilizes eukaryotic or prokaryotic host cells which are stably transformed with recombinant nucleic acids expressing the polypeptide or fragment. Drugs are screened against such transformed cells in competitive binding assays. One may measure, for example, the formulation of complexes between the agent being tested and a polypeptide of the present invention.  
       [0824] Thus, the present invention provides methods of screening for drugs or any other agents, which affect activities mediated by the polypeptides of the present invention. These methods comprise contacting such an agent with a polypeptide of the present invention or a fragment thereof and assaying for the presence of a complex between the agent and the polypeptide or a fragment thereof, by methods well known in the art. In such a competitive binding assay, the agents to screen are typically labeled. Following incubation, free agent is separated from that present in bound form, and the amount of free or uncomplexed label is a measure of the ability of a particular agent to bind to the polypeptides of the present invention.  
       [0825] Another technique for drug screening provides high throughput screening for compounds having suitable binding affinity to the polypeptides of the present invention, and is described in great detail in European Patent Application 84/03564, published on Sep. 13, 1984, which is incorporated herein by reference herein. Briefly stated, large numbers of different small peptide test compounds are synthesized on a solid substrate, such as plastic pins or some other surface. The peptide test compounds are reacted with polypeptides of the present invention and washed. Bound polypeptides are then detected by methods well known in the art. Purified polypeptides are coated directly onto plates for use in the aforementioned drug screening techniques. In addition, non-neutralizing antibodies may be used to capture the peptide and immobilize it on the solid support.  
       [0826] This invention also contemplates the use of competitive drug screening assays in which neutralizing antibodies capable of binding polypeptides of the present invention specifically compete with a test compound for binding to the polypeptides or fragments thereof. In this manner, the antibodies are used to detect the presence of any peptide, which shares one or more antigenic epitopes with a polypeptide of the invention.  
       [0827] Antisense And Ribozyme (Antagonists)  
       [0828] In specific embodiments, antagonists according to the present invention are nucleic acids corresponding to the sequences contained in SEQ ID NO: X, or the complementary strand thereof, and/or to cDNA sequences contained in cDNA Clone ID NO: Z identified for example, in Table 1A. In one embodiment, antisense sequence is generated internally, by the organism, in another embodiment, the antisense sequence is separately administered (see, for example, O&#39;Connor, J., Neurochem. 56:560 (1991). Oligodeoxynucleotides as Antisense Inhibitors of Gene Expression, CRC Press, Boca Raton, Fla. (1988). Antisense technology can be used to control gene expression through antisense DNA or RNA, or through triple-helix formation. Antisense techniques are discussed for example, in Okano, J., Neurochem. 56:560 (1991); Oligodeoxynucleotides as Antisense Inhibitors of Gene Expression, CRC Press, Boca Raton, Fla. (1988). Triple helix formation is discussed in, for instance, Lee et al., Nucleic Acids Research.6:3073 (1979); Cooney et al., Science 241:456 (1988); and Dervan et al., Science 251:1300 (1991). The methods are based on binding of a polynucleotide to a complementary DNA or RNA.  
       [0829] For example, the use of c-myc and c-myb antisense RNA constructs to inhibit the growth of the non-lymphocytic leukemia cell line HL-60 and other cell lines was previously described. (Wickstrom et al. (1988); Anfossi et al. (1989)). These experiments were performed in vitro by incubating cells with the oligoribonucleotide. A similar procedure for in vivo use is described in WO 91/15580. Briefly, a pair of oligonucleotides for a given antisense RNA is produced as follows: A sequence complimentary to the first 15 bases of the open reading frame is flanked by an EcoR1 site on the 5′ end and a HindIll site on the 3′ end. Next, the pair of oligonucleotides is heated at 90° C. for one minute and then annealed in 2×ligation buffer (20 mM TRIS HCl pH 7.5, 10 mM MgC12, 10 MM dithiothreitol (DTT) and 0.2 mM ATP) and then ligated to the EcoR1/Hind III site of the retroviral vector PMV7 (WO 91/15580).  
       [0830] For example, the 5′ coding portion of a polynucleotide that encodes the polypeptide of the present invention may be used to design an antisense RNA oligonucleotide of from about 10 to 40 base pairs in length. A DNA oligonucleotide is designed to be complementary to a region of the gene involved in transcription thereby preventing transcription and the production of the receptor. The antisense RNA oligonucleotide hybridizes to the mRNA in vivo and blocks translation of the mRNA molecule into receptor polypeptide.  
       [0831] In one embodiment, the antisense nucleic acid of the invention is produced intracellularly by transcription from an exogenous sequence. For example, a vector or a portion thereof, is transcribed, producing an antisense nucleic acid (RNA) of the invention. Such a vector would contain a sequence encoding the antisense nucleic acid. Such a vector can remain episomal or become chromosomally integrated, as long as it can be transcribed to produce the desired antisense RNA. Such vectors can be constructed by recombinant DNA technology methods standard in the art. Vectors can be plasmid, viral, or others known in the art, used for replication and expression in vertebrate cells. Expression of the sequence encoding the polypeptide of the present invention or fragments thereof, can be by any promoter known in the art to act in vertebrate, preferably human cells. Such promoters can be inducible or constitutive. Such promoters include, but are not limited to, the SV40 early promoter region (Bernoist and Chambon, Nature 29:304-310 (1981), the promoter contained in the 3′ long terminal repeat of Rous sarcoma virus (Yamamoto et al., Cell 22:787-797 (1980), the herpes thymidine promoter (Wagner et al., Proc. Natl. Acad. Sci. U.S.A. 78:1441-1445 (1981), the regulatory sequences of the metallothionein gene (Brinster, et al., Nature 296:39-42 (1982)), etc.  
       [0832] The antisense nucleic acids of the invention comprise a sequence complementary to at least a portion of an RNA transcript of a gene of the present invention. However, absolute complementarity, although preferred, is not required. A sequence “complementary to at least a portion of an RNA,” referred to herein, means a sequence having sufficient complementarity to be able to hybridize with the RNA, forming a stable duplex; in the case of double stranded antisense nucleic acids, a single strand of the duplex DNA may thus be tested, or triplex formation may be assayed. The ability to hybridize will depend on both the degree of complementarity and the length of the antisense nucleic acid. Generally, the larger the hybridizing nucleic acid, the more base mismatches with a RNA it may contain and still form a stable duplex (or triplex as the case may be). One skilled in the art can ascertain a tolerable degree of mismatch by use of standard procedures to determine the melting point of the hybridized complex.  
       [0833] Oligonucleotides that are complementary to the 5′ end of the message, e.g., the 5′ untranslated sequence up to and including the AUG initiation codon, should work most efficiently at inhibiting translation. However, sequences complementary to the 3′ untranslated sequences of mRNAs have been shown to be effective at inhibiting translation of mRNAs as well. See generally, Wagner, R., 1994, Nature 372:333-335. Thus, oligonucleotides complementary to either the 5′- or 3′-non-translated, non-coding regions of polynucleotide sequences described herein could be used in an antisense approach to inhibit translation of endogenous mRNA. Oligonucleotides complementary to the 5′ untranslated region of the mRNA should include the complement of the AUG start codon. Antisense oligonucleotides complementary to mRNA coding regions are less efficient inhibitors of translation but could be used in accordance with the invention. Whether designed to hybridize to the 5′-, 3′- or coding region of mRNA of the present invention, antisense nucleic acids should be at least six nucleotides in length, and are preferably oligonucleotides ranging from 6 to about 50 nucleotides in length. In specific aspects the oligonucleotide is at least 10 nucleotides, at least 17 nucleotides, at least 25 nucleotides or at least 50 nucleotides.  
       [0834] The polynucleotides of the invention can be DNA or RNA or chimeric mixtures or derivatives or modified versions thereof, single-stranded or double-stranded. The oligonucleotide can be modified at the base moiety, sugar moiety, or phosphate backbone, for example, to improve stability of the molecule, hybridization, etc. The oligonucleotide may include other appended groups such as peptides (e.g., for targeting host cell receptors in vivo), or agents facilitating transport across the cell membrane (see, e.g., Letsinger et al., 1989, Proc. Natl. Acad. Sci. U.S.A. 86:6553-6556; Lemaitre et al., 1987, Proc. Natl. Acad. Sci. 84:648-652; PCT Publication No. WO88/09810, published Dec. 15, 1988) or the blood-brain barrier (see, e.g., PCT Publication No. WO89/10134, published Apr. 25, 1988), hybridization-triggered cleavage agents. (See, e.g., Krol et al., 1988, BioTechniques 6:958-976) or intercalating agents. (See, e.g., Zon, 1988, Pharm. Res. 5:539-549). To this end, the oligonucleotide may be conjugated to another molecule, e.g., a peptide, hybridization triggered cross-linking agent, transport agent, hybridization-triggered cleavage agent, etc.  
       [0835] The antisense oligonucleotide may comprise at least one modified base moiety which is selected from the group including, but not limited to, 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xantine, 4-acetylcytosine, 5-(carboxyhydroxylmethyl) uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5-methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine, 5′-methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid (v), wybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid (v), 5-methyl-2-thiouracil, 3-(3 -amino-3-N-2-carboxypropyl) uracil, (acp3)w, and 2,6-diaminopurine.  
       [0836] The antisense oligonucleotide may also comprise at least one modified sugar moiety selected from the group including, but not limited to, arabinose, 2-fluoroarabinose, xylulose, and hexose.  
       [0837] In yet another embodiment, the antisense oligonucleotide comprises at least one modified phosphate backbone selected from the group including, but not limited to, a phosphorothioate, a phosphorodithioate, a phosphoramidothioate, a phosphoramidate, a phosphordiamidate, a methylphosphonate, an alkyl phosphotriester, and a formacetal or analog thereof.  
       [0838] In yet another embodiment, the antisense oligonucteotide is an a-anomeric oligonucleotide. An a-anomeric oligonucleotide forms specific double-stranded hybrids with complementary RNA in which, contrary to the usual b-units, the strands run parallel to each other (Gautier et al., 1987, Nucl. Acids Res. 15:6625-6641). The oligonucleotide is a 2′-0-methylribonucleotide (Inoue et al., 1987, Nucl. Acids Res. 15:6131-6148), or a chimeric RNA-DNA analogue (Inoue et al., 1987, FEBS Lett. 215:327-330).  
       [0839] Polynucleotides of the invention may be synthesized by standard methods known in the art, e.g. by use of an automated DNA synthesizer (such as are commercially available from Biosearch, Applied Biosystems, etc.). As examples, phosphorothioate oligonucleotides may be synthesized by the method of Stein et al. (1988, Nucl. Acids Res. 16:3209), methylphosphonate oligonucleotides can be prepared by use of controlled pore glass polymer supports (Sarin et al., 1988, Proc. Natl. Acad. Sci. U.S.A. 85:7448-7451), etc.  
       [0840] While antisense nucleotides complementary to the coding region sequence could be used, those complementary to the transcribed untranslated region are most preferred.  
       [0841] Potential antagonists according to the invention also include catalytic RNA, or a ribozyme (See, e.g., PCT International Publication WO 90/11364, published Oct. 4, 1990; Sarver et al, Science 247:1222-1225 (1990). While ribozymes that cleave mRNA at site specific recognition sequences can be used to destroy mRNAs, the use of hammerhead ribozymes is preferred. Hammerhead ribozymes cleave mRNAs at locations dictated by flanking regions that form complementary base pairs with the target mRNA. The sole requirement is that the target mRNA have the following sequence of two bases: 5′-UG-3′. The construction and production of hammerhead ribozymes is well known in the art and is described more fully in Haseloff and Gerlach, Nature 334:585-591 (1988). There are numerous potential hammerhead ribozyme cleavage sites within the nucleotide sequence of SEQ ID NO: X. Preferably, the ribozyme is engineered so that the cleavage recognition site is located near the 5′ end of the mRNA; i.e., to increase efficiency and minimize the intracellular accumulation of non-functional mRNA transcripts.  
       [0842] As in the antisense approach, the ribozymes of the invention can be composed of modified oligonucleotides (e.g. for improved stability, targeting, etc.) and should be delivered to cells, which express in vivo. DNA constructs encoding the ribozyme may be introduced into the cell in the same manner as described above for the introduction of antisense encoding DNA. A preferred method of delivery involves using a DNA construct “encoding” the ribozyme under the control of a strong constitutive promoter, such as, for example, pol III or pol II promoter, so that transfected cells will produce sufficient quantities of the ribozyme to destroy endogenous messages and inhibit translation. Since ribozymes unlike antisense molecules, are catalytic, a lower intracellular concentration is required for efficiency.  
       [0843] Antagonist/agonist compounds may be employed to inhibit the cell growth and proliferation effects of the polypep ides of the present invention on neoplastic cells and tissues, i.e. stimulation of angiogenesis of tumors, and, therefore, retard or prevent abnormal cellular growth and proliferation, for example, in tumor formation or growth.  
       [0844] The antagonist/agonist may also be employed to prevent hyper-vascular diseases, and prevent the proliferation of epithelial lens cells after extracapsular cataract surgery. Prevention of the mitogenic activity of the polypeptides of the present invention may also be desirous in cases such as restenosis after balloon angioplasty.  
       [0845] The antagonist/agonist may also be employed to prevent the growth of scar tissue during wound healing.  
       [0846] The antagonist/agonist may also be employed to treat the diseases described herein.  
       [0847] Thus, the invention provides a method of treating disorders or diseases, including but not limited to the disorders or diseases listed throughout this application, associated with overexpression of a polynucleotide of the present invention by administering to a patient (a) an antisense molecule directed to the polynucleotide of the present invention, and/or (b) a ribozyme directed to the polynucleotide of the present invention.  
       [0848] Binding Peptides and Other Molecules  
       [0849] The invention also encompasses screening methods for identifying polypeptides and nonpolypeptides that bind excretory system antigen polypeptides, and the excretory system antigen binding molecules identified thereby. These binding molecules are useful, for example, as agonists and antagonists of the excretory system antigen polypeptides. Such agonists and antagonists can be used, in accordance with the invention, in the therapeutic embodiments described in detail, below.  
       [0850] This method comprises the steps of:  
       [0851] contacting excretory system antigen polypeptides or excretory system antigen-like polypeptides with a plurality of molecules; and  
       [0852] identifying a molecule that binds the excretory system antigen polypeptides or excretory system antigen-like polypeptides.  
       [0853] The step of contacting the excretory system antigen polypeptides or excretory system antigen-like polypeptides with the plurality of molecules may be effected in a number of ways. For example, one may contemplate immobilizing the excretory system antigen polypeptides or excretory system antigen-like polypeptides on a solid support and bringing a solution of the plurality of molecules in contact with the immobilized excretory system antigen polypeptides or excretory system antigen-like polypeptides. Such a procedure would be akin to an affinity chromatographic process, with the affinity matrix being comprised of the immobilized excretory system antigen polypeptides or excretory system antigen-like polypeptides. The molecules having a selective affinity for the excretory system antigen polypeptides or excretory system antigen-like polypeptides can then be purified by affinity selection. The nature of the solid support, process for attachment of the excretory system antigen polypeptides or excretory system antigen-like polypeptides to the solid support, solvent, and conditions of the affinity isolation or selection are largely conventional and well known to those of ordinary skill in the art.  
       [0854] Alternatively, one may also separate a plurality of polypeptides into substantially separate fractions comprising a subset of or individual polypeptides. For instance, one can separate the plurality of polypeptides by gel electrophoresis, column chromatography, or like method known to those of ordinary skill for the separation of polypeptides. The individual polypeptides can also be produced by a transformed host cell in such a way as to be expressed on or about its outer surface (e.g., a recombinant phage). Individual isolates can then be “probed” by the excretory system antigen polypeptides or excretory system antigen-like polypeptides, optionally in the presence of an inducer should one be required for expression, to determine if any selective affinity interaction takes place between the excretory system antigen polypeptides or excretory system antigen-like polypeptides and the individual clone. Prior to contacting the excretory system antigen polypeptides or excretory system antigen-like polypeptides with each fraction comprising individual polypeptides, the polypeptides could first be transferred to a solid support for additional convenience. Such a solid support may simply be a piece of filter membrane, such as one made of nitrocellulose or nylon. In this manner, positive clones could be identified from a collection of transformed host cells of an expression library, which harbor a DNA construct encoding a polypeptide having a selective affinity for excretory system antigen polypeptides or excretory system antigen-like polypeptides. Furthermore, the amino acid sequence of the polypeptide having a selective affinity for the excretory system antigen polypeptides or excretory system antigen-like polypeptides can be determined directly by conventional means or the coding sequence of the DNA encoding the polypeptide can frequently be determined more conveniently. The primary sequence can then be deduced from the corresponding DNA sequence. If the amino acid sequence is to be determined from the polypeptide itself, one may use microsequencing techniques. The sequencing technique may include mass spectroscopy.  
       [0855] In certain situations, it may be desirable to wash away any unbound excretory system antigen polypeptides or excretory system antigen-like polypeptides, or alternatively, unbound potypeptides, from a mixture of the excretory system antigen polypeptides or excretory system antigen-like polypeptides and the plurality of polypeptides prior to attempting to determine or to detect the presence of a selective affinity interaction. Such a wash step may be particularly desirable when the excretory system antigen polypeptides or excretory system antigen-like polypeptides or the plurality of polypeptides is bound to a solid support.  
       [0856] The plurality of molecules provided according to this method may be provided by way of diversity libraries, such as random or combinatorial peptide or nonpeptide libraries, which can be screened for molecules that specifically bind excretory system antigen polypeptides. Many libraries are known in the art that can be used, e.g., chemically synthesized libraries, recombinant (e.g., phage display libraries), and in vitro translation-based libraries. Examples of chemically synthesized libraries are described in Fodor et al., 1991, Science 251:767-773; Houghten et al., 1991, Nature 354:84-86; Lam et al., 1991, Nature 354:82-84; Medynski, 1994, Bio/Technology 12:709-710;Gallop et al., 1994, J. Medicinal Chemistry 37(9):1233-1251; Ohlmeyer et al., 1993, Proc. Natl. Acad. Sci. USA 90:10922-10926; Erb et al., 1994, Proc. Natl. Acad. Sci. USA 91:11422-11426; Houghten et al., 1992, Biotechniques 13:412; Jayawickreme et al., 1994, Proc. Natl. Acad. Sci. USA 91:1614-1618; Salmon et al., 1993, Proc. Natl. Acad. Sci. USA 90:11708-11712; PCT Publication No. WO 93/20242; and Brenner and Lemer, 1992, Proc. Natl. Acad. Sci. USA 89:5381-5383.  
       [0857] Examples of phage display libraries are described in Scott and Smith, 1990, Science 249:386-390; Devlin et al., 1990, Science, 249:404-406; Christian, R. B., et al., 1992, J. Mol. Biol. 227:711-718); Lenstra, 1992, J. Immunol. Meth. 152:149-157; Kay et al., 1993, Gene 128:59-65; and PCT Publication No. WO 94/18318 dated Aug. 18, 1994.  
       [0858] In vitro translation-based libraries include but are not limited to those described in PCT Publication No. WO 91/05058 dated Apr. 18, 1991; and Mattheakis et al., 1994, Proc. Natl. Acad. Sci. USA 91:9022-9026.  
       [0859] By way of examples of nonpeptide libraries, a benzodiazepine library (see e.g., Bunin et al., 1994, Proc. Natl. Acad. Sci. USA 91:4708-4712) can be adapted for use. Peptoid libraries (Simon et al., 1992, Proc. Natl. Acad. Sci. USA 89:9367-9371) can also be used. Another example of a library that can be used, in which the amide functionalities in peptides have been permethylated to generate a chemically transformed combinatorial library, is described by Ostresh et al. (1994, Proc. Natl. Acad. Sci. USA 91:11138-11142).  
       [0860] The variety of non-peptide libraries that are useful in the present invention is great. For example, Ecker and Crooke, 1995, Bio/Technology 13:351-360 list benzodiazepines, hydantoins, piperazinediones, biphenyls, sugar analogs, beta-mercaptoketones, arylacetic acids, acylpiperidines, benzopyrans, cubanes, xanthines, aminimides, and oxazolones as among the chemical species that form the basis of various libraries.  
       [0861] Non-peptide libraries can be classified broadly into two types: decorated monomers and oligomers. Decorated monomer libraries employ a relatively simple scaffold structure upon which a variety functional groups is added. Often the scaffold will be a molecule with a known useful pharmacological activity. For example, the scaffold might be the benzodiazepine structure.  
       [0862] Non-peptide oligomer libraries utilize a large number of monomers that are assembled together in ways that create new shapes that depend on the order of the monomers. Among the monomer units that have been used are carbamates, pyrrolinones, and morpholinos. Peptoids, peptide-like oligomers in which the side chain is attached to the alpha amino group rather than the alpha carbon, form the basis of another version of non-peptide oligomer libraries. The first non-peptide oligomer libraries utilized a single type of monomer and thus contained a repeating backbone. Recent libraries have utilized more than one monomer, giving the libraries added flexibility.  
       [0863] Screening the libraries can be accomplished by any of a variety of commonly known methods. See, e.g., the following references, which disclose screening of peptide libraries: Parmley and Smith, 1989, Adv. Exp. Med. Biol. 251:215-218; Scott and Smith, 1990, Science 249:386-390; Fowlkes et al., 1992; BioTechniques 13:422-427; Oldenburg et al., 1992, Proc. Natl. Acad. Sci. USA 89:5393-5397; Yu et al., 1994, Cell 76:933-945; Staudt et al., 1988, Science 241:577-580; Bock et al., 1992, Nature 355:564-566; Tuerk et al., 1992, Proc. Natl. Acad. Sci. USA 89:6988-6992; Ellington et al., 1992, Nature 355:850-852; U.S. Pat. No. 5,096,815, U.S. Pat. No. 5,223,409, and U.S. Pat. No. 5,198,346, all to Ladner et al.; Rebar and Pabo, 1993, Science 263:671-673; and CT Publication No. WO 94/18318.  
       [0864] In a specific embodiment, screening to identify a molecule that binds excretory system antigen polypeptides can be carried out by contacting the library members with an excretory system antigen polypeptides or excretory system antigen-like polypeptides immobilized on a solid phase and harvesting those library members that bind to the excretory system antigen polypeptides or excretory system antigen-like polypeptides. Examples of such screening methods, termed “panning” techniques are described by way of example in Parmley and Smith, 1988, Gene 73:305-318; Fowlkes et al., 1992, BioTechniques 13:422-427; International Publication No. WO 94/18318; and in references cited herein.  
       [0865] In another embodiment, the two-hybrid system for selecting interacting proteins in yeast (Fields and Song, 1989, Nature 340:245-246; Chien et al., 1991, Proc. Natl. Acad. Sci. USA 88:9578-9582) can be used to identify molecules that specifically bind to excretory system antigen polypeptides or excretory system antigen-like polypeptides.  
       [0866] Where the excretory system antigen binding molecule is a polypeptide, the polypeptide can be conveniently selected from any peptide library, including random peptide libraries, combinatorial peptide libraries, or biased peptide libraries. The term “biased” is used herein to mean that the method of generating the library is manipulated so as to restrict one or more parameters that govern the diversity of the resulting collection of molecules, in this case peptides.  
       [0867] Thus, a truly random peptide library would generate a collection of peptides in which the probability of finding a particular amino acid at a given position of the peptide is the same for all 20 amino acids. A bias can be introduced into the library, however, by specifying, for example, that a lysine occurs every fifth amino acid or that positions 4, 8, and 9 of a decapeptide library be fixed to include only arginine. Clearly, many types of biases can be contemplated, and the present invention is not restricted to any particular bias. Furthermore, the present invention contemplates specific types of peptide libraries, such as phage displayed peptide libraries and those that utilize a DNA construct comprising a lambda phage vector with a DNA insert.  
       [0868] As mentioned above, in the case of an excretory system antigen binding molecule that is a polypeptide, the polypeptide may have about 6 to less than about 60 amino acid residues, preferably about 6 to about 10 amino acid residues, and most preferably, about 6 to about 22 amino acids. In another embodiment, an excretory system antigen binding polypeptide has in the range of 15-100 amino acids, or 20-50 amino acids.  
       [0869] The selected excretory system antigen binding polypeptide can be obtained by chemical synthesis or recombinant expression.  
       [0870] Other Activities  
       [0871] A polypeptide, polynucleotide, agonist, or antagonist of the present invention, as a result of the ability to stimulate vascular endothelial cell growth, may be employed in treatment for stimulating re-vascularization of ischemic tissues due to various disease conditions such as thrombosis, arteriosclerosis, and other cardiovascular conditions. The polypeptide, polynucleotide, agonist, or antagonist of the present invention may also be employed to stimulate angiogenesis and limb regeneration, as discussed above.  
       [0872] A polypeptide, polynucleotide, agonist, or antagonist of the present invention may also be employed for treating wounds due to injuries, burns, post-operative tissue repair, and ulcers since they are mitogenic to various cells of different origins, such as fibroblast cells and skeletal muscle cells, and therefore, facilitate the repair or replacement of damaged or diseased tissue.  
       [0873] A polypeptide, polynucleotide, agonist, or antagonist of the present invention may also be employed to stimulate neuronal growth and to treat and prevent neuronal damage which occurs in certain neuronal disorders or neuro-degenerative conditions such as Alzheimer&#39;s disease, Parkinson&#39;s disease, and AIDS-related complex. A polypeptide, polynucleotide, agonist, or antagonist of the present invention may have the ability to stimulate chondrocyte growth; therefore, they may be employed to enhance bone and periodontal regeneration and aid in tissue transplants or bone grafts.  
       [0874] A polypeptide, polynucleotide, agonist, or antagonist of the present invention may be also be employed to prevent skin aging due to sunburn by stimulating keratinocyte growth.  
       [0875] A polypeptide, polynucleotide, agonist, or antagonist of the present invention may also be employed for preventing hair loss, since FGF family members activate hair-forming cells and promotes melanocyte growth. Along the same lines, a polypeptide, polynucleotide, agonist, or antagonist of the present invention may be employed to stimulate growth and differentiation of hematopoietic cells and bone marrow cells when used in combination with other cytokines.  
       [0876] A polypeptide, polynucleotide, agonist, or antagonist of the present invention may also be employed to maintain organs before transplantation or for supporting cell culture of primary tissues. A polypeptide, polynucleotide, agonist, or antagonist of the present invention may also be employed for inducing tissue of mesodermal origin to differentiate in early embryos.  
       [0877] A polypeptide, polynucleotide, agonist, or antagonist of the present invention may also increase or decrease the differentiation or proliferation of embryonic stem cells, besides, as discussed above, hematopoietic lineage.  
       [0878] A polypeptide, polynucleotide, agonist, or antagonist of the present invention may also be used to modulate mammalian characteristics, such as body height, weight, hair color, eye color, skin, percentage of adipose tissue, pigmentation, size, and shape (e.g., cosmetic surgery). Similarly, a polypeptide, polynucleotide, agonist, or antagonist of the present invention may be used to modulate mammalian metabolism affecting catabolism, anabolism, processing, utilization, and storage of energy.  
       [0879] A polypeptide, polynucleotide, agonist, or antagonist of the present invention may be used to change a mammal&#39;s mental state or physical state by influencing biorhythms, caricadic rhythms, depression (including depressive disorders), tendency for violence, tolerance for pain, reproductive capabilities (preferably by Activin or Inhibin-like activity), hormonal or endocrine levels, appetite, libido, memory, stress, or other cognitive qualities.  
       [0880] A polypeptide, polynucleotide, agonist, or antagonist of the present invention may also be used as a food additive or preservative, such as to increase or decrease storage capabilities, fat content, lipid, protein, carbohydrate, vitamins, minerals, cofactors or other nutritional components.  
       [0881] The above-recited applications have uses in a wide variety of hosts. Such hosts include, but are not limited to, human, murine, rabbit, goat, guinea pig, camel, horse, mouse, rat, hamster, pig, micro-pig, chicken, goat, cow, sheep, dog, cat, non-human primate, and human. In specific embodiments, the host is a mouse, rabbit, goat, guinea pig, chicken, rat, hamster, pig, sheep, dog or cat. In preferred embodiments, the host is a mammal. In most preferred embodiments, the host is a human.  
       [0882] Other Preferred Embodiments  
       [0883] Other preferred embodiments of the claimed invention include an isolated nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to a sequence of at least about 50 contiguous nucleotides in the nucleotide sequence of SEQ ID NO: X or the complementary strand thereto, the nucleotide sequence as defined in column 4 of Table 1A or columns 8 and 9 of Table 2 or the complementary strand thereto, and/or cDNA contained in Clone ID NO: Z.  
       [0884] Also preferred is a nucleic acid molecule wherein said sequence of contiguous nucleotides is included in the nucleotide sequence of the portion of SEQ ID NO: X as defined in column 4, “ORF (From-To)”, in Table 1A.  
       [0885] Also preferred is a nucleic acid molecule wherein said sequence of contiguous nucleotides is included in the nucleotide sequence of the portion of SEQ ID NO: X as defined in columns 8 and 9, “NT From” and “NT To” respectively, in Table 2.  
       [0886] Also preferred is an isolated nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to a sequence of at least about 150 contiguous nucleotides in the nucleotide sequence of SEQ ID NO: X or the complementary strand thereto, the nucleotide sequence as defined in column 4 of Table 1A or columns 8 and 9 of Table 2 or the complementary strand thereto, and/or cDNA contained in Clone ID NO: Z.  
       [0887] Further preferred is an isolated nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to a sequence of at least about 500 contiguous nucleotides in the nucleotide sequence of SEQ ID NO: X or the complementary strand thereto, the nucleotide sequence as defined in column 4 of Table 1A or columns 8 and 9 of Table 2 or the complementary strand thereto, and/or cDNA contained in Clone ID NO: Z.  
       [0888] A further preferred embodiment is a nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to the nucleotide sequence of the portion of SEQ ID NO: X defined in column 4, “ORF (From-To)”, in Table 1A.  
       [0889] A further preferred embodiment is a nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to the nucleotide sequence of the portion of SEQ ID NO: X defined in columns 8 and 9, “NT From” and “NT To”, respectively, in Table 2.  
       [0890] A further preferred embodiment is an isolated nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to the complete nucleotide sequence of SEQ ID NO: X or the complementary strand thereto, the nucleotide sequence as defined in column 4 of Table 1A or columns 8 and 9 of Table 2 or the complementary strand thereto, and/or cDNA contained in Clone ID NO: Z.  
       [0891] Also preferred is an isolated nucleic acid molecule which hybridizes under stringent hybridization conditions to a nucleic acid molecule comprising a nucleotide sequence of SEQ ID NO: X or the complementary strand thereto, the nucleotide sequence as defined in column 4 of Table 1A or columns 8 and 9 of Table 2 or the complementary strand thereto, and/or cDNA contained in Clone ID NO: Z, wherein said nucleic acid molecule which hybridizes does not hybridize under stringent hybridization conditions to a nucleic acid molecule having a nucleotide sequence consisting of only A residues or of only T residues.  
       [0892] Also preferred is a composition of matter comprising a DNA molecule which comprises the cDNA contained in Clone ID NO: Z.  
       [0893] Also preferred is an isolated nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to a sequence of at least 50 contiguous nucleotides of the cDNA sequence contained in Clone ID NO: Z.  
       [0894] Also preferred is an isolated nucleic acid molecule, wherein said sequence of at least 50 contiguous nucleotides is included in the nucleotide sequence of an open reading frame sequence encoded by cDNA contained in Clone ID NO: Z.  
       [0895] Also preferred is an isolated nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to sequence of at least 150 contiguous nucleotides in the nucleotide sequence encoded by cDNA contained in Clone ID NO: Z.  
       [0896] A further preferred embodiment is an isolated nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to sequence of at least 500 contiguous nucleotides in the nucleotide sequence encoded by cDNA contained in Clone ID NO: Z.  
       [0897] A further preferred embodiment is an isolated nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to the complete nucleotide sequence encoded by cDNA contained in Clone ID NO: Z.  
       [0898] A further preferred embodiment is a method for detecting in a biological sample a nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to a sequence of at least 50 contiguous nucleotides in a sequence selected from the group consisting of: a nucleotide sequence of SEQ ID NO: X or the complementary strand thereto; the nucleotide sequence as defined in column 4 of Table 1A or columns 8 and 9 of Table 2 or the complementary strand thereto; and a nucleotide sequence encoded by cDNA contained in Clone ID NO: Z; which method comprises a step of comparing a nucleotide sequence of at least one nucleic acid molecule in said sample with a sequence selected from said group and determining whether the sequence of said nucleic acid molecule in said sample is at least 95% identical to said selected sequence.  
       [0899] Also preferred is the above method wherein said step of comparing sequences comprises determining the extent of nucleic acid hybridization between nucleic acid molecules in said sample and a nucleic acid molecule comprising said sequence selected from said group. Similarly, also preferred is the above method wherein said step of comparing sequences is performed by comparing the nucleotide sequence determined from a nucleic acid molecule in said sample with said sequence selected from said group. The nucleic acid molecules can comprise DNA molecules or RNA molecules.  
       [0900] A further preferred embodiment is a method for identifying the species, tissue or cell type of a biological sample which method comprises a step of detecting nucleic acid molecules in said sample, if any, comprising a nucleotide sequence that is at least 95% identical to a sequence of at least 50 contiguous nucleotides in a sequence selected from the group consisting of: a nucleotide sequence of SEQ ID NO: X or the complementary strand thereto; the nucleotide sequence as defined in column 4 of Table 1A or columns 8 and 9 of Table 2 or the complementary strand thereto; and a nucleotide sequence of the cDNA contained in Clone ID NO: Z.  
       [0901] The method for identifying the species, tissue or cell type of a biological sample can comprise a step of detecting nucleic acid molecules comprising a nucleotide sequence in a panel of at least two nucleotide sequences, wherein at least one sequence in said panel is at least 95% identical to a sequence of at least 50 contiguous nucleotides in a sequence selected from said group.  
       [0902] Also preferred is a method for diagnosing in a subject a pathological condition associated with abnormal structure or expression of a nucleotide sequence of SEQ ID NO: X or the complementary strand thereto; the nucleotide sequence as defined in column 4 of Table 1A or columns 8 and 9 of Table 2 or the complementary strand thereto; or the cDNA contained in Clone ID NO: Z which encodes a protein, wherein the method comprises a step of detecting in a biological sample obtained from said subject nucleic acid molecules, if any, comprising a nucleotide sequence that is at least 95% identical to a sequence of at least 50 contiguous nucleotides in a sequence selected from the group consisting of: a nucleotide sequence of SEQ ID NO: X or the complementary strand thereto; the nucleotide sequence as defined in column 4 of Table 1A or columns 8 and 9 of Table 2 or the complementary strand thereto; and a nucleotide sequence of cDNA contained in Clone ID NO: Z.  
       [0903] The method for diagnosing a pathological condition can comprise a step of detecting nucleic acid molecules comprising a nucleotide sequence in a panel of at least two nucleotide sequences, wherein at least one sequence in said panel is at least 95% identical to a sequence of at least 50 contiguous nucleotides in a sequence selected from said group.  
       [0904] Also preferred is a composition of matter comprising isolated nucleic acid molecules wherein the nucleotide sequences of said nucleic acid molecules comprise a panel of at least two nucleotide sequences, wherein at least one sequence in said panel is at least 95% identical to a sequence of at least 50 contiguous nucleotides in a sequence selected from the group consisting of: a nucleotide sequence of SEQ ID NO: X or the complementary strand thereto; the nucleotide sequence as defined in column 4 of Table 1A or columns 8 and 9 of Table 2 or the complementary strand thereto; and a nucleotide sequence encoded by cDNA contained in Clone ID NO: Z. The nucleic acid molecules can comprise DNA molecules or RNA molecules.  
       [0905] Also preferred is a composition of matter comprising isolated nucleic acid molecules wherein the nucleotide sequences of said nucleic acid molecules comprise a DNA microarray or “chip” of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 100, 150, 200, 250, 300, 500, 1000, 2000, 3000, or 4000 nucleotide sequences, wherein at least one sequence in said DNA microarray or “chip” is at least 95% identical to a sequence of at least 50 contiguous nucleotides in a sequence selected from the group consisting of: a nucleotide sequence of SEQ ID NO: X wherein X is any integer as defined in Table 1A; and a nucleotide sequence encoded by a human cDNA clone identified by a cDNA “Clone ID” in Table 1A.  
       [0906] Also preferred is an isolated polypeptide comprising an amino acid sequence at least 90% identical to a sequence of at least about 10 contiguous amino acids in the polypeptide sequence of SEQ ID NO: Y; a polypeptide encoded by SEQ ID NO: X or the complementary strand thereto; the polypeptide encoded by the nucleotide sequence as defined in columns 8 and 9 of Table 2; and/or a polypeptide encoded by cDNA contained in Clone ID NO: Z.  
       [0907] Also preferred is an isolated polypeptide comprising an amino acid sequence at least 95% identical to a sequence of at least about 30 contiguous amino acids in the amino acid sequence of SEQ ID NO: Y; a polypeptide encoded by SEQ ID NO: X or the complementary strand thereto; the polypeptide encoded by the nucleotide sequence as defined in columns 8 and 9 of Table 2; and/or a polypeptide encoded by cDNA contained in Clone ID NO: Z.  
       [0908] Further preferred is an isolated polypeptide comprising an amino acid sequence at least 95% identical to a sequence of at least about 100 contiguous amino acids in the amino acid sequence of SEQ ID NO: Y; a polypeptide encoded by SEQ ID NO: X or the complementary strand thereto; the polypeptide encoded by the nucleotide sequence as defined in columns 8 and 9 of Table 2; and/or a polypeptide encoded by cDNA contained in Clone ID NO: Z.  
       [0909] Further preferred is an isolated polypeptide comprising an amino acid sequence at least 95% identical to the complete amino acid sequence of SEQ ID NO: Y; a polypeptide encoded by SEQ ID NO: X or the complementary strand thereto; the polypeptide encoded by the nucleotide sequence as defined in columns 8 and 9 of Table 2; and/or a polypeptide encoded by cDNA contained in Clone ID NO: Z.  
       [0910] Further preferred is an isolated polypeptide comprising an amino acid sequence at least 90% identical to a sequence of at least about 10 contiguous amino acids in the complete amino acid sequence of a polypeptide encoded by contained in Clone ID NO: Z  
       [0911] Also preferred is a polypeptide wherein said sequence of contiguous amino acids is included in the amino acid sequence of a portion of said polypeptide encoded by cDNA contained in Clone ID NO: Z; a polypeptide encoded by SEQ ID NO: X or the complementary strand thereto; the polypeptide encoded by the nucleotide sequence as defined in columns 8 and 9 of Table 2; and/or the polypeptide sequence of SEQ ID NO: Y.  
       [0912] Also preferred is an isolated polypeptide comprising an amino acid sequence at least 95% identical to a sequence of at least about 30 contiguous amino acids in the amino acid sequence of a polypeptide encoded by the cDNA contained in Clone ID NO: Z.  
       [0913] Also preferred is an isolated polypeptide comprising an amino acid sequence at least 95% identical to a sequence of at least about 100 contiguous amino acids in the amino acid sequence of a polypeptide encoded by cDNA contained in Clone ID NO: Z.  
       [0914] Also preferred is an isolated polypeptide comprising an amino acid sequence at least 95% identical to the amino acid sequence of a polypeptide encoded by the cDNA contained in Clone ID NO: Z.  
       [0915] Further preferred is an isolated antibody which binds specifically to a polypeptide comprising an amino acid sequence that is at least 90% identical to a sequence of at least 10 contiguous amino acids in a sequence selected from the group consisting of: a polypeptide sequence of SEQ ID NO: Y; a polypeptide encoded by SEQ ID NO: X or the complementary strand thereto; the polypeptide encoded by the nucleotide sequence as defined in columns 8 and 9 of Table 2; and a polypeptide encoded by the cDNA contained in Clone ID NO: Z.  
       [0916] Further preferred is a method for detecting in a biological sample a polypeptide comprising an amino acid sequence which is at least 90% identical to a sequence of at least 10 contiguous amino acids in a sequence selected from the group consisting of: a polypeptide sequence of SEQ ID NO: Y; a polypeptide encoded by SEQ ID NO: X or the complementary strand thereto; the polypeptide encoded by the nucleotide sequence as defined in columns 8 and 9 of Table 2; and a polypeptide encoded by the cDNA contained in Clone ID NO: Z; which method comprises a step of comparing an amino acid sequence of at least one polypeptide molecule in said sample with a sequence selected from said group and determining whether the sequence of said polypeptide molecule in said sample is at least 90% identical to said sequence of at least 10 contiguous amino acids.  
       [0917] Also preferred is the above method wherein said step of comparing an amino acid sequence of at least one polypeptide molecule in said sample with a sequence selected from said group comprises determining the extent of specific binding of polypeptides in said sample to an antibody which binds specifically to a polypeptide comprising an amino acid sequence that is at least 90% identical to a sequence of at least 10 contiguous amino acids in a sequence selected from the group consisting of: a polypeptide sequence of SEQ ID NO: Y; a polypeptide encoded by SEQ ID NO: X or the complementary strand thereto; the polypeptide encoded by the nucleotide sequence as defined in columns 8 and 9 of Table 2; and a polypeptide encoded by the cDNA contained in Clone ID NO: Z.  
       [0918] Also preferred is the above method wherein said step of comparing sequences is performed by comparing the amino acid sequence determined from a polypeptide molecule in said sample with said sequence selected from said group.  
       [0919] Also preferred is a method for identifying the species, tissue or cell type of a biological sample which method comprises a step of detecting polypeptide molecules in said sample, if any, comprising an amino acid sequence that is at least 90% identical to a sequence of at least 10 contiguous amino acids in a sequence selected from the group consisting of: polypeptide sequence of SEQ ID NO: Y; a polypeptide encoded by SEQ ID NO: X or the complementary strand thereto; the polypeptide encoded by the nucleotide sequence as defined in columns 8 and 9 of Table 2; and a polypeptide encoded by the cDNA contained in Clone ID NO: Z.  
       [0920] Also preferred is the above method for identifying the species, tissue or cell type of a biological sample, which method comprises a step of detecting polypeptide molecules comprising an amino acid sequence in a panel of at least two amino acid sequences, wherein at least one sequence in said panel is at least 90% identical to a sequence of at least 10 contiguous amino acids in a sequence selected from the above group.  
       [0921] Also preferred is a method for diagnosing in a subject a pathological condition associated with abnormal structure or expression of a nucleic acid sequence identified in Table 1A or Table 2 encoding a polypeptide, which method comprises a step of detecting in a biological sample obtained from said subject polypeptide molecules comprising an amino acid sequence in a panel of at least two amino acid sequences, wherein at least one sequence in said panel is at least 90% identical to a sequence of at least 10 contiguous amino acids in a sequence selected from the group consisting of: polypeptide sequence of SEQ ID NO: Y; a polypeptide encoded by SEQ ID NO: X or the complementary strand thereto; the polypeptide encoded by the nucleotide sequence as defined in columns 8 and 9 of Table 2; and a polypeptide encoded by the cDNA contained in Clone ID NO: Z.  
       [0922] In any of these methods, the step of detecting said polypeptide molecules includes using an antibody.  
       [0923] Also preferred is an isolated nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to a nucleotide sequence encoding a polypeptide wherein said polypeptide comprises an amino acid sequence that is at least 90% identical to a sequence of at least 10 contiguous amino acids in a sequence selected from the group consisting of: polypeptide sequence of SEQ ID NO: Y; a polypeptide encoded by SEQ ID NO: X or the complementary strand thereto; the polypeptide encoded by the nucleotide sequence as defined in columns 8 and 9 of Table 2; and a polypeptide encoded by the cDNA contained in Clone ID NO: Z.  
       [0924] Also preferred is an isolated nucleic acid molecule, wherein said nucleotide sequence encoding a polypeptide has been optimized for expression of said polypeptide in a prokaryotic host.  
       [0925] Also preferred is a polypeptide molecule, wherein said polypeptide comprises an amino acid sequence selected from the group consisting of: polypeptide sequence of SEQ ID NO: Y; a polypeptide encoded by SEQ ID NO: X or the complementary strand thereto; the polypeptide encoded by the nucleotide sequence as defined in columns 8 and 9 of Table 2; and a polypeptide encoded by the cDNA contained in Clone ID NO: Z.  
       [0926] Further preferred is a method of making a recombinant vector comprising inserting any of the above isolated nucleic acid molecule into a vector. Also preferred is the recombinant vector produced by this method. Also preferred is a method of making a recombinant host cell comprising introducing the vector into a host cell, as well as the recombinant host cell produced by this method.  
       [0927] Also preferred is a method of making an isolated polypeptide comprising culturing this recombinant host cell under conditions such that said polypeptide is expressed and recovering said polypeptide. Also preferred is this method of making an isolated polypeptide, wherein said recombinant host cell is a eukaryotic cell and said polypeptide is a human protein comprising an amino acid sequence selected from the group consisting of: polypeptide sequence of SEQ ID NO: Y; a polypeptide encoded by SEQ ID NO: X or the complementary strand thereto; the polypeptide encoded by the nucleotide sequence as defined in columns 8 and 9 of Table 2; and a polypeptide encoded by the cDNA contained in Clone ID NO: Z. The isolated polypeptide produced by this method is also preferred.  
       [0928] Also preferred is a method of treatment of an individual in need of an increased level of a protein activity, which method comprises administering to such an individual a Therapeutic comprising an amount of an isolated polypeptide, polynucleotide, immunogenic fragment or analogue thereof, binding agent, antibody, or antigen binding fragment of the claimed invention effective to increase the level of said protein activity in said individual.  
       [0929] Also preferred is a method of treatment of an individual in need of a decreased level of a protein activity, which method comprised administering to such an individual a Therapeutic comprising an amount of an isolated polypeptide, polynucleotide, immunogenic fragment or analogue thereof, binding agent, antibody, or antigen binding fragment of the claimed invention effective to decrease the level of said protein activity in said individual.  
       [0930] Also preferred is a method of treatment of an individual in need of a specific delivery of toxic compositions to diseased cells (e.g., tumors, leukemias or lymphomas), which method comprises administering to such an individual a Therapeutic comprising an amount of an isolated polypeptide of the invention, including, but not limited to a binding agent, or antibody of the claimed invention that are associated with toxin or cytotoxic prodrugs.  
       [0931] Having generally described the invention, the same will be more readily understood by reference to the following examples, which are provided by way of illustration and are not intended as limiting.  
                       TABLE 6                       ATCC Deposits   Deposit Date   ATCC Designation Number                  LP01, LP02, LP03,   May-20-97   209059, 209060, 209061, 209062,       LP04, LP05, LP06,       209063, 209064, 209065, 209066,       LP07, LP08, LP09,       209067, 209068, 209069       LP10, LP11,       LP12   Jan-12-98   209579       LP13   Jan-12-98   209578       LP14   Jul-16-98   203067       LP15   Jul-16-98   203068       LP16   Feb-1-99   203609       LP17   Feb-1-99   203610       LP20   Nov-17-98   203485       LP21   Jun-18-99   PTA-252       LP22   Jun-18-99   PTA-253       LP23   Dec-22-99   PTA-1081                  
 
     
    
    
     EXAMPLES  
     Example 1  
     Isolation of a Selected cDNA Clone From the Deposited Sample  
     [0932] Each Clone ID NO: Z is contained in a plasmid. Table 7 identifies the vectors used to construct the cDNA library from which each clone was isolated. In many cases, the vector used to construct the library is a phage vector from which a plasmid has been excised. The following correlates the related plasmid for each phage vector used in constructing the cDNA library. For example, where a particular clone is identified in Table 7 as being isolated in the vector “Lambda Zap,” the corresponding deposited clone is in “pBluescript.” 
                                   Vector Used to Construct Library   Corresponding Deposited Plasmid                  Lambda Zap   pBluescript (pBS)       Uni-Zap XR   pBluescript (pBS)       Zap Express   pBK       lafmid BA   plafmid BA       pSport 1   pSport 1       pCMVSport 2.0   pCMVSport 2.0       pCMVSport 3.0   pCMVSport 3.0       pCR ®2.1   pCR ®2.1                  
 
     [0933] Vectors Lambda Zap (U.S. Pat. Nos. 5,128,256 and 5,286,636), Uni-Zap XR (U.S. Pat. Nos. 5,128,256 and 5,286,636), Zap Express (U.S. Pat. Nos. 5,128,256 and 5,286,636), pBluescript (pBS) (Short, J. M. et al., Nucleic Acids Res. 16:7583-7600 (1988); Alting-Mees, M. A. and Short, J. M., Nucleic Acids Res. 17:9494 (1989)) and pBK (Alting-Mees, M. A. et al., Strategies 5:58-61 (1992)) are commercially available from Stratagene Cloning Systems, Inc., 11011 N. Torrey Pines Road, La Jolla, Calif., 92037. pBS contains an ampicillin resistance gene and pBK contains a neomycin resistance gene. Both can be transformed into  E. coli  strain XL-1 Blue, also available from Stratagene. pBS comes in 4 forms SK+, SK−, KS+ and KS. The S and K refers to the orientation of the polylinker to the T7 and T3 primer sequences which flank the polylinker region (“S” is for SacI and “K” is for KpnI which are the first sites on each respective end of the linker). “+” or “−” refer to the orientation of the f1 origin of replication (“ori”), such that in one orientation, single stranded rescue initiated from the f1 ori generates sense strand DNA and in the other, antisense.  
     [0934] Vectors pSport1, pCMVSport 2.0 and pCMVSport 3.0, were obtained from Life Technologies, Inc., P.O. Box 6009, Gaithersburg, Md. 20897. All Sport vectors contain an ampicillin resistance gene and may be transformed into  E. coli  strain DH10B, also available from Life Technologies. (See, for instance, Gruber, C. E., et al., Focus 15:59 (1993).) Vector lafmid BA (Bento Soares, Columbia University, N.Y.) contains an ampicillin resistance gene and can be transformed into  E. coli  strain XL-1 Blue. Vector pCR®2.1, which is available from Invitrogen, 1600 Faraday Avenue, Carlsbad, Calif. 92008, contains an ampicillin resistance gene and may be transformed into  E. coli  strain DH10B, available from Life Technologies. (See, for instance, Clark, J. M., Nuc. Acids Res. 16:9677-9686 (1988) and Mead, D. et al., Bio/Technology 9: (1991).) Preferably, a polynucleotide of the present invention does not comprise the vector sequences identified for the particular clone in Table 7, as well as the corresponding plasmid vector sequences designated above.  
     [0935] The deposited material in the sample assigned the ATCC Deposit Number cited by reference to Tables 1A, 2, 6 and 7 for any given cDNA clone also may contain one or more additional plasmids, each comprising a cDNA clone different from that given clone. Thus, deposits sharing the same ATCC Deposit Number contain at least a plasmid for each Clone ID NO: Z.  
                           TABLE 7                                   ATCC       Libraries owned by Catalog   Catalog Description   Vector   Deposit                  HUKA HUKB HUKC HUKD HUKE   Human Uterine Cancer   Lambda ZAP II   LP01       HUKF HUKG       HCNA HCNB   Human Colon   Lambda Zap II   LP01       HFFA   Human Fetal Brain, random primed   Lambda Zap II   LP01       HTWA   Resting T-Cell   Lambda ZAP II   LP01       HBQA   Early Stage Human Brain, random   Lambda ZAP II   LP01           primed       HLMB HLMF HLMG HLMH HLMI   breast lymph node CDNA library   Lambda ZAP II   LP01       HLMJ HLMM HLMN       HCQA HCQB   human colon cancer   Lamda ZAP II   LP01       HMEA HMEC HMED HMEE HMEF   Human Microvascular Endothelial   Lambda ZAP II   LP01       HMEG HMEI HMEJ HMEK HMEL   Cells, fract. A       HUSA HUSC   Human Umbilical Vein Endothelial   Lambda ZAP II   LP01           Cells, fract. A       HLQA HLQB   Hepatocellular Tumor   Lambda ZAP II   LP01       HHGA HHGB HHGC HHGD   Hemangiopericytoma   Lambda ZAP II   LP01       HSDM   Human Striatum Depression, re-rescue   Lambda ZAP II   LP01       HUSH   H Umbilical Vein Endothelial Cells,   Lambda ZAP II   LP01           frac A, re-excision       HSGS   Salivary gland, subtracted   Lambda ZAP II   LP01       HFXA HFXB HFXC HFXD HFXE   Brain frontal cortex   Lambda ZAP II   LP01       HFXF HFXG HFXH       HPQA HPQB HPQC   PERM TF274   Lambda ZAP II   LP01       HFXJ HFXK   Brain Frontal Cortex, re-excision   Lambda ZAP II   LP01       HCWA HCWB HCWC HCWD HCWE   CD34 positive cells (Cord Blood)   ZAP Express   LP02       HCWF HCWG HCWH HCWI HCWJ       HCWK       HCUA HCUB HCUC   CD34 depleted Buffy Coat (Cord   ZAP Express   LP02           Blood)       HRSM   A-14 cell line   ZAP Express   LP02       HRSA   A1-CELL LINE   ZAP Express   LP02       HCUD HCUE HCUF HCUG HCUH   CD34 depleted Buffy Coat (Cord   ZAP Express   LP02       HCUI   Blood), re-excision       HBXE HBXF HBXG   H. Whole Brain #2, re-excision   ZAP Express   LP02       HRLM   L8 cell line   ZAP Express   LP02       HBXA HBXB HBXC HBXD   Human Whole Brain #2 - Oligo dT &gt;   ZAP Express   LP02           1.5 Kb       HUDA HUDB HUDC   Testes   ZAP Express   LP02       HHTM HHTN HHTO   H. hypothalamus, frac A; re-excision   ZAP Express   LP02       HHTL   H. hypothalamus, frac A   ZAP Express   LP02       HASA HASD   Human Adult Spleen   Uni-ZAP XR   LP03       HFKC HFKD HFKE HFKF HFKG   Human Fetal Kidney   Uni-ZAP XR   LP03       HE8A HE8B HE8C HE8D HE8E HE8F   Human 8 Week Whole Embryo   Uni-ZAP XR   LP03       HE8M HE8N       HGBA HGBD HGBE HGBF HGBG   Human Gall Bladder   Uni-ZAP XR   LP03       HGBH HGBI       HLHA HLHB HLHC HLHD HLHE   Human Fetal Lung III   Uni-ZAP XR   LP03       HLHF HLHG HLHH HLHQ       HPMA HPMB HPMC HPMD HPME   Human Placenta   Uni-ZAP XR   LP03       HPMF HPMG HPMH       HPRA HPRB HPRC HPRD   Human Prostate   Uni-ZAP XR   LP03       HSIA HSIC HSID HSIE   Human Adult Small Intestine   Uni-ZAP XR   LP03       HTEA HTEB HTEC HTED HTEE   Human Testes   Uni-ZAP XR   LP03       HTEF HTEG HTEH HTEI HTEJ HTEK       HTPA HTPB HTPC HTPD HTPE   Human Pancreas Tumor   Uni-ZAP XR   LP03       HTTA HTTB HTTC HTTD HTTE   Human Testes Tumor   Uni-ZAP XR   LP03       HTTF       HAPA HAPB HAPC HAPM   Human Adult Pulmonary   Uni-ZAP XR   LP03       HETA HETB HETC HETD HETE   Human Endometrial Tumor   Uni-ZAP XR   LP03       HETF HETG HETH HETI       HHFB HHFC HHFD HHFE HHFF   Human Fetal Heart   Uni-ZAP XR   LP03       HHFG HHFH HHFI       HHPB HHPC HHPD HHPE HHPF   Human Hippocampus   Uni-ZAP XR   LP03       HHPG HHPH       HCE1 HCE2 HCE3 HCE4 HCE5 HCEB   Human Cerebellum   Uni-ZAP XR   LP03       HCEC HCED HCEE HCEF HCEG       HUVB HUVC HUVD HUVE   Human Umbilical Vein, Endo remake   Uni-ZAP XR   LP03       HSTA HSTB HSTC HSTD   Human Skin Tumor   Uni-ZAP XR   LP03       HTAA HTAB HTAC HTAD HTAE   Human Activated T-Cells   Uni-ZAP XR   LP03       HFEA HFEB HFEC   Human Fetal Epithelium (Skin)   Uni-ZAP XR   LP03       HJPA HJPB HJPC HJPD   HUMAN JURKAT MEMBRANE   Uni-ZAP XR   LP03           BOUND POLYSOMES       HESA   Human epithelioid sarcoma   Uni-Zap XR   LP03       HLTA HLTB HLTC HLTD HLTE   Human T-Cell Lymphoma   Uni-ZAP XR   LP03       HLTF       HFTA HFTB HFTC HFTD   Human Fetal Dura Mater   Uni-ZAP XR   LP03       HRDA HRDB HRDC HRDD HRDE   Human Rhabdomyosarcoma   Uni-ZAP XR   LP03       HRDF       HCAA HCAB HCAC   Cem cells cyclohexamide treated   Uni-ZAP XR   LP03       HRGA HRGB HRGC HRGD   Raji Cells, cyclohexamide treated   Uni-ZAP XR   LP03       HSUA HSUB HSUC HSUM   Supt Cells, cyclohexamide treated   Uni-ZAP XR   LP03       HT4A HT4C HT4D   Activated T-Cells, 12 hrs.   Uni-ZAP XR   LP03       HE9A HE9B HE9C HE9D HE9E HE9F   Nine Week Old Early Stage Human   Uni-ZAP XR   LP03       HE9G HE9H HE9M HE9N       HATA HATB HATC HATD HATE   Human Adrenal Gland Tumor   Uni-ZAP XR   LP03       HT5A   Activated T-Cells, 24 hrs.   Uni-ZAP XR   LP03       HFGA HFGM   Human Fetal Brain   Uni-ZAP XR   LP03       HNEA HNEB HNEC HNED HNEE   Human Neutrophil   Uni-ZAP XR   LP03       HBGB HBGD   Human Primary Breast Cancer   Uni-ZAP XR   LP03       HBNA HBNB   Human Normal Breast   Uni-ZAP XR   LP03       HCAS   Cem Cells, cyclohexamide treated;   Uni-ZAP XR   LP03           subtra       HHPS   Human Hippocampus, subtracted   pBS   LP03       HKCS HKCU   Human Colon Cancer, subtracted   pBS   LP03       HRGS   Raji cells, cyclohexamide treated,   pBS   LP03           subtracted       HSUT   Supt cells, cyclohexamide treated,   pBS   LP03           differentially expressed       HT4S   Activated T-Cells, 12 hrs, subtracted   Uni-ZAP XR   LP03       HCDA HCDB HCDC HCDD HCDE   Human Chondrosarcoma   Uni-ZAP XR   LP03       HOAA HOAB HOAC   Human Osteosarcoma   Uni-ZAP XR   LP03       HTLA HTLB HTLC HTLD HTLE   Human adult testis, large inserts   Uni-ZAP XR   LP03       HTLF       HLMA HLMC HLMD   Breast Lymph node cDNA library   Uni-ZAP XR   LP03       H6EA H6EB H6EC   HL-60, PMA 4H   Uni-ZAP XR   LP03       HTXA HTXB HTXC HTXD HTXE   Activated T-Cell (12 hs)/Thiouridine   Uni-ZAP XR   LP03       HTXF HTXG HTXH   labelledEco       HNFA HNFB HNFC HNFD HNFE   Human Neutrophil, Activated   Uni-ZAP XR   LP03       HNFF HNFG HNFH HNFJ       HTOB HTOC   HUMAN TONSILS, FRACTION 2   Uni-ZAP XR   LP03       HMGB   Human OB MG63 control fraction I   Uni-ZAP XR   LP03       HOPB   Human OB HOS control fraction I   Uni-ZAP XR   LP03       HORB   Human OB HOS treated (10 nM E2)   Uni-ZAP XR   LP03           fraction I       HSVA HSVB HSVC   Human Chronic Synovitis   Uni-ZAP XR   LP03       HROA   HUMAN STOMACH   Uni-ZAP XR   LP03       HBJA HBJB HBJC HBJD HBJE HBJF   HUMAN B CELL LYMPHOMA   Uni-ZAP XR   LP03       HBJG HBJH HBJI HBJJ HBJK       HCRA HCRB HCRC   human corpus colosum   Uni-ZAP XR   LP03       HODA HODB HODC HODD   human ovarian cancer   Uni-ZAP XR   LP03       HDSA   Dermatofibrosarcoma Protuberance   Uni-ZAP XR   LP03       HMWA HMWB HMWC HMWD   Bone Marrow Cell Line (RS4; 11)   Uni-ZAP XR   LP03       HMWE HMWF HMWG HMWH       HMWI HMWJ       HSOA   stomach cancer (human)   Uni-ZAP XR   LP03       HERA   SKIN   Uni-ZAP XR   LP03       HMDA   Brain-medulloblastoma   Uni-ZAP XR   LP03       HGLA HGLB HGLD   Glioblastoma   Uni-ZAP XR   LP03       HEAA   H. Atrophic Endometrium   Uni-ZAP XR   LP03       HBCA HBCB   H. Lymph node breast Cancer   Uni-ZAP XR   LP03       HPWT   Human Prostate BPH, re-excision   Uni-ZAP XR   LP03       HFVG HFVH HFVI   Fetal Liver, subtraction II   pBS   LP03       HNFI   Human Neutrophils, Activated, re-   pBS   LP03           excision       HBMB HBMC HBMD   Human Bone Marrow, re-excision   pBS   LP03       HKML HKMM HKMN   H. Kidney Medulla, re-excision   pBS   LP03       HKIX HKIY   H. Kidney Cortex, subtracted   pBS   LP03       HADT   H. Amygdala Depression, subtracted   pBS   LP03       H6AS   HI-60, untreated, subtracted   Uni-ZAP XR   LP03       H6ES   HL-60, PMA 4H, subtracted   Uni-ZAP XR   LP03       H6BS   HL-60, RA 4h, Subtracted   Uni-ZAP XR   LP03       H6CS   HL-60, PMA 1d, subtracted   Uni-ZAP XR   LP03       HTXJ HTXK   Activated T-cell(12 h)/Thiouridine-re-   Uni-ZAP XR   LP03           excision       HMSA HMSB HMSC HMSD HMSE   Monocyte activated   Uni-ZAP XR   LP03       HMSF HMSG HMSH HMSI HMSJ       HMSK       HAGA HAGB HAGC HAGD HAGE   Human Amygdala   Uni-ZAP XR   LP03       HAGF       HSRA HSRB HSRE   STROMAL-OSTEOCLASTOMA   Uni-ZAP XR   LP03       HSRD HSRF HSRG HSRH   Human Osteoclastoma Stromal Cells -   Uni-ZAP XR   LP03           unamplified       HSQA HSQB HSQC HSQD HSQE   Stromal cell TF274   Uni-ZAP XR   LP03       HSQF HSQG       HSKA HSKB HSKC HSKD HSKE   Smooth muscle, serum treated   Uni-ZAP XR   LP03       HSKF HSKZ       HSLA HSLB HSLC HSLD HSLE   Smooth muscle, control   Uni-ZAP XR   LP03       HSLF HSLG       HSDA HSDD HSDE HSDF HSDG   Spinal cord   Uni-ZAP XR   LP03       HSDH       HPWS   Prostate-BPH subtracted II   pBS   LP03       HSKW HSKX HSKY   Smooth Muscle- HASTE normalized   pBS   LP03       HFPB HFPC HFPD   H. Frontal cortex, epileptic; re-excision   Uni-ZAP XR   LP03       HSDI HSDJ HSDK   Spinal Cord, re-excision   Uni-ZAP XR   LP03       HSKN HSKO   Smooth Muscle Serum Treated, Norm   pBS   LP03       HSKG HSKH HSKI   Smooth muscle, serum induced, re-exc   pBS   LP03       HFCA HFCB HFCC HFCD HFCE   Human Fetal Brain   Uni-ZAP XR   LP04       HFCF       HPTA HPTB HPTD   Human Pituitary   Uni-ZAP XR   LP04       HTHB HTHC HTHD   Human Thymus   Uni-ZAP XR   LP04       HE6B HE6C HE6D HE6E HE6F HE6G   Human Whole Six Week Old Embryo   Uni-ZAP XR   LP04       HE6S       HSSA HSSB HSSC HSSD HSSE HSSF   Human Synovial Sarcoma   Uni-ZAP XR   LP04       HSSG HSSH HSSI HSSJ HSSK       HE7T   7 Week Old Early Stage Human,   Uni-ZAP XR   LP04           subtracted       HEPA HEPB HEPC   Human Epididymus   Uni-ZAP XR   LP04       HSNA HSNB HSNC HSNM HSNN   Human Synovium   Uni-ZAP XR   LP04       HPFB HPFC HPFD HPFE   Human Prostate Cancer, Stage C   Uni-ZAP XR   LP04           fraction       HE2A HE2D HE2E HE2H HE2I HE2M   12 Week Old Early Stage Human   Uni-ZAP XR   LP04       HE2N HE2O       HE2B HE2C HE2F HE2G HE2P HE2Q   12 Week Old Early Stage Human, II   Uni-ZAP XR   LP04       HPTS HPTT HPTU   Human Pituitary, subtracted   Uni-ZAP XR   LP04       HAUA HAUB HAUC   Amniotic Cells - TNF induced   Uni-ZAP XR   LP04       HAQA HAQB HAQC HAQD   Amniotic Cells - Primary Culture   Uni-ZAP XR   LP04       HWTA HWTB HWTC   wilm&#39;s tumor   Uni-ZAP XR   LP04       HBSD   Bone Cancer, re-excision   Uni-ZAP XR   LP04       HSGB   Salivary gland, re-excision   Uni-ZAP XR   LP04       HSJA HSJB HSJC   Smooth muscle-ILb induced   Uni-ZAP XR   LP04       HSXA HSXB HSXC HSXD   Human Substantia Nigra   Uni-ZAP XR   LP04       HSHA HSHB HSHC   Smooth muscle, IL1b induced   Uni-ZAP XR   LP04       HOUA HOUB HOUC HOUD HOUE   Adipocytes   Uni-ZAP XR   LP04       HPWA HPWB HPWC HPWD HPWE   Prostate BPH   Uni-ZAP XR   LP04       HELA HELB HELC HELD HELE   Endothelial cells-control   Uni-ZAP XR   LP04       HELF HELG HELH       HEMA HEMB HEMC HEMD HEME   Endothelial-induced   Uni-ZAP XR   LP04       HEMF HEMG HEMH       HBIA HBIB HBIC   Human Brain, Striatum   Uni-ZAP XR   LP04       HHSA HHSB HHSC HHSD HHSE   Human Hypothalmus, Schizophrenia   Uni-ZAP XR   LP04       HNGA HNGB HNGC HNGD HNGE   neutrophils control   Uni-ZAP XR   LP04       HNGF HNGG HNGH HNGI HNGJ       HNHA HNHB HNHC HNHD HNHE   Neutrophils IL-1 and LPS induced   Uni-ZAP XR   LP04       HNHF HNHG HNHH HNHI HNHJ       HSDB HSDC   STRIATUM DEPRESSION   Uni-ZAP XR   LP04       HHPT   Hypothalamus   Uni-ZAP XR   LP04       HSAT HSAU HSAV HSAW HSAX   Anergic T-cell   Uni-ZAP XR   LP04       HSAY HSAZ       HBMS HBMT HBMU HBMV HBMW   Bone marrow   Uni-ZAP XR   LP04       HBMX       HOEA HOEB HOEC HOED HOEE   Osteoblasts   Uni-ZAP XR   LP04       HOEF HOEJ       HAIA HAIB HAIC HAID HAIE HAIF   Epithelial-TNFa and INF induced   Uni-ZAP XR   LP04       HTGA HTGB HTGC HTGD   Apoptotic T-cell   Uni-ZAP XR   LP04       HMCA HMCB HMCC HMCD HMCE   Macrophage-oxLDL   Uni-ZAP XR   LP04       HMAA HMAB HMAC HMAD HMAE   Macrophage (GM-CSF treated)   Uni-ZAP XR   LP04       HMAF HMAG       HPHA   Normal Prostate   Uni-ZAP XR   LP04       HPIA HPIB HPIC   LNCAP prostate cell line   Uni-ZAP XR   LP04       HPJA HPJB HPJC   PC3 Prostate cell line   Uni-ZAP XR   LP04       HOSE HOSF HOSG   Human Osteoclastoma, re-excision   Uni-ZAP XR   LP04       HTGE HTGF   Apoptotic T-cell, re-excision   Uni-ZAP XR   LP04       HMAJ HMAK   H Macrophage (GM-CSF treated), re-   Uni-ZAP XR   LP04           excision       HACB HACC HACD   Human Adipose Tissue, re-excision   Uni-ZAP XR   LP04       HFPA   H. Frontal Cortex, Epileptic   Uni-ZAP XR   LP04       HFAA HFAB HFAC HFAD HFAE   Alzheimer&#39;s, spongy change   Uni-ZAP XR   LP04       HFAM   Frontal Lobe, Dementia   Uni-ZAP XR   LP04       HMIA HMIB HMIC   Human Manic Depression Tissue   Uni-ZAP XR   LP04       HTSA HTSE HTSF HTSG HTSH   Human Thymus   pBS   LP05       HPBA HPBB HPBC HPBD HPBE   Human Pineal Gland   pBS   LP05       HSAA HSAB HSAC   HSA 172 Cells   pBS   LP05       HSBA HSBB HSBC HSBM   HSC172 cells   pBS   LP05       HJAA HJAB HJAC HJAD   Jurkat T-cell G1 phase   pBS   LP05       HJBA HJBB HJBC HJBD   Jurkat T-Cell, S phase   pBS   LP05       HAFA HAFB   Aorta endothelial cells + TNF-a   pBS   LP05       HAWA HAWB HAWC   Human White Adipose   pBS   LP05       HTNA HTNB   Human Thyroid   pBS   LP05       HONA   Normal Ovary, Premenopausal   pBS   LP05       HARA HARB   Human Adult Retina   pBS   LP05       HLJA HLJB   Human Lung   pCMVSport 1   LP06       HOFM HOFN HOFO   H. Ovarian Tumor, II, OV5232   pCMVSport 2.0   LP07       HOGA HOGB HOGC   OV 10-3-95   pCMVSport 2.0   LP07       HCGL   CD34+ cells, II   pCMVSport 2.0   LP07       HDLA   Hodgkin&#39;s Lymphoma I   pCMVSport 2.0   LP07       HDTA HDTB HDTC HDTD HDTE   Hodgkin&#39;s Lymphoma II   pCMVSport 2.0   LP07       HKAA HKAB HKAC HKAD HKAE   Keratinocyte   pCMVSport 2.0   LP07       HKAF HKAG HKAH       HCIM   CAPFINDER, Crohn&#39;s Disease, lib 2   pCMVSport 2.0   LP07       HKAL   Keratinocyte, lib 2   pCMVSport 2.0   LP07       HKAT   Keratinocyte, lib 3   pCMVSport 2.0   LP07       HNDA   Nasal polyps   pCMVSport 2.0   LP07       HDRA   H. Primary Dendritic Cells, lib 3   pCMVSport 2.0   LP07       HOHA HOHB HOHC   Human Osteoblasts II   pCMVSport 2.0   LP07       HLDA HLDB HLDC   Liver, Hepatoma   pCMVSport 3.0   LP08       HLDN HLDO HLDP   Human Liver, normal   pCMVSport 3.0   LP08       HMTA   pBMC stimulated w/poly I/C   pCMVSport 3.0   LP08       HNTA   NTERA2, control   pCMVSport 3.0   LP08       HDPA HDPB HDPC HDPD HDPF   Primary Dendritic Cells, lib 1   pCMVSport 3.0   LP08       HDPG HDPH HDPI HDPJ HDPK       HDPM HDPN HDPO HDPP   Primary Dendritic cells, frac 2   pCMVSport 3.0   LP08       HMUA HMUB HMUC   Myoloid Progenitor Cell Line   pCMVSport 3.0   LP08       HHEA HHEB HHEC HHED   T Cell helper I   pCMVSport 3.0   LP08       HHEM HHEN HHEO HHEP   T cell helper II   pCMVSport 3.0   LP08       HEQA HEQB HEQC   Human endometrial stromal cells   pCMVSport 3.0   LP08       HJMA HJMB   Human endometrial stromal cells-   pCMVSport 3.0   LP08           treated with progesterone       HSWA HSWB HSWC   Human endometrial stromal cells-   pCMVSport 3.0   LP08           treated with estradiol       HSYA HSYB HSYC   Human Thymus Stromal Cells   pCMVSport 3.0   LP08       HLWA HLWB HLWC   Human Placenta   pCMVSport 3.0   LP08       HRAA HRAB HRAC   Rejected Kidney, lib 4   pCMVSport 3.0   LP08       HMTM   PCR, pBMC I/C treated   PCRII   LP09       HMJA   H. Meniingima, M6   pSport 1   LP10       HMKA HMKB HMKC HMKD HMKE   H. Meningima, M1   pSport 1   LP10       HUSG HUSI   Human umbilical vein endothelial cells,   pSport 1   LP10           IL-4 induced       HUSX HUSY   Human Umbilical Vein Endothelial   pSport 1   LP10           Cells, uninduced       HOFA   Ovarian Tumor I, OV5232   pSport 1   LP10       HCFA HCFB HCFC HCFD   T-Cell PHA 16 hrs   pSport 1   LP10       HCFL HCFM HCFN HCFO   T-Cell PHA 24 hrs   pSport 1   LP10       HADA HADC HADD HADE HADF   Human Adipose   pSport 1   LP10       HADG       HOVA HOVB HOVC   Human Ovary   pSport 1   LP10       HTWB HTWC HTWD HTWE HTWF   Resting T-Cell Library, II   pSport 1   LP10       HMMA   Spleen metastic melanoma   pSport 1   LP10       HLYA HLYB HLYC HLYD HLYE   Spleen, Chronic lymphocytic leukemia   pSport 1   LP10       HCGA   CD34+ cell, I   pSport 1   LP10       HEOM HEON   Human Eosinophils   pSport 1   LP10       HTDA   Human Tonsil, Lib 3   pSport 1   LP10       HSPA   Salivary Gland, Lib 2   pSport 1   LP10       HCHA HCHB HCHC   Breast Cancer cell line, MDA 36   pSport 1   LP10       HCHM HCHN   Breast Cancer Cell line, angiogenic   pSport 1   LP10       HCIA   Crohn&#39;s Disease   pSport 1   LP10       HDAA HDAB HDAC   HEL cell line   pSport 1   LP10       HABA   Human Astrocyte   pSport 1   LP10       HUFA HUFB HUFC   Ulcerative Colitis   pSport 1   LP10       HNTM   NTERA2 + retinoic acid, 14 days   pSport 1   LP10       HDQA   Primary Dendritic cells, CapFinder2,   pSport 1   LP10           frac 1       HDQM   Primary Dendritic Cells, CapFinder,   pSport 1   LP10           frac 2       HLDX   Human Liver, normal, CapFinder   pSport 1   LP10       HULA HULB HULC   Human Dermal Endothelial   pSport 1   LP10           Cells, untreated       HUMA   Human Dermal Endothelial cells, treated   pSport 1   LP10       HCJA   Human Stromal Endometrial   pSport 1   LP10           fibroblasts, untreated       HCJM   Human Stromal endometrial fibroblasts,   pSport 1   LP10           treated w/estradiol       HEDA   Human Stromal endometrial fibroblasts,   pSport 1   LP10           treated with progesterone       HFNA   Human ovary tumor cell OV350721   pSport 1   LP10       HKGA HKGB HKGC HKGD   Merkel Cells   pSport 1   LP10       HISA HISB HISC   Pancreas Islet Cell Tumor   pSport 1   LP10       HLSA   Skin, burned   pSport 1   LP10       HBZA   Prostate, BPH, Lib 2   pSport 1   LP10       HBZS   Prostate BPH, Lib 2, subtracted   pSport 1   LP10       HFIA HFIB HFIC   Synovial Fibroblasts (control)   pSport 1   LP10       HFIH HFII HFIJ   Synovial hypoxia   pSport 1   LP10       HFIT HFIU HFIV   Synovial IL-1/TNF stimulated   pSport 1   LP10       HGCA   Messangial cell, frac 1   pSport 1   LP10       HMVA HMVB HMVC   Bone Marrow Stromal Cell, untreated   pSport 1   LP10       HFIX HFIY HFIZ   Synovial Fibroblasts (III/TNF), subt   pSport 1   LP10       HFOX HFOY HFOZ   Synovial hypoxia-RSF subtracted   pSport 1   LP10       HMQA HMQB HMQC HMQD   Human Activated Monocytes   Uni-ZAP XR   LP11       HLIA HLIB HLIC   Human Liver   pCMVSport 1   LP012       HHBA HHBB HHBC HHBD HHBE   Human Heart   pCMVSport 1   LP012       HBBA HBBB   Human Brain   pCMVSport 1   LP012       HLJA HLJB HUJC HLJD HLJE   Human Lung   pCMVSport 1   LP012       HOGA HOGB HOGC   Ovarian Tumor   pCMVSport 2.0   LP012       HTJM   Human Tonsils, Lib 2   pCMVSport 2.0   LP012       HAMF HAMG   KMH2   pCMVSport 3.0   LP012       HAJA HAJB HAJC   L428   pCMVSport 3.0   LP012       HWBA HWBB HWBC HWBD HWBE   Dendritic cells, pooled   pCMVSport 3.0   LP012       HWAA HWAB HWAC HWAD HWAE   Human Bone Marrow, treated   pCMVSport 3.0   LP012       HYAA HYAB HYAC   B Cell lymphoma   pCMVSport 3.0   LP012       HWHG HWHH HWHI   Healing groin wound, 6.5 hours post   pCMVSport 3.0   LP012           incision       HWHP HWHQ HWHR   Healing groin wound; 7.5 hours post   pCMVSport 3.0   LP012           incision       HARM   Healing groin wound - zero hr post-   pCMVSport 3.0   LP012           incision (control)       HBIM   Olfactory epithelium; nasalcavity   pCMVSport 3.0   LP012       HWDA   Healing Abdomen wound; 70&amp;90 min   pCMVSport 3.0   LP012           post incision       HWEA   Healing Abdomen Wound; 15 days post   pCMVSport 3.0   LP012           incision       HWJA   Healing Abdomen Wound; 21&amp;29 days   pCMVSport 3.0   LP012       HNAL   Human Tongue, frac 2   pSport 1   LP012       HMJA   H. Meniingima, M6   pSport 1   LP012       HMKA HMKB HMKC HMKD HMKE   H. Meningima, M1   pSport 1   LP012       HOFA   Ovarian Tumor I, OV5232   pSport 1   LP012       HCFA HCFB HCFC HCFD   T-Cell PHA 16 hrs   pSport 1   LP012       HCFL HCFM HCFN HCFO   T-Cell PHA 24 hrs   pSport 1   LP012       HMMA HMMB HMMC   Spleen metastic melanoma   pSport 1   LP012       HTDA   Human Tonsil, Lib 3   pSport 1   LP012       HDBA   Human Fetal Thymus   pSport 1   LP012       HDUA   Pericardium   pSport 1   LP012       HBZA   Prostate, BPH, Lib 2   pSport 1   LP012       HWCA   Larynx tumor   pSport 1   LP012       HWKA   Normal lung   pSport 1   LP012       HSMB   Bone marrow stroma, treated   pSport 1   LP012       HBHM   Normal trachea   pSport 1   LP012       HLFC   Human Larynx   pSport 1   LP012       HLRB   Siebben Polyposis   pSport 1   LP012       HNIA   Mammary Gland   pSport 1   LP012       HNJB   Palate carcinoma   pSport 1   LP012       HNKA   Palate normal   pSport 1   LP012       HMZA   Pharynx carcinoma   pSport 1   LP012       HABG   Cheek Carcinoma   pSport 1   LP012       HMZM   Pharynx Carcinoma   pSport 1   LP012       HDRM   Larynx Carcinoma   pSport 1   LP012       HVAA   Pancreas normal PCA4 No   pSport 1   LP012       HICA   Tongue carcinoma   pSport 1   LP012       HUKA HUKB HUKC HUKD HUKE   Human Uterine Cancer   Lambda ZAP II   LP013       HFFA   Human Fetal Brain, random primed   Lambda ZAP II   LP013       HTUA   Activated T-cell labeled with 4-thioluri   Lambda ZAP II   LP013       HBQA   Early Stage Human Brain, random   Lambda ZAP II   LP013           primed       HMEB   Human microvascular Endothelial cells,   Lambda ZAP II   LP013           fract. B       HUSH   Human Umbilical Vein Endothelial   Lambda ZAP II   LP013           cells, fract. A, re-excision       HLQC HLQD   Hepatocellular tumor, re-excision   Lambda ZAP II   LP013       HTWJ HTWK HTWL   Resting T-cell, re-excision   Lambda ZAP II   LP013       HF6S   Human Whole 6 week Old Embryo (II),   pBluescript   LP013           subt       HHPS   Human Hippocampus, subtracted   pBluescript   LP013       HL1S   LNCAP, differential expression   pBluescript   LP013       HLHS HLHT   Early Stage Human Lung, Subtracted   pBluescript   LP013       HSUS   Supt cells, cyclohexamide treated,   pBluescript   LP013           subtracted       HSUT   Supt cells, cyclohexamide treated,   pBluescript   LP013           differentially expressed       HSDS   H. Striatum Depression, subtracted   pBluescript   LP013       HPTZ   Human Pituitary, Subtracted VII   pBluescript   LP013       HSDX   H. Striatum Depression, subt II   pBluescript   LP013       HSDZ   H. Striatum Depression, subt   pBluescript   LP013       HPBA HPBB HPBC HPBD HPBE   Human Pineal Gland   pBluescript SK-   LP013       HRTA   Colorectal Tumor   pBluescript SK-   LP013       HSBA HSBB HSBC HSBM   HSC172 cells   pBluescript SK-   LP013       HJAA HJAB HJAC HJAD   Jurkat T-cell G1 phase   pBluescript SK-   LP013       HJBA HJBB HJBC HJBD   Jurkat T-cell, S1 phase   pBluescript SK-   LP013       HTNA HTNB   Human Thyroid   pBluescript SK-   LP013       HAHA HAHB   Human Adult Heart   Uni-ZAP XR   LP013       HE6A   Whole 6 week Old Embryo   Uni-ZAP XR   LP013       HFCA HFCB HFCC HFCD HFCE   Human Fetal Brain   Uni-ZAP XR   LP013       HFKC HFKD HFKE HFKF HFKG   Human Fetal Kidney   Uni-ZAP XR   LP013       HGBA HGBD HGBE HGBF HGBG   Human Gall Bladder   Uni-ZAP XR   LP013       HPRA HPRB HPRC HPRD   Human Prostate   Uni-ZAP XR   LP013       HTEA HTEB HTEC HTED HTEE   Human Testes   Uni-ZAP XR   LP013       HTTA HTTB HTTC HTTD HTTE   Human Testes Tumor   Uni-ZAP XR   LP013       HYBA HYBB   Human Fetal Bone   Uni-ZAP XR   LP013       HFLA   Human Fetal Liver   Uni-ZAP XR   LP013       HHFB HHFC HHFD HHFE HHFF   Human Fetal Heart   Uni-ZAP XR   LP013       HUVB HUVC HUVD HUVE   Human Umbilical Vein, End. remake   Uni-ZAP XR   LP013       HTHB HTHC HTHD   Human Thymus   Uni-ZAP XR   LP013       HSTA HSTB HSTC HSTD   Human Skin Tumor   Uni-ZAP XR   LP013       HTAA HTAB HTAC HTAD HTAE   Human Activated T-cells   Uni-ZAP XR   LP013       HFEA HFEB HFEC   Human Fetal Epithelium (skin)   Uni-ZAP XR   LP013       HJPA HJPB HJPC HJPD   Human Jurkat Membrane Bound   Uni-ZAP XR   LP013           Polysomes       HESA   Human Epithelioid Sarcoma   Uni-ZAP XR   LP013       HALS   Human Adult Liver, Subtracted   Uni-ZAP XR   LP013       HFTA HFTB HFTC HFTD   Human Fetal Dura Mater   Uni-ZAP XR   LP013       HCAA HCAB HCAC   Cem cells, cyclohexamide treated   Uni-ZAP XR   LP013       HRGA HRGB HRGC HRGD   Raji Cells, cyclohexamide treated   Uni-ZAP XR   LP013       HE9A HE9B HE9C HE9D HE9E   Nine Week Old Early Stage Human   Uni-ZAP XR   LP013       HSFA   Human Fibrosarcoma   Uni-ZAP XR   LP013       HATA HATB HATC HATD HATE   Human Adrenal Gland Tumor   Uni-ZAP XR   LP013       HTRA   Human Trachea Tumor   Uni-ZAP XR   LP013       HE2A HE2D HE2E HE2H HE2I   12 Week Old Early Stage Human   Uni-ZAP XR   LP013       HE2B HE2C HE2F HE2G HE2P   12 Week Old Early Stage Human, II   Uni-ZAP XR   LP013       HNEA HNEB HNEC HNED HNEE   Human Neutrophil   Uni-ZAP XR   LP013       HBGA   Human Primary Breast Cancer   Uni-ZAP XR   LP013       HPTS HPTT HPTU   Human Pituitary, subtracted   Uni-ZAP XR   LP013       HMQA HMQB HMQC HMQD   Human Activated Monocytes   Uni-ZAP XR   LP013       HOAA HOAB HOAC   Human Osteosarcoma   Uni-ZAP XR   LP013       HTOA HTOD HTOE HTOF HTOG   human tonsils   Uni-ZAP XR   LP013       HMGB   Human OB MG63 control fraction I   Uni-ZAP XR   LP013       HOPB   Human OB HOS control fraction I   Uni-ZAP XR   LP013       HOQB   Human OB HOS treated (1 nM E2)   Uni-ZAP XR   LP013           fraction I       HAUA HAUB HAUC   Amniotic Cells - TNF induced   Uni-ZAP XR   LP013       HAQA HAQB HAQC HAQD   Amniotic Cells - Primary Culture   Uni-ZAP XR   LP013       HROA HROC   HUMAN STOMACH   Uni-ZAP XR   LP013       HBJA HBJB HBJC HBJD HBJE   HUMAN B CELL LYMPHOMA   Uni-ZAP XR   LP013       HODA HODB HODC HODD   human ovarian cancer   Uni-ZAP XR   LP013       HCPA   Corpus Callosum   Uni-ZAP XR   LP013       HSOA   stomach cancer (human)   Uni-ZAP XR   LP013       HERA   SKIN   Uni-ZAP XR   LP013       HMDA   Brain-medulloblastoma   Uni-ZAP XR   LP013       HGLA HGLB HGLD   Glioblastoma   Uni-ZAP XR   LP013       HWTA HWTB HWTC   wilm&#39;s tumor   Uni-ZAP XR   LP013       HEAA   H. Atrophic Endometrium   Uni-ZAP XR   LP013       HAPN HAPO HAPP HAPQ HAPR   Human Adult Pulmonary; re-excision   Uni-ZAP XR   LP013       HLTG HLTH   Human T-cell lymphoma; re-excision   Uni-ZAP XR   LP013       HAHC HAHD HAHE   Human Adult Heart; re-excision   Uni-ZAP XR   LP013       HAGA HAGB HAGC HAGD HAGE   Human Amygdala   Uni-ZAP XR   LP013       HSJA HSJB HSJC   Smooth muscle-ILb induced   Uni-ZAP XR   LP013       HSHA HSHB HSHC   Smooth muscle, IL1b induced   Uni-ZAP XR   LP013       HPWA HPWB HPWC HPWD HPWE   Prostate BPH   Uni-ZAP XR   LP013       HPIA HPIB HPIC   LNCAP prostate cell line   Uni-ZAP XR   LP013       HPJA HPJB HPJC   PC3 Prostate cell line   Uni-ZAP XR   LP013       HBTA   Bone Marrow Stroma, TNF&amp;LPS ind   Uni-ZAP XR   LP013       HMCF HMCG HMCH HMCI HMCJ   Macrophage-oxLDL; re-excision   Uni-ZAP XR   LP013       HAGG HAGH HAGI   Human Amygdala; re-excision   Uni-ZAP XR   LP013       HACA   H. Adipose Tissue   Uni-ZAP XR   LP013       HKFB   K562 + PMA (36 hrs), re-excision   ZAP Express   LP013       HCWT HCWU HCWV   CD34 positive cells (cord blood), re-ex   ZAP Express   LP013       HBWA   Whole brain   ZAP Express   LP013       HBXA HBXB HBXC HBXD   Human Whole Brain #2 - Oligo dT &gt;   ZAP Express   LP013           1.5 Kb       HAVM   Temporal cortex-Alzheizmer   pT-Adv   LP014       HAVT   Hippocampus, Alzheimer Subtracted   pT-Adv   LP014       HHAS   CHME Cell Line   Uni-ZAP XR   LP014       HAJR   Larynx normal   pSport 1   LP014       HWLE HWLF HWLG HWLH   Colon Normal   pSport 1   LP014       HCRM HCRN HCRO   Colon Carcinoma   pSport 1   LP014       HWLI HWLJ HWLK   Colon Normal   pSport 1   LP014       HWLQ HWLR HWLS HWLT   Colon Tumor   pSport I   LP014       HBFM   Gastrocnemius Muscle   pSport 1   LP014       HBOD HBOE   Quadriceps Muscle   pSport 1   LP014       HBKD HBKE   Soleus Muscle   pSport 1   LP014       HCCM   Pancreatic Langerhans   pSport 1   LP014       HWGA   Larynx carcinoma   pSport 1   LP014       HWGM HWGN   Larynx carcinoma   pSport 1   LP014       HWLA HWLB HWLC   Normal colon   pSport 1   LP014       HWLM HWLN   Colon Tumor   pSport 1   LP014       HVAM HVAN HVAO   Pancreas Tumor   pSport 1   LP014       HWGQ   Larynx carcinoma   pSport 1   LP014       HAQM HAQN   Salivary Gland   pSport 1   LP014       HASM   Stomach; normal   pSport 1   LP014       HBCM   Uterus; normal   pSport 1   LP014       HCDM   Testis; normal   pSport 1   LP014       HDJM   Brain; normal   pSport 1   LP014       HEFM   Adrenal Gland, normal   pSport 1   LP014       HBAA   Rectum normal   pSport 1   LP014       HFDM   Rectum tumour   pSport 1   LP014       HGAM   Colon, normal   pSport 1   LP014       HHMM   Colon, tumour   pSport 1   LP014       HCLB HCLC   Human Lung Cancer   Lambda Zap II   LP015       HRLA   L1 Cell line   ZAP Express   LP015       HHAM   Hypothalamus, Alzheimer&#39;s   pCMVSport 3.0   LP015       HKBA   Ku 812F Basophils Line   pSport 1   LP015       HS2S   Saos2, Dexamethosome Treated   pSport 1   LP016       HA5A   Lung Carcinoma A549 TNFalpha   pSport 1   LP016           activated       HTFM   TF-1 Cell Line GM-CSF Treated   pSport 1   LP016       HYAS   Thyroid Tumour   pSport 1   LP016       HUTS   Larynx Normal   pSport 1   LP016       HXOA   Larynx Tumor   pSport 1   LP016       HEAH   Ea.hy.926 cell line   pSport 1   LP016       HINA   Adenocarcinoma Human   pSport 1   LP016       HRMA   Lung Mesothelium   pSport 1   LP016       HLCL   Human Pre-Differentiated Adipocytes   Uni-Zap XR   LP017       HS2A   Saos2 Cells   pSport 1   LP020       HS2I   Saos2 Cells; Vitamin D3 Treated   pSport 1   LP020       HUCM   CHME Cell Line, untreated   pSport 1   LP020       HEPN   Aryepiglottis Normal   pSport 1   LP020       HPSN   Sinus Piniformis Tumour   pSport 1   LP020       HNSA   Stomach Normal   pSport 1   LP020       HNSM   Stomach Tumour   pSport 1   LP020       HNLA   Liver Normal Met5No   pSport 1   LP020       HUTA   Liver Tumour Met 5 Tu   pSport 1   LP020       HOCN   Colon Normal   pSport 1   LP020       HOCT   Colon Tumor   pSport 1   LP020       HTNT   Tongue Tumour   pSport 1   LP020       HLXN   Larynx Normal   pSport 1   LP020       HLXT   Larynx Tumour   pSport 1   LP020       HTYN   Thymus   pSport 1   LP020       HPLN   Placenta   pSport 1   LP020       HTNG   Tongue Normal   pSport 1   LP020       HZAA   Thyroid Normal (SDCA2 No)   pSport 1   LP020       HWES   Thyroid Thyroiditis   pSport 1   LP020       HFHD   Ficolled Human Stromal Cells, 5Fu   pTrip1Ex2   LP021           treated       HFHM, HFHN   Ficolled Human Stromal Cells,   pTrip1Ex2   LP021           Untreated       HPCI   Hep G2 Cells, lambda library   lambda Zap-CMV XR   LP021       HBCA, HBCB, HBCC   H. Lymph node breast Cancer   Uni-ZAP XR   LP021       HCOK   Chondrocytes   pSPORT1   LP022       HDCA, HDCB, HDCC   Dendritic Cells From CD34 Cells   pSPORT 1   LP022       HDMA, HDMB   CD40 activated monocyte dendritic   pSPORT 1   LP022           cells       HDDM, HDDN, HDDO   LPS activated derived dendritic cells   pSPORT 1   LP022       HPCR   Hep G2 Cells, PCR library   lambda Zap-CMV XR   LP022       HAAA, HAAB, HAAC   Lung, Cancer (4005313A3): Invasive   pSPORT 1   LP022           Poorly Differentiated Lung           Adenocarcinoma       HIPA, HIPB, HIPC   Lung, Cancer (4005163 B7): Invasive,   pSPORT 1   LP022           Poorly Diff. Adenocarcinoma,           Metastatic       HOOH, HOOI   Ovary, Cancer: (4004562 B6) Papillary   pSPORT 1   LP022           Serous Cystic Neoplasm, Low           Malignant Pot       HIDA   Lung, Normal: (4005313 B1)   pSPORT 1   LP022       HUJA, HUJB, HUJC, HUJD, HUJE   B-Cells   pCMVSport 3.0   LP022       HNOA, HNOB, HNOC, HNOD   Ovary, Normal: (9805C040R)   pSPORT 1   LP022       HNLM   Lung, Normal: (4005313 B1)   pSPORT 1   LP022       HSCL   Stromal Cells   pSPORT 1   LP022       HAAX   Lung, Cancer: (4005313 A3) Invasive   pSPORT 1   LP022           Poorly-differentiated Metastatic lung           adenocarcinoma       HUUA, HUUB, HUUC, HUUD   B-cells (unstimulated)   pTrip1Ex2   LP022       HWWA, HWWB, HWWC, HWWD, HW   B-cells (stimulated)   pSPORT 1   LP022       WE, HWWF, HWWG       HCCC   Colon, Cancer: (9808C064R)   pCMVSport 3.0   LP023       HPDO HPDP HPDQ HPDR HPD   Ovary, Cancer (9809C332): Poorly   pSport 1   LP023           differentiated adenocarcinoma       HPCO HPCP HPCQ HPCT   Ovary, Cancer (15395A1F): Grade II   pSport 1   LP023           Papillary Carcinoma       HOCM HOCO HOCP HOCQ   Ovary, Cancer: (15799A1F) Poorly   pSport 1   LP023           differentiated carcinoma       HCBM HCBN HCBO   Breast, Cancer: (4004943 A5)   pSport 1   LP023       HNBT HNBU HNBV   Breast, Normal: (4005522B2)   pSport 1   LP023       HBCP HBCQ   Breast, Cancer: (4005522 A2)   pSport 1   LP023       HBCJ   Breast, Cancer: (9806C012R)   pSport 1   LP023       HSAM HSAN   Stromal cells 3.88   pSport 1   LP023       HVCA HVCB HVCC HVCD   Ovary, Cancer: (4004332 A2)   pSport 1   LP023       HSCK HSEN HSEO   Stromal cells (HBM3.18)   pSport 1   LP023       HSCP HSCQ   stromal cell clone 2.5   pSport 1   LP023       HUXA   Breast Cancer: (4005385 A2)   pSport 1   LP023       HCOM HCON HCOO HCOP HCOQ   Ovary, Cancer (4004650 A3): Well-   pSport 1   LP023           Differentiated Micropapillary Serous           Carcinoma       HBNM   Breast, Cancer: (9802C020E)   pSport 1   LP023       HVVA HVVB HVVC HVVD HVVE   Human Bone Marrow, treated   pSport 1   LP023                  
 
     [0936] Two nonlimiting examples are provided below for isolating a particular clone from the deposited sample of plasmid cDNAs cited for that clone in Table 7. First, a plasmid is directly isolated by screening the clones using a polynucleotide probe corresponding to the nucleotide sequence of SEQ ID NO: X.  
     [0937] Particularly, a specific polynucleotide with 30-40 nucleotides is synthesized using an Applied Biosystems DNA synthesizer according to the sequence reported. The oligonucleotide is labeled, for instance, with  32 P-γ-ATP using T4 polynucleotide kinase and purified according to routine methods. (E.g., Maniatis et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press, Cold Spring, N.Y. (1982).) The plasmid mixture is transformed into a suitable host, as indicated above (such as XL-1 Blue (Stratagene)) using techniques known to those of skill in the art, such as those provided by the vector supplier or in related publications or patents cited above. The transformants are plated on 1.5% agar plates (containing the appropriate selection agent, e.g., ampicillin) to a density of about 150 transformants (colonies) per plate. These plates are screened using Nylon membranes according to routine methods for bacterial colony screening (e.g., Sambrook et al., Molecular Cloning: A Laboratory Manual, 2nd Edit., (1989), Cold Spring Harbor Laboratory Press, pages 1.93 to 1.104), or other techniques known to those of skill in the art.  
     [0938] Alternatively, two primers of 17-20 nucleotides derived from both ends of the nucleotide sequence of SEQ ID NO: X are synthesized and used to amplify the desired cDNA using the deposited cDNA plasmid as a template. The polymerase chain reaction is carried out under routine conditions, for instance, in 25 μl of reaction mixture with 0.5 ug of the above cDNA template. A convenient reaction mixture is 1.5-5 mM MgCl 2 , 0.01% (w/v) gelatin, 20 μM each of dATP, dCTP, dGTP, dTTP, 25 pmol of each primer and 0.25 Unit of Taq polymerase. Thirty five cycles of PCR (denaturation at 94° C. for 1 min; annealing at 55° C for I min; elongation at 72° C. for 1 min) are performed with a Perkin-Elmer Cetus automated thermal cycler. The amplified product is analyzed by agarose gel electrophoresis and the DNA band with expected molecular weight is excised and purified. The PCR product is verified to be the selected sequence by subcloning and sequencing the DNA product.  
     [0939] Several methods are available for the identification of the 5′ or 3′ non-coding portions of a gene which may not be present in the deposited clone. These methods include but are not limited to, filter probing, clone enrichment using specific probes, and protocols similar or identical to 5′ and 3′ “RACE” protocols which are well known in the art. For instance, a method similar to 5′ RACE is available for generating the missing 5′ end of a desired full-length transcript. (Fromont-Racine et al., Nucleic Acids Res. 21(7):1683-1684 (1993).)  
     [0940] Briefly, a specific RNA oligonucleotide is ligated to the 5′ ends of a population of RNA presumably containing full-length gene RNA transcripts. A primer set containing a primer specific to the ligated RNA oligonucleotide and a primer specific to a known sequence of the gene of interest is used to PCR amplify the 5′ portion of the desired full-length gene. This amplified product may then be sequenced and used to generate the full length gene.  
     [0941] This above method starts with total RNA isolated from the desired source, although poly-A+ RNA can be used. The RNA preparation can then be treated with phosphatase if necessary to eliminate 5′ phosphate groups on degraded or damaged RNA which may interfere with the later RNA ligase step. The phosphatase should then be inactivated and the RNA treated with tobacco acid pyrophosphatase in order to remove the cap structure present at the 5′ ends of messenger RNAs. This reaction leaves a 5′ phosphate group at the 5′ end of the cap cleaved RNA which can then be ligated to an RNA oligonucleotide using T4 RNA ligase.  
     [0942] This modified RNA preparation is used as a template for first strand cDNA synthesis using a gene specific oligonucleotide. The first strand synthesis reaction is used as a template for PCR amplification of the desired 5′ end using a primer specific to the ligated RNA oligonucleotide and a primer specific to the known sequence of the gene of interest. The resultant product is then sequenced and analyzed to confirm that the 5′ end sequence belongs to the desired gene.  
     Example 2  
     Isolation of Genomic Clones Corresponding to a Polynucleotide  
     [0943] A human genomic P1 library (Genomic Systems, Inc.) is screened by PCR using primers selected for the sequence corresponding to SEQ ID NO: X according to the method described in Example 1. (See also, Sambrook et al., Molecular Cloning: A Laboratory Manual, 2nd Edn., (1989), Cold Spring Harbor Laboratory Press).  
     Example 3  
     Tissue Specific Expression Analysis  
     [0944] The Human Genome Sciences, Inc. (HGS) database is derived from sequencing tissue and/or disease specific cDNA libraries. Libraries generated from a particular tissue are selected and the specific tissue expression pattern of EST groups or assembled contigs within these libraries is determined by comparison of the expression patterns of those groups or contigs within the entire database. ESTs and assembled contigs which show tissue specific expression are selected.  
     [0945] The original clone from which the specific EST sequence was generated, or in the case of an assembled contig, the clone from which the 5′ most EST sequence was generated, is obtained from the catalogued library of clones and the insert amplified by PCR using methods known in the art. The PCR product is denatured and then transferred in 96 or 384 well format to a nylon membrane (Schleicher and Scheull) generating an array filter of tissue specific clones. Housekeeping genes, maize genes, and known tissue specific genes are included on the filters. These targets can be used in signal normalization and to validate assay sensitivity. Additional targets are included to monitor probe length and specificity of hybridization.  
     [0946] Radioactively labeled hybridization probes are generated by first strand cDNA synthesis per the manufacturer&#39;s instructions (Life Technologies) from mRNA/RNA samples prepared from the specific tissue being analyzed (e.g., kidney, kidney cancer, bladder, bladder cancer, ureter, ureter cancer, urethra, urthra cancer, prostate, prostate cancer, ovarian, ovarian cancer, etc.). The hybridization probes are purified by gel exclusion chromatography, quantitated, and hybridized with the array filters in hybridization bottles at 65° C. overnight. The filters are washed under stringent conditions and signals are captured using a Fuji phosphorimager.  
     [0947] Data is extracted using AIS software and following background subtraction, signal normalization is performed. This includes a normalization of filter-wide expression levels between different experimental runs. Genes that are differentially expressed in the tissue of interest are identified.  
     Example 4  
     Chromosomal Mapping of the Polynucleotides  
     [0948] An oligonucleotide primer set is designed according to the sequence at the 5′ end of SEQ ID NO: X. This primer preferably spans about 100 nucleotides. This primer set is then used in a polymerase chain reaction under the following set of conditions: 30 seconds, 95° C.; 1 minute, 56° C.; 1 minute, 70° C. This cycle is repeated 32 times followed by one 5 minute cycle at 70° C. Human, mouse, and hamster DNA is used as template in addition to a somatic cell hybrid panel containing individual chromosomes or chromosome fragments (Bios, Inc). The reactions are analyzed on either 8% polyacrylamide gels or 3.5% agarose gels. Chromosome mapping is determined by the presence of an approximately 100 bp PCR fragment in the particular somatic cell hybrid.  
     Example 5  
     Bacterial Expression of a Polypeptide  
     [0949] A polynucleotide encoding a polypeptide of the present invention is amplified using PCR oligonucleotide primers corresponding to the 5′ and 3′ ends of the DNA sequence, as outlined in Example 1, to synthesize insertion fragments. The primers used to amplify the cDNA insert should preferably contain restriction sites, such as BamHI and XbaI, at the 5′ end of the primers in order to clone, the amplified product into the expression vector. For example, BamHI and XbaI correspond to the restriction enzyme sites on the bacterial expression vector pQE-9. (Qiagen, Inc., Chatsworth, Calif.). This plasmid vector encodes antibiotic resistance (Amp r ), a bacterial origin of replication (ori), an IPTG-regulatable promoter/operator (P/O), a ribosome binding site (RBS), a 6-histidine tag (6-His), and restriction enzyme cloning sites.  
     [0950] The pQE-9 vector is digested with BamHI and XbaI and the amplified fragment is ligated into the pQE-9 vector maintaining the reading frame initiated at the bacterial RBS. The ligation mixture is then used to transform the  E. coli  strain M15/rep4 (Qiagen, Inc.) which contains multiple copies of the plasmid pREP4, which expresses the lacl repressor and also confers kanamycin resistance (Kan r ). Transformants are identified by their ability to grow on LB plates and ampicillin/kanamycin resistant colonies are selected. Plasmid DNA is isolated and confirmed by restriction analysis.  
     [0951] Clones containing the desired constructs are grown overnight (O/N) in liquid culture in LB media supplemented with both Amp (100 ug/ml) and Kan (25 ug/ml). The O/N culture is used to inoculate a large culture at a ratio of 1:100 to 1:250. The cells are grown to an optical density 600 (O.D. 600 ) of between 0.4 and 0.6. IPTG (Isopropyl-B-D-thiogalacto pyranoside) is then added to a final concentration of 1 mM. IPTG induces by inactivating the lacI repressor, clearing the P/O leading to increased gene expression.  
     [0952] Cells are grown for an extra 3 to 4 hours. Cells are then harvested by centrifugation (20 mins at 6000×g). The cell pellet is solubilized in the chaotropic agent 6 Molar Guanidine HCl by stirring for 3-4 hours at 4° C. The cell debris is removed by centrifugation, and the supernatant containing the polypeptide is loaded onto a nickel-nitrilo-tri-acetic acid (“Ni-NTA”) affinity resin column (available from QIAGEN, Inc., supra). Proteins with a 6×His tag bind to the Ni—NTA resin with high affinity and can be purified in a simple one-step procedure (for details see: The QIAexpressionist (1995) QIAGEN, Inc., supra).  
     [0953] Briefly, the supernatant is loaded onto the column in 6 M guanidine-HCl, pH 8. The column is first washed with 10 volumes of 6 M guanidine-HCl, pH 8, then washed with 10 volumes of 6 M guanidine-HCl pH 6, and finally the polypeptide is eluted with 6 M guanidine-HCl, pH 5.  
     [0954] The purified protein is then renatured by dialyzing it against phosphate-buffered saline (PBS) or 50 mM Na-acetate, pH 6 buffer plus 200 mM NaCl. Alternatively, the protein can be successfully refolded while immobilized on the Ni-NTA column. The recommended conditions are as follows: renature using a linear 6M-1M urea gradient in 500 mM NaCl, 20% glycerol, 20 mM Tris/HCl pH 7.4, containing protease inhibitors. The renaturation should be performed over a period of 1.5 hours or more. After renaturation the proteins are eluted by the addition of 250 mM immidazole. Immidazole is removed by a final dialyzing step against PBS or 50 mM sodium acetate pH 6 buffer plus 200 mM NaCl. The purified protein is stored at 4° C. or frozen at −80° C.  
     [0955] In addition to the above expression vector, the present invention further includes an expression vector, called pHE4a (ATCC Accession Number 209645, deposited on Feb. 25, 1998) which contains phage operator and promoter elements operatively linked to a polynucleotide of the present invention. This vector contains: 1) a neomycinphosphotransferase gene as a selection marker, 2) an  E. coli  origin of replication, 3) a T5 phage promoter sequence, 4) two lac operator sequences, 5) a Shine-Delgamo sequence, and 6) the lactose operon repressor gene (lacIq). The origin of replication (oriC) is derived from pUC19 (LTI, Gaithersburg, Md.). The promoter and operator sequences are made synthetically.  
     [0956] DNA can be inserted into the pHE4a by restricting the vector with NdeI and XbaI, BamHI, XhoI, or Asp718, running the restricted product on a gel, and isolating the larger fragment (the stuffer fragment should be about 310 base pairs). The DNA insert is generated according to the PCR protocol described in Example 1, using PCR primers having restriction sites for NdeI (5′ primer) and XbaI, BamHI, XhoI, or Asp718 (3′ primer). The PCR insert is gel purified and restricted with compatible enzymes. The insert and vector are ligated according to standard protocols.  
     [0957] The engineered vector could easily be substituted in the above protocol to express protein in a bacterial system.  
     Example 6  
     Purification of a Polypeptide from an Inclusion Body  
     [0958] The following alternative method can be used to purify a polypeptide expressed in  E. coli  when it is present in the form of inclusion bodies. Unless otherwise specified, all of the following steps are conducted at 4-10° C.  
     [0959] Upon completion of the production phase of the  E. coli  fermentation, the cell culture is cooled to 4-10° C. and the cells harvested by continuous centrifugation at 15,000 rpm (Heraeus Sepatech). On the basis of the expected yield of protein per unit weight of cell paste and the amount of purified protein required, an appropriate amount of cell paste, by weight, is suspended in a buffer solution containing 100 mM Tris, 50 mM EDTA, pH 7.4. The cells are dispersed to a homogeneous suspension using a high shear mixer.  
     [0960] The cells are then lysed by passing the solution through a microfluidizer (Microfuidics, Corp. or APV Gaulin, Inc.) twice at 4000-6000 psi. The homogenate is then mixed with NaCl solution to a final concentration of 0.5 M NaCl, followed by centrifugation at 7000×g for 15 min. The resultant-pellet is washed again using 0.5M NaCl, 100 mM Tris, 50 mM EDTA, pH 7.4.  
     [0961] The resulting washed inclusion bodies are solubilized with 1.5 M guanidine hydrochloride (GuHCl) for 2-4 hours. After 7000×g centrifugation for 15 min., the pellet is discarded and the polypeptide containing supernatant is incubated at 4° C. overnight to allow further GuHCl extraction.  
     [0962] Following high speed centrifugation (30,000×g) to remove insoluble particles, the GuHCl solubilized protein is refolded by quickly mixing the GuHCl extract with 20 volumes of buffer containing 50 mM sodium, pH 4.5, 150 mM NaCl, 2 mM EDTA by vigorous stirring. The refolded diluted protein solution is kept at 4° C. without mixing for 12 hours prior to further purification steps.  
     [0963] To clarify the refolded polypeptide solution, a previously prepared tangential filtration unit equipped with 0.16 μm membrane filter with appropriate surface area (e.g., Filtron), equilibrated with 40 mM sodium acetate, pH 6.0 is employed. The filtered sample is loaded onto a cation exchange resin (e.g., Poros HS-50 Perseptive Biosystems). The column is washed with 40 mM sodium acetate, pH 6.0 and eluted with 250 mM, 500 mM, 1000 mM, and 1500 mM NaCl in the same buffer, in a stepwise manner. The absorbance at 280 nm of the effluent is continuously monitored. Fractions are collected and further analyzed by SDS-PAGE.  
     [0964] Fractions containing the polypeptide are then pooled and mixed with 4 volumes of water. The diluted sample is then loaded onto a previously prepared set of tandem columns of strong anion (Poros HQ-50, Perseptive Biosystems) and weak anion (Poros CM-20, Perseptive Biosystems) exchange resins. The columns are equilibrated with 40 mM sodium acetate, pH 6.0. Both columns are washed with 40 mM sodium acetate, pH 6.0, 200 mM NaCl. The CM-20 column is then eluted using a 10 column volume linear gradient ranging from 0.2 M NaCl, 50 mM sodium acetate, pH 6.0 to 1.0 M NaCl, 50 mM sodium acetate, pH 6.5. Fractions are collected under constant A 280  monitoring of the effluent. Fractions containing the polypeptide (determined, for instance, by 16% SDS-PAGE) are then pooled.  
     [0965] The resultant polypeptide should exhibit greater than 95% purity after the above refolding and purification steps. No major contaminant bands should be observed from Commassie blue stained 16% SDS-PAGE gel when 5 μg of purified protein is loaded. The purified protein can also be tested for endotoxin/LPS contamination, and typically the LPS content is less than 0.1 ng/ml according to LAL assays.  
     Example 7  
     Cloning and Expression of a Polypeptide in a Baculovirus Expression System  
     [0966] In this example, the plasmid shuttle vector pA2 is used to insert a polynucleotide into a baculovirus to express a polypeptide. This expression vector contains the strong polyhedrin promoter of the  Autographa californica  nuclear polyhedrosis virus (AcMNPV) followed by convenient restriction sites such as BamHI, Xba I and Asp718. The polyadenylation site of the simian virus 40 (“SV40”) is used for efficient polyadenylation. For easy selection of recombinant virus, the plasmid contains the beta-galactosidase gene from  E. coli  under control of a weak Drosophila promoter in the same orientation, followed by the polyadenylation signal of the polyhedrin gene. The inserted genes are flanked on both sides by viral sequences for cell-mediated homologous recombination with wild-type viral DNA to generate a viable virus that express the cloned polynucleotide.  
     [0967] Many other baculovirus vectors can be used in place of the vector above, such as pAc373, pVL941, and pAcIM1, as one skilled in the art would readily appreciate, as long as the construct provides appropriately located signals for transcription, translation, secretion and the like, including a signal peptide and an in-frame AUG as required. Such vectors are described, for instance, in Luckow et al., Virology 170:31-39 (1989).  
     [0968] Specifically, the cDNA sequence contained in the deposited clone, including the AUG initiation codon, is amplified using the PCR protocol described in Example 1. If a naturally occurring signal sequence is used to produce the polypeptide of the present invention, the pA2 vector does not need a second signal peptide. Alternatively, the vector can be modified (pA2 GP) to include a baculovirus leader sequence, using the standard methods described in Summers et al., “A Manual of Methods for Baculovirus Vectors and Insect Cell Culture Procedures,” Texas Agricultural Experimental Station Bulletin No. 1555 (1987).  
     [0969] The amplified fragment is isolated from a 1% agarose gel using a commercially available kit (“Geneclean,” BIO 101 Inc., La Jolla, Calif.). The fragment then is digested with appropriate restriction enzymes and again purified on a 1% agarose gel.  
     [0970] The plasmid is digested with the corresponding restriction enzymes and optionally, can be dephosphorylated using calf intestinal phosphatase, using routine procedures known in the art. The DNA is then isolated from a 1% agarose gel using a commercially available kit (“Geneclean” BIO 101 Inc., La Jolla, Calif.).  
     [0971] The fragment and the dephosphorylated plasmid are ligated together with T4D DNA ligase.  E. coli  HB101 or other suitable  E. coli  hosts such as XL-1 Blue (Stratagene Cloning Systems, La Jolla, Calif.) cells are transformed with the ligation mixture and spread on culture plates. Bacteria containing the plasmid are identified by digesting DNA from individual colonies and analyzing the digestion product by gel electrophoresis. The sequence of the cloned fragment is confirmed by DNA sequencing.  
     [0972] Five μg of a plasmid containing the polynucleotide is co-transfected with 1.0 μg of a commercially available linearized baculovirus DNA (“BaculoGold™ baculovirus DNA”, Pharmingen, San Diego, Calif.), using the lipofection method described by Feigner et al., Proc. Natl. Acad. Sci. USA 84:7413-7417 (1987). One μg of BaculoGold™ virus DNA and 5 μg of the plasmid are mixed in a sterile well of a microtiter plate containing 50 μl of serum-free Grace&#39;s medium (Life Technologies Inc., Gaithersburg, Md.). Afterwards, 10 μl Lipofectin plus 90 μl Grace&#39;s medium are added, mixed and incubated for 15 minutes at room temperature. Then the transfection mixture is added drop-wise to Sf9 insect cells (ATCC CRL 1711) seeded in a 35 mm tissue culture plate with 1 ml Grace&#39;s medium without serum. The plate is then incubated for 5 hours at 27° C. The transfection solution is then removed from the plate and 1 ml of Grace&#39;s insect medium supplemented with 10% fetal calf serum is added. Cultivation is then continued at 27° C. for four days.  
     [0973] After four days the supernatant is collected and a plaque assay is performed, as described by Summers and Smith, supra. An agarose gel with “Blue Gal” (Life Technologies Inc., Gaithersburg) is used to allow easy identification and isolation of gal-expressing clones, which produce blue-stained plaques. (A detailed description of a “plaque assay” of this type can also be found in the user&#39;s guide for insect cell culture and baculovirology distributed by Life Technologies Inc., Gaithersburg, page 9-10.) After appropriate incubation, blue stained plaques are picked with the tip of a micropipettor (e.g., Eppendorf). The agar containing the recombinant viruses is then resuspended in a microcentrifuge tube containing 200 μl of Grace&#39;s medium and the suspension containing the recombinant baculovirus is used to infect Sf9 cells seeded in 35 mm dishes. Four days later the supernatants of these culture dishes are harvested and then they are stored at 4° C.  
     [0974] To verify the expression of the polypeptide, Sf9 cells are grown in Grace&#39;s medium supplemented with 10% heat-inactivated FBS. The cells are infected with the recombinant baculovirus containing the polynucleotide at a multiplicity of infection (“MOI”) of about 2. If radiolabeled proteins are desired, 6 hours later the medium is removed and is replaced with SF900 II medium minus methionine and cysteine (available from Life Technologies Inc., Rockville, Md.). After 42 hours, 5 μCi of 35 S-methionine and 5 μCi  35 S-cysteine (available from Amersham) are added. The cells are further incubated for 16 hours and then are harvested by centrifugation. The proteins in the supernatant as well as the intracellular proteins are analyzed by SDS-PAGE followed by autoradiography (if radiolabeled).  
     [0975] Microsequencing of the amino acid sequence of the amino terminus of purified protein may be used to determine the amino terminal sequence of the produced protein.  
     Example 8  
     Expression of a Polypeptide in Mammalian Cells  
     [0976] The polypeptide of the present invention can be expressed in a mammalian cell. A typical mammalian expression vector contains a promoter element, which mediates the initiation of transcription of mRNA, a protein coding sequence, and signals required for the termination of transcription and polyadenylation of the transcript. Additional elements include enhancers, Kozak sequences and intervening sequences flanked by donor and acceptor sites for RNA splicing. Highly efficient transcription is achieved with the early and late promoters from SV40, the long terminal repeats (LTRs) from Retroviruses, e.g., RSV, HTLVI, HIVI and the early promoter of the cytomegalovirus (CMV). However, cellular elements can also be used (e.g., the human actin promoter).  
     [0977] Suitable expression vectors for use in practicing the present invention include, for example, vectors such as pSVL and pMSG (Pharmacia, Uppsala, Sweden), pRSVcat (ATCC 37152), pSV2dhfr (ATCC 37146), pBC12MI (ATCC 67109), pCMVSport 2.0, and pCMVSport 3.0. Mammalian host cells that could be used include, human Hela, 293, H9 and Jurkat cells, mouse NIH3T3 and C127 cells, Cos 1, Cos 7 and CVI, quail QC1-3 cells, mouse L cells and Chinese hamster ovary (CHO) cells.  
     [0978] Alternatively, the polypeptide can be expressed in stable cell lines containing the polynucleotide integrated into a chromosome. The co-transfection with a selectable marker such as DHFR, gpt, neomycin, or hygromycin allows the identification and isolation of the transfected cells.  
     [0979] The transfected gene can also be amplified to express large amounts of the encoded protein. The DHFR (dihydrofolate reductase) marker is useful in developing cell lines that carry several hundred or even several thousand copies of the gene of interest. (See, e.g., Alt, F. W., et al., J. Biol. Chem. 253:1357-1370 (1978); Hamlin, J. L. and Ma, C., Biochem. et Biophys. Acta, 1097:107-143 (1990); Page, M. J. and Sydenham, M. A., Biotechnology 9:64-68 (1991).) Another useful selection marker is the enzyme glutamine synthase (GS) (Murphy et al., Biochem J. 227:277-279 (1991); Bebbington et al., Bio/Technology 10:169-175 (1992). Using these markers, the mammalian cells are grown in selective medium and the cells with the highest resistance are selected. These cell lines contain the amplified gene(s) integrated into a chromosome. Chinese hamster ovary (CHO) and NSO cells are often used for the production of proteins.  
     [0980] Derivatives of the plasmid pSV2-dhfr (ATCC Accession No. 37146), the expression vectors pC4 (ATCC Accession No. 209646) and pC6 (ATCC Accession No.209647) contain the strong promoter (LTR) of the Rous Sarcoma Virus (Cullen et al., Molecular and Cellular Biology, 438-447 (March, 1985)) plus a fragment of the CMV-enhancer (Boshart et al., Cell 41:521-530 (1985).) Multiple cloning sites, e.g., with the restriction enzyme cleavage sites BamHI, XbaI and Asp718, facilitate the cloning of the gene of interest. The vectors also contain the 3′ intron, the polyadenylation and termination signal of the rat preproinsulin gene, and the mouse DHFR gene under control of the SV40 early promoter.  
     [0981] Specifically, the plasmid pC6, for example, is digested with appropriate restriction enzymes and then dephosphorylated using calf intestinal phosphates by procedures known in the art. The vector is then isolated from a 1% agarose gel.  
     [0982] A polynucleotide of the present invention is amplified according to the protocol outlined in Example 1. If a naturally occurring signal sequence is used to produce the polypeptide of the present invention, the vector does not need a second signal peptide. Alternatively, if a naturally occurring signal sequence is not used, the vector can be modified to include a heterologous signal sequence. (See, e.g., International Publication No. WO 96/34891.)  
     [0983] The amplified fragment is isolated from a 1% agarose gel using a commercially available kit (“Geneclean,” BIO 101 Inc., La Jolla, Calif.). The fragment then is digested with appropriate restriction enzymes and again purified on a 1% agarose gel.  
     [0984] The amplified fragment is then digested with the same restriction enzyme and purified on a 1% agarose gel. The isolated fragment and the dephosphorylated vector are then ligated with T4 DNA ligase.  E. coli  HB101 or XL-1 Blue cells are then transformed and bacteria are identified that contain the fragment inserted into plasmid pC6 using, for instance, restriction enzyme analysis.  
     [0985] Chinese hamster ovary cells lacking an active DHFR gene is used for transfection. Five μg of the expression plasmid pC6 or pC4 is cotransfected with 0.5 μg of the plasmid pSVneo using lipofectin (Felgner et al., supra). The plasmid pSV2-neo contains a dominant selectable marker, the neo gene from Tn5 encoding an enzyme that confers resistance to a group of antibiotics including G418. The cells are seeded in alpha minus MEM supplemented with 1 mg/ml G418. After 2 days, the cells are trypsinized and seeded in hybridoma cloning plates (Greiner, Germany) in alpha minus MEM supplemented with 10, 25, or 50 ng/ml of methottexate plus 1 mg/ml G418. After about 10-14 days single clones are trypsinized and then seeded in 6-well petri dishes or 10 ml flasks using different concentrations of methotrexate (50 nM, 100 nM, 200 nM, 400 nM, 800 nM). Clones growing at the highest concentrations of methotrexate are then transferred to new 6-well plates containing even higher concentrations of methotrexate (1 μM, 2 μM, 5 μM, 10 mM, 20 mM). The same procedure is repeated until clones are obtained which grow at a concentration of 100 -200 μM. Expression of the desired gene product is analyzed, for instance, by SDS-PAGE and Western blot or by reversed phase HPLC analysis.  
     Example 9  
     Protein Fusions  
     [0986] The polypeptides of the present invention are preferably fused to other proteins. These fusion proteins can be used for a variety of applications. For example, fusion of the present polypeptides to His-tag, HA-tag, protein A, IgG domains, and maltose binding protein facilitates purification. (See Example 5; see also EP A 394,827; Traunecker, et al., Nature 331:84-86 (1988).) Similarly, fusion to IgG-1, IgG-3, and albumin increases the halflife time in vivo. Nuclear localization signals fused to the polypeptides of the present invention can target the protein to a specific subcellular localization, while covalent heterodimer or homodimers can increase or decrease the activity of a fusion protein. Fusion proteins can also create chimeric molecules having more than one function. Finally, fusion proteins can increase solubility and/or stability of the fused protein compared to the non-fused protein. All of the types of fusion proteins described above can be made by modifying the following protocol, which outlines the fusion of a polypeptide to an IgG molecule, or the protocol described in Example 5.  
     [0987] Briefly, the human Fc portion of the IgG molecule can be PCR amplified, using primers that span the 5′ and 3′ ends of the sequence described below. These primers also should have convenient restriction enzyme sites that will facilitate cloning into an expression vector, preferably a mammalian expression vector.  
     [0988] For example, if pC4 (ATCC Accession No. 209646) is used, the human Fc portion can be ligated into the BamHI cloning site. Note that the 3′ BamHI site should be destroyed. Next, the vector containing the human Fc portion is re-restricted with BamHI, linearizing the vector, and a polynucleotide of the present invention, isolated by the PCR protocol described in Example 1, is ligated into this BamHI site. Note that the polynucleotide is cloned without a stop codon, otherwise a fusion protein will not be produced.  
     [0989] If the naturally occurring signal sequence is used to produce the polypeptide of the present invention, pC4 does not need a second signal peptide. Alternatively, if the naturally occurring signal sequence is not used, the vector can be modified to include a heterologous signal sequence. (See, e.g., International Publication No. WO 96/34891.)  
                                   Human IgG Fc region:                                        (SEQ ID NO: 1)                         GGGATCCGGAGCCCAAATCTTCTGACAAAACTCACACATGCCCACCGTGCC                   CAGCACCTGAATTCGAGGGTGCACCGTCAGTCTTCCTCTTCCCCCCAAAAC               CCAAGGACACCCTCATGATCTCCCGGACTCCTGAGGTCACATGCGTGGTGG               TGGACGTAAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTCGACG               GCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACA               GCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGA               ATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAACCCCCA               TCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGT               ACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGA               GCTGCCTGGTCAAAGGCTTCTATCCAAGCGACATCGCCGTGGAGTGGGAGA               GCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACT               CCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGT               GGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACA               ACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAATGAGTGCGAC               GGCCGCGACTCTAGAGGAT                  
 
     Example 10  
     Production of an Antibody from a Polypeptide  
     [0990] Hybridoma Technology  
     [0991] The antibodies of the present invention can be prepared by a variety of methods. (See, Current Protocols, Chapter 2.) As one example of such methods, cells expressing polypeptide of the present invention are administered to an animal to induce the production of sera containing polyclonal antibodies. In a preferred method, a preparation of polypeptide of the present invention is prepared and purified to render it substantially free of natural contaminants. Such a preparation is then introduced into an animal in order to produce polyclonal antisera of greater specific activity.  
     [0992] Monoclonal antibodies specific for polypeptide of the present invention are prepared using hybridoma technology (Kohler et al., Nature 256:495 (1975); Kohler et al., Eur. J. Immunol. 6:511 (1976); Kohler et al., Eur. J. Immunol. 6:292 (1976); Hammerling et al., in: Monoclonal Antibodies and T-Cell Hybridomas, Elsevier, N.Y., pp. 563-681 (1981)). In general, an animal (preferably a mouse) is immunized with polypeptide of the present invention or, more preferably, with a secreted polypeptide of the present invention-expressing cell. Such polypeptide-expressing cells are cultured in any suitable tissue culture medium, preferably in Earle&#39;s modified Eagle&#39;s medium supplemented with 10% fetal bovine serum (inactivated at about 56° C.), and supplemented with about 10 g/l of nonessential amino acids, about 1,000 U/ml of penicillin, and about 100 μg/ml of streptomycin.  
     [0993] The splenocytes of such mice are extracted and fused with a suitable myeloma cell line. Any suitable myeloma cell line may be employed in accordance with the present invention; however, it is preferable to employ the parent myeloma cell line (SP2O), available from the ATCC. After fusion, the resulting hybridoma cells are selectively maintained in HAT medium, and then cloned by limiting dilution as described by Wands et al. (Gastroenterology 80:225-232 (1981)). The hybridoma cells obtained through such a selection are then assayed to identify clones which secrete antibodies capable of binding the polypeptide of the present invention.  
     [0994] Alternatively, additional antibodies capable of binding to polypeptide of the present invention can be produced in a two-step procedure using anti-idiotypic antibodies. Such a method makes use of the fact that antibodies are themselves antigens, and therefore, it is possible to obtain an antibody which binds to a second antibody. In accordance with this method, protein specific antibodies are used to immunize an animal, preferably a mouse. The splenocytes of such an animal are then used to produce hybridoma cells, and the hybridoma cells are screened to identify clones which produce an antibody whose ability to bind to the polypeptide of the present invention-specific antibody can be blocked by polypeptide of the present invention. Such antibodies comprise anti-idiotypic antibodies to the polypeptide of the present invention-specific antibody and are used to immunize an animal to induce formation of further polypeptide of the present invention-specific antibodies.  
     [0995] For in vivo use of antibodies in humans, an antibody is “humanized”. Such antibodies can be produced using genetic constructs derived from hybridoma cells producing the monoclonal antibodies described above. Methods for producing chimeric and humanized antibodies are known in the art and are discussed herein. (See, for review, Morrison, Science 229:1202 (1985); Oi et al., BioTechniques 4:214 (1986); Cabilly et al., U.S. Pat. No. 4,816,567; Taniguchi et al., EP 171496; Morrison et al., EP 173494; Neuberger et al., WO 8601533; Robinson et al., International Publication No. WO 8702671; Boulianne et al., Nature 312:643 (1984); Neuberger et al., Nature 314:268 (1985).)  
     [0996] Isolation Of Antibody Fragments Directed Against Polypeptide of the Present Invention From A Library Of scFvs  
     [0997] Naturally occurring V-genes isolated from human PBLs are constructed into a library of antibody fragments which contain reactivities against polypeptide of the present invention to which the donor may or may not have been exposed (see e.g., U.S. Pat. No. 5,885,793 incorporated herein by reference in its entirety).  
     [0998] Rescue of the Library. A library of scFvs is constructed from the RNA of human PBLs as described in International Publication No. WO 92/01047. To rescue phage displaying antibody fragments, approximately 10 9    E. coli  harboring the phagemid are used to inoculate 50 ml of 2×TY containing 1% glucose and 100 μg/ml of ampicillin (2×TY-AMP-GLU) and grown to an O.D. of 0.8 with shaking. Five ml of this culture is used to inoculate 50 ml of 2×TY-AMP-GLU, 2×108 TU of delta gene 3 helper (M13 delta gene III, see International Publication No. WO 92/01047) are added and the culture incubated at 37° C. for 45 minutes without shaking and then at 37° C. for 45 minutes with shaking. The culture is centrifuged at 4000 r.p.m. for 10 min. and the pellet resuspended in 2 liters of 2×TY containing 100 μg/ml ampicillin and 50 ug/ml kanamycin and grown overnight. Phage are prepared as described in International Application No. WO 92/01047.  
     [0999] M13 delta gene III is prepared as follows: M13 delta gene III helperphage does not encode gene III protein, hence the phage(mid) displaying antibody fragments have a greater avidity of binding to antigen. Infectious M13 delta gene III particles are made by growing the helper phage in cells harboring a pUC19 derivative supplying the wild type gene III protein during phage morphogenesis. The culture is incubated for 1 hour at 37° C. without shaking and then for a further hour at 37° C. with shaking. Cells are spun down (IEC-Centra 8,400 r.p.m. for 10 min), resuspended in 300 ml 2×TY broth containing 100 μg ampicillin/ml and 25 μg kanamycin/ml (2×TY-AMP-KAN) and grown overnight, shaking at 37° C. Phage particles are purified and concentrated from the culture medium by two PEG-precipitations (Sambrook et al., 1990), resuspended in 2 ml PBS and passed through a 0.45 μm filter (Minisart NML; Sartorius) to give a final concentration of approximately 10 13  transducing units/ml (ampicillin-resistant clones).  
     [1000] Panning of the Library. Immunotubes (Nunc) are coated overnight in PBS with 4 ml of either 100 μg/ml or 10 μg/mt of a polypeptide of the present invention. Tubes are blocked with 2% Marvel-PBS for 2 hours at 37° C. and then washed 3 times in PBS. Approximately 10 13  TU of phage is applied to the tube and incubated for 30 minutes at room temperature tumbling on an over and under turntable and then left to stand for another 1.5 hours. Tubes are washed 10 times with PBS 0.1% Tween-20 and 10 times with PBS. Phage are eluted by adding 1 ml of 100 mM triethylamine and rotating 15 minutes on an under and over turntable after which the solution is immediately neutralized with 0.5 ml of 1.0M Tris-HCl, pH 7.4. Phage are then used to infect 10 ml of mid-log  E. coli  TG1 by incubating eluted phage with bacteria for 30 minutes at 37° C. The  E. coli  are then plated on TYE plates containing 1% glucose and 100 μg/ml ampicillin. The resulting bacterial library is then rescued with delta gene 3 helper phage as described above to prepare phage for a subsequent round of selection. This process is then repeated for a total of 4 rounds of affinity purification with tube-washing increased to 20 times with PBS, 0.1% Tween-20 and 20 times with PBS for rounds 3 and 4.  
     [1001] Characterization of Binders. Eluted phage from the 3rd and 4th rounds of selection are used to infect  E. coli  HB 2151 and soluble scFv is produced (Marks, et al., 1991) from single colonies for assay. ELISAs are performed with microtitre plates coated with 10 pg/ml of the polypeptide of the present invention in 50 mM bicarbonate pH 9.6. Clones positive in ELISA are further characterized by PCR fingerprinting (see, e.g., International Application No. WO 92/01047) and then by sequencing. These ELISA positive clones may also be further characterized by techniques known in the art, such as, for example, epitope mapping, binding affinity, receptor signal transduction, ability to block or competitively inhibit antibody/antigen binding, and competitive agonistic or antagonistic activity.  
     Example 11  
     Method of Determining Alterations in a Gene Corresponding to a Polynucleotide  
     [1002] RNA isolated from entire families or individual patients presenting with a phenotype of interest (such as a disease) is isolated. cDNA is then generated from these RNA samples using protocols known in the art. (See, Sambrook.) The cDNA is then used as a template for PCR, employing primers surrounding regions of interest in SEQ ID NO: X; and/or the nucleotide sequence of the cDNA contained in Clone ID NO: Z. Suggested PCR conditions consist of 35 cycles at 95 degrees C. for 30 seconds; 60-120 seconds at 52-58 degrees C.; and 60-120 seconds at 70 degrees C., using buffer solutions described in Sidransky et al., Science 252:706 (1991).  
     [1003] PCR products are then sequenced using primers labeled at their 5′ end with T4 polynucleotide kinase, employing SequiTherm Polymerase (Epicentre Technologies). The intron-exon boundaries of selected exons is also determined and genomic PCR products analyzed to confirm the results. PCR products harboring suspected mutations are then cloned and sequenced to validate the results of the direct sequencing.  
     [1004] PCR products are cloned into T-tailed vectors as described in Holton et al., Nucleic Acids Research, 19:1156 (1991) and sequenced with T7 polymerase (United States Biochemical). Affected individuals are identified by mutations not present in unaffected individuals.  
     [1005] Genomic rearrangements are also observed as a method of determining alterations in a gene corresponding to a polynucleotide. Genomic clones isolated according to Example 2 are nick-translated with digoxigenindeoxy-uridine 5′-triphosphate (Boehringer Manheim), and FISH performed as described in Johnson et al., Methods Cell Biol. 35:73-99 (1991). Hybridization with the labeled probe is carried out using a vast excess of human cot-1 DNA for specific hybridization to the corresponding genomic locus.  
     [1006] Chromosomes are counterstained with 4,6-diamino-2-phenylidole and propidium iodide, producing a combination of C- and R-bands. Aligned images for precise mapping are obtained using a triple-band filter set (Chroma Technology, Brattleboro, Vt.) in combination with a cooled charge-coupled device camera (Photometrics, Tucson, Ariz.) and variable excitation wavelength filters. (Johnson et al., Genet. Anal. Tech. Appl., 8:75 (1991).) Image collection, analysis and chromosomal fractional length measurements are performed using the ISee Graphical Program System. (Inovision Corporation, Durham, N.C.) Chromosome alterations of the genomic region hybridized by the probe are identified as insertions, deletions, and translocations. These alterations are used as a diagnostic marker for an associated disease.  
     Example 12  
     Method of Detecting Abnormal Levels of a Polypeptide in a Biological Sample  
     [1007] A polypeptide of the present invention can be detected in a biological sample, and if an increased or decreased level of the polypeptide is detected, this polypeptide is a marker for a particular phenotype. Methods of detection are numerous, and thus, it is understood that one skilled in the art can modify the following assay to fit their particular needs.  
     [1008] For example, antibody-sandwich ELISAs are used to detect polypeptides in a sample, preferably a biological sample. Wells of a microtiter plate are coated with specific antibodies, at a final concentration of 0.2 to 10 ug/ml. The antibodies are either monoclonal or polyclonal and are produced by the method described in Example 10. The wells are blocked so that non-specific binding of the polypeptide to the well is reduced.  
     [1009] The coated wells are then incubated for &gt;2 hours at RT with a sample containing the polypeptide. Preferably, serial dilutions of the sample should be used to validate results. The plates are then washed three times with deionized or distilled water to remove unbound polypeptide.  
     [1010] Next, 50 ul of specific antibody-alkaline phosphatase conjugate, at a concentration of 25-400 ng, is added and incubated for 2 hours at room temperature. The plates are again washed three times with deionized or distilled water to remove unbound conjugate.  
     [1011] Add 75 ul of 4-methylumbelliferyl phosphate (MUP) or p-nitrophenyl phosphate (NPP) substrate solution to each well and incubate 1 hour at room temperature. Measure the reaction by a microtiter plate reader. Prepare a standard curve, using serial dilutions of a control sample, and plot polypeptide concentration on the X-axis (log scale) and fluorescence or absorbance of the Y-axis (linear scale). Interpolate the concentration of the polypeptide in the sample using the standard curve.  
     Example 13  
     Formulation  
     [1012] The invention also provides methods of treatment and/or prevention of diseases or disorders (such as, for example, any one or more of the diseases or disorders disclosed herein) by administration to a subject of an effective amount of a Therapeutic. By therapeutic is meant polynucleotides or polypeptides of the invention (including fragments and variants), agonists or antagonists thereof, and/or antibodies thereto, in combination with a pharmaceutically acceptable carrier type (e.g., a sterile carrier).  
     [1013] The Therapeutic will be formulated and dosed in a fashion consistent with good medical practice, taking into account the clinical condition of the individual patient (especially the side effects of treatment with the Therapeutic alone), the site of delivery, the method of administration, the scheduling of administration, and other factors known to practitioners. The “effective amount” for purposes herein is thus determined by such considerations.  
     [1014] As a general proposition, the total pharmaceutically effective amount of the Therapeutic administered parenterally per dose will be in the range of about 1 ug/kg/day to 10 mg/kg/day of patient body weight, although, as noted above, this will be subject to therapeutic discretion. More preferably, this dose is at least 0.01 mg/kg/day, and most preferably for humans between about 0.01 and 1 mg/kg/day for the hormone. If given continuously, the Therapeutic is typically administered at a dose rate of about 1 ug/kg/hour to about 50 ug/kg/hour, either by 1-4 injections per day or by continuous subcutaneous infusions, for example, using a mini-pump. An intravenous bag solution may also be employed. The length of treatment needed to observe changes and the interval following treatment for responses to occur appears to vary depending on the desired effect.  
     [1015] Therapeutics can be are administered orally, rectally, parenterally, intracistemally, intravaginally, intraperitoneally, topically (as by powders, ointments, gels, drops or transdermal patch), bucally, or as an oral or nasal spray. “Pharmaceutically acceptable carrier” refers to a non-toxic solid, semisolid or liquid filler, diluent, encapsulating material or formulation auxiliary of any. The term “parenteral” as used herein refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.  
     [1016] Therapeutics of the invention are also suitably administered by sustained-release systems. Suitable examples of sustained-release Therapeutics are administered orally, rectally, parenterally, intracistemally, intravaginally, intraperitoneally, topically (as by powders, ointments, gels, drops or transdernal patch), bucally, or as an oral or nasal spray. “Pharmaceutically acceptable carrier” refers to a non-toxic solid, semisolid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. The term “parenteral” as used herein refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.  
     [1017] Therapeutics of the invention are also suitably administered by sustained-release systems. Suitable examples of sustained-release Therapeutics include suitable polymeric materials (such as, for example, semi-permeable polymer matrices in the form of shaped articles, e.g., films, or mirocapsules), suitable hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, and sparingly soluble derivatives (such as, for example, a sparingly soluble salt).  
     [1018] Sustained-release matrices include polylactides (U.S. Pat. No. 3,773,919, EP 58,481), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate (Sidman et al., Biopolymers 22:547-556 (1983)), poly (2-hydroxyethyl methacrylate) (Langer et al., J. Biomed. Mater. Res. 15:167-277 (1981), and Langer, Chem. Tech. 12:98-105 (1982)), ethylene vinyl acetate (Langer et al., Id.) or poly-D-(-)-3-hydroxybutyric acid (EP 133,988).  
     [1019] Sustained-release Therapeutics also include liposomally entrapped Therapeutics of the invention (see generally, Langer,  Science  249:1527-1533 (1990); Treat et al., in  Liposomes in the Therapy of Infectious Disease and Cancer,  Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 317 -327 and 353-365 (1989)). Liposomes containing the Therapeutic are prepared by methods known per se: DE 3,218,121; Epstein et al., Proc. Natl. Acad. Sci. (USA) 82:3688-3692 (1985); Hwang et al., Proc. Natl. Acad. Sci.(USA) 77:4030-4034 (1980); EP 52,322; EP 36,676; EP 88,046; EP 143,949; EP 142,641; Japanese Pat. Appl. 83-118008; U.S. Pat. Nos. 4,485,045 and 4,544,545; and EP 102,324. Ordinarily, the liposomes are of the small (about 200-800 Angstroms) unilamellar type in which the lipid content is greater than about 30 mol. percent cholesterol, the selected proportion being adjusted for the optimal Therapeutic.  
     [1020] In yet an additional embodiment, the Therapeutics of the invention are delivered by way of a pump (see Langer, supra; Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574 (1989)).  
     [1021] Other controlled release systems are discussed in the review by Langer ( Science  249:1527-1533 (1990)).  
     [1022] For parenteral administration, in one embodiment, the Therapeutic is formulated generally by mixing it at the desired degree of purity, in a unit dosage injectable form (solution, suspension, or emulsion), with a pharmaceutically acceptable carrier, i.e., one that is non-toxic to recipients at the dosages and concentrations employed and is compatible with other ingredients of the formulation. For example, the formulation preferably does not include oxidizing agents and other compounds that are known to be deleterious to the Therapeutic.  
     [1023] Generally, the formulations are prepared by contacting the Therapeutic uniformly and intimately with liquid carriers or finely divided solid carriers or both. Then, if necessary, the product is shaped into the desired formulation. Preferably the carrier is a parenteral carrier, more preferably a solution that is isotonic with the blood of the recipient. Examples of such carrier vehicles include water, saline, Ringer&#39;s solution, and dextrose solution. Non-aqueous vehicles such as fixed oils and ethyl oleate are also useful herein, as well as liposomes.  
     [1024] The carrier suitably contains minor amounts of additives such as substances that enhance isotonicity and chemical stability. Such materials are non-toxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, succinate, acetic acid, and other organic acids or their salts; antioxidants such as ascorbic acid; low molecular weight (less than about ten residues) potypeptides, e.g., polyarginine or tripeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids, such as glycine, glutamic acid, aspartic acid, or arginine; monosaccharides, disaccharides, and other carbohydrates including cellulose or its derivatives, glucose, manose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; counterions such as sodium; and/or nonionic surfactants such as polysorbates, poloxamers, or PEG.  
     [1025] The Therapeutic is typically formulated in such vehicles at a concentration of about 0.1 mg/ml to 100 mg/ml, preferably 1-10 mg/ml, at a pH of about 3 to 8. It will be understood that the use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of polypeptide salts.  
     [1026] Any pharmaceutical used for therapeutic administration can be sterile. Sterility is readily accomplished by filtration through sterile filtration membranes (e.g., 0.2 micron membranes). Therapeutics generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.  
     [1027] Therapeutics ordinarily will be stored in unit or multi-dose containers, for example, sealed ampoules or vials, as an aqueous solution or as a lyophilized formulation for reconstitution. As an example of a lyophilized formulation, 10-ml vials are filled with 5 ml of sterile-filtered 1% (w/v) aqueous Therapeutic solution, and the resulting mixture is lyophilized. The infusion solution is prepared by reconstituting the lyophilized Therapeutic using bacteriostatic Water-for-Injection.  
     [1028] The invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the Therapeutics of the invention. Associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration. In addition, the Therapeutics may be employed in conjunction with other therapeutic compounds.  
     [1029] The Therapeutics of the invention may be administered alone or in combination with adjuvants. Adjuvants that may be administered with the Therapeutics of the invention include, but are not limited to, alum, alum plus deoxycholate (ImmunoAg), MTP-PE (Biocine Corp.), QS21 (Genentech, Inc.), BCG (e.g., THERACYS®), MPL and nonviable prepartions of  Corynebacterium parvum.  In a specific embodiment, Therapeutics of the invention are administered in combination with alum. In another specific embodiment, Therapeutics of the invention are administered in combination with QS-21. Further adjuvants that may be administered with the Therapeutics of the invention include, but are not limited to, Monophosphoryl lipid immunomodulator, AdjuVax 100a, QS-21, QS-18, CRL1005, Aluminum salts, MF-59, and Virosomal adjuvant technology. Vaccines that may be administered with the Therapeutics of the invention include, but are not limited to, vaccines directed toward protection against MMR (measles, mumps, rubella), polio, varicella, tetanus/diptheria, hepatitis A, hepatitis B, haemophilus influenzae B, whooping cough, pneumonia, influenza, Lyme&#39;s Disease, rotavirus, cholera, yellow fever; Japanese encephalitis, poliomyelitis, rabies, typhoid fever, and pertussis. Combinations may be administered either concomitantly, e.g., as an admixture, separately but simultaneously or concurrently; or sequentially. This includes presentations in which the combined agents are administered together as a therapeutic mixture, and also procedures in which the combined agents are administered separately but simultaneously, e.g., as through separate intravenous lines into the same individual. Administration “in combination” further includes the separate administration of one of the compounds or agents given first, followed by the second.  
     [1030] The Therapeutics of the invention may be administered alone or in combination with other therapeutic agents. Therapeutic agents that may be administered in combination with the Therapeutics of the invention, include but not limited to, chemotherapeutic agents, antibiotics, steroidal and non-steroidal anti-inflammatories, conventional immunotherapeutic agents, and/or therapeutic treatments described below. Combinations may be administered either concomitantly, e.g., as an admixture, separately but simultaneously or concurrently; or sequentially. This includes presentations in which the combined agents are administered together as a therapeutic mixture, and also procedures in which the combined agents are administered separately but simultaneously, e.g., as through separate intravenous lines into the same individual. Administration “in combination” further includes the separate administration of one of the compounds or agents given first, followed by the second.  
     [1031] In certain embodiments, Therapeutics of the invention are administered in combination with antiretroviral agents, nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and/or protease inhibitors (PIs). NRTIs that may be administered in combination with the Therapeutics of the invention, include, but are not limited to, RETROVIR™ (zidovudine/AZT), VIDEX™ (didanosine/ddI), HIVID™ (zalcitabine/ddC), ZERIT™ (stavudine/d4T), EPIVIR™ (lamivudine/3TC), and COMBIVIR™ (zidovudine/lamivudine). NNRTIs that may be administered in combination with the Therapeutics of the invention, include, but are not limited to, VIRAMUNE™ (nevirapine), RESCRIPTOR™ (delavirdine), and SUSTIVA™ (efavirenz). Protease inhibitors that may be administered in combination with the Therapeutics of the invention, include, but are not limited to, CRIXIVAN™ (indinavir), NORVIR™ (ritonavir), INVIRASE™ (saquinavir), and VIRACEPT™ (nelfinavir). In a specific embodiment, antiretroviral agents, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and/or protease inhibitors may be used in any combination with Therapeutics of the invention to treat AIDS and/or to prevent or treat HIV infection.  
     [1032] Additional NRTIs include LODENOSINE™ (F-ddA; an acid-stable adenosine NRTI; Triangle/Abbott; COVIRACIL™ (emtricitabine/FTC; structurally related to lamivudine (3TC) but with 3- to 10-fold greater activity in vitro; Triangle/Abbott); dOTC (BCH-10652, also structurally related to lamivudine but retains activity against a substantial proportion of lamivudine-resistant isolates; Biochem Pharma); Adefovir (refused approval for anti-HIV therapy by FDA; Gilead Sciences); PREVEON® (Adefovir Dipivoxil, the active prodrug of adefovir; its active form is PMEA-pp); TENOFOVIR™ (bis-POC PMPA, a PMPA prodrug; Gilead); DAPD/DXG (active metabolite of DAPD; Triangle/Abbott); D-D4FC (related to 3TC, with activity against AZT/3TC-resistant virus); GW420867X (Glaxo Wellcome); ZIAGEN™ (abacavir/159U89; Glaxo Wellcome Inc.); CS-87 (3′ azido-2′, 3′-dideoxyuridine; WO 99/66936); and S-acyl-2-thioethyl (SATE)-bearing prodrug forms of β-L-FD4C and β-L-FddC (WO 98/17281).  
     [1033] Additional NNRTIs include COACTINON™ (Emivirine/MKC-442, potent NNRTI of the HEPT class; Triangle/Abbott); CAPRAVIRINE™ (AG-1549/S-1153, a next generation NNRTI with activity against viruses containing the K103N mutation; Agouron); PNU-142721 (has 20- to 50-fold greater activity than its predecessor delavirdine and is active against K103N mutants; Pharmacia &amp; Upjohn); DPC-961 and DPC-963 (second-generation derivatives of efavirenz, designed to be active against viruses with the K103N mutation; DuPont); GW-420867X (has 25-fold greater activity than HBY097 and is active against K103N mutants; Glaxo Wellcome); CALANOLIDE A (naturally occurring agent from the latex tree; active against viruses containing either or both the Y181C and K103N mutations); and Propolis (WO 99/49830).  
     [1034] Additional protease inhibitors include LOPINAVIR™ (ABT378/r; Abbott Laboratories); BMS-232632 (an azapeptide; Bristol-Myres Squibb); TIPRANAVIR™ (PNU-140690, a non-peptic dihydropyrone; Pharmacia &amp; Upjohn); PD-178390 (a nonpeptidic dihydropyrone; Parke-Davis); BMS 232632 (an azapeptide; Bristol-Myers Squibb); L-756,423 (an indinavir analog; Merck); DMP-450 (a cyclic urea compound; Avid &amp; DuPont); AG-1776 (a peptidomimetic with in vitro activity against protease inhibitor-resistant viruses; Agouron); VX-175/GW-433,908 (phosphate prodrug of amprenavir; Vertex &amp; Glaxo Welcome); CGP61755 (Ciba); and AGENERASE™ (amprenavir; Glaxo Wellcome Inc.).  
     [1035] Additional antiretroviral agents include fusion inhibitors/gp41 binders. Fusion inhibitors/gp41 binders include T-20 (a peptide from residues 643-678 of the HIV gp41 transmembrane protein ectodomain which binds to gp41 in its resting state and prevents transformation to the fusogenic state; Trimeris) and T-1249 (a second-generation fusion inhibitor; Trimeris).  
     [1036] Additional antiretroviral agents include fusion inhibitors/chemokine receptor antagonists. Fusion inhibitors/chemokine receptor antagonists include CXCR4 antagonists such as AMD 3100 (a bicyclam), SDF-1 and its analogs, and ALX40-4C (a cationic peptide), T22 (an 18 amino acid peptide; Trimeris) and the T22 analogs T134 and T140; CCR5 antagonists such as RANTES (9-68), AOP-RANTES, NNY-RANTES, and TAK-779; and CCR5/CXCR4 antagonists such as NSC 651016 (a distamycin analog). Also included are CCR2B, CCR3, and CCR6 antagonists. Chemokine recpetor agonists such as RANTES, SDF-1, MIP-1α, MIP-1β, etc., may also inhibit fusion.  
     [1037] Additional antiretroviral agents include integrase inhibitors. Integrase inhibitors include dicaffeoylquinic (DFQA) acids; L-chicoric acid (a dicaffeoyltartaric (DCTA) acid); quinalizarin (QLC) and related anthraquinones; ZINTEVIR™ (AR 177, an oligonucleotide that probably acts at cell surface rather than being a true integrase inhibitor; Arondex); and naphthols such as those disclosed in WO 98/50347.  
     [1038] Additional antiretroviral agents include hydroxyurea-like compunds such as BCX-34 (a purine nucleoside phosphorylase inhibitor; Biocryst); ribonucleotide reductase inhibitors such as DIDOX™ (Molecules for Health); inosine monophosphate dehydrogenase (IMPDH) inhibitors sucha as VX-497 (Vertex); and myvopholic acids such as CellCept (mycophenolate mofetil; Roche).  
     [1039] Additional antiretroviral agents include inhibitors of viral integrase, inhibitors of viral genome nuclear translocation such as arylene bis(methylketone) compounds; inhibitors of HIV entry such as AOP-RANTES, NNY-RANTES, RANTES-IgG fusion protein, soluble complexes of RANTES and glycosaminoglycans (GAG), and AMD-3100; nucleocapsid zinc finger inhibitors such as dithiane compounds; targets of HIV Tat and Rev; and pharmacoenhancers such as ABT-378.  
     [1040] Other antiretroviral therapies and adjunct therapies include cytokines and lymphokines such as MIP-1α, MIP-1β, SDF-1α, IL-2, PROLEUKIN™ (aldesleukin/L2-7001; Chiron), IL-4, IL-10, IL-12, and IL-13; interferons such as IFN-α2a; antagonists of TNFs, NFκB, GM-CSF, M-CSF, and IL-10; agents that modulate immune activation such as cyclosporin and prednisone; vaccines such as Remune™ (HIV Immunogen), APL 400-003 (Apollon), recombinant gp120 and fragments, bivalent (B/E) recombinant envelope glycoprotein, rgp120CM235, MN rgp120, SF-2 rgp120, gp120/soluble CD4 complex, Delta JR-FL protein, branched synthetic peptide derived from discontinuous gp120 C3/C4 domain, fusion-competent immunogens, and Gag, Pol, Nef, and Tat vaccines; gene-based therapies such as genetic suppressor elements (GSEs; WO 98/54366), and intrakines (genetically modified CC chemokines targetted to the ER to block surface expression of newly synthesized CCR5 (Yang et al.,  PNAS  94:11567-72 (1997); Chen et al.,  Nat. Med.  3:1110-16 (1997)); antibodies such as the anti-CXCR4 antibody 12G5, the anti-CCR5 antibodies 2D7, 5C7, PA8, PA9, PA10, PA11, PA12, and PA14, the anti-CD4 antibodies Q4120 and RPA-T4, the anti-CCR3 antibody 7B11, the anti-gp120 antibodies 17b, 48d, 447-52D, 257-D, 268-D and 50.1, anti-Tat antibodies, anti-TNF-α antibodies, and monoclonal antibody 33A; aryl hydrocarbon (AH) receptor agonists and antagonists such as TCDD, 3,3′,4,4′,5-pentachlorobiphenyl, 3,3′,4,4′-tetrachlorobiphenyl, and α-naphthoflavone (WO 98/30213); and antioxidants such as γ-L-glutamyl-L-cysteine ethyl ester (γ-GCE; WO 99/56764).  
     [1041] In a further embodiment, the Therapeutics of the invention are administered in combination with an antiviral agent. Antiviral agents that may be administered with the Therapeutics of the invention include, but are not limited to, acyclovir, ribavirin, amantadine, and remantidine.  
     [1042] In other embodiments, Therapeutics of the invention may be administered in combination with anti-opportunistic infection agents. Anti-opportunistic agents that may be administered in combination with the Therapeutics of the invention, include, but are not limited to, TRIMETHOPRIM-SULFAMETHOXAZOLE™, DAPSONE™, PENTAMIDINE™, ATOVAQUONE™, ISONIAZID™, RIFAMPIN™, PYRAZINAMIDE™, ETHAMBUTOL™, RIFABUTIN™, CLARITHROMYCIN™, AZITHROMYCIN™, GANCICLOVIR™, FOSCARNET™, CIDOFOVIR™, FLUCONAZOLE™, ITRACONAZOLE™, KETOCONAZOLE™, ACYCLOVIR™, FAMCICOLVIR™, PYRIMETHAMINE™, LEUCOVORIN™, NEUPOGEN™ (filgrastim/G-CSF), and LEUKINE™ (sargramostim/GM-CSF). In a specific embodiment, Therapeutics of the invention are used in any combination with TRIMETHOPRIM-SULFAMETHOXAZOLE™, DAPSONE™, PENTAMIDINE™, and/or ATOVAQUONE™ to prophylactically treat or prevent an opportunistic  Pneumocystis carinii  pneumonia infection. In another specific embodiment, Therapeutics of the invention are used in any combination with ISONIAZID™, RIFAMPIN™, PYRAZINAMIDE™, and/or ETHAMBUTOL™ to prophylactically treat or prevent an opportunistic  Mycobacterium avium  complex infection. In another specific embodiment, Therapeutics of the invention are used in any combination with RIFABUTIN™, CLARITHROMYCIN™, and/or AZITHROMYCIN™ to prophylactically treat or prevent an opportunistic  Mycobacterium tuberculosis  infection. In another specific embodiment, Therapeutics of the invention are used in any combination with GANCICLOVIR™, FOSCARNET™, and/or CIDOFOVIR™ to prophylactically treat or prevent an opportunistic cytomegalovirus infection. In another specific embodiment, Therapeutics of the invention are used in any combination with FLUCONAZOLE™, ITRACONAZOLE™, and/or KETOCONAZOLE™ to prophylactically treat or prevent an opportunistic fungal infection. In another specific embodiment, Therapeutics of the invention are used in any combination with ACYCLOVIR™ and/or FAMCICOLVIR™ to prophylactically treat or prevent an opportunistic herpes simplex virus type I and/or type II infection. In another specific embodiment, Therapeutics of the invention are used in any combination with PYRIMETHAMINE™ and/or LEUCOVORIN™ to prophylactically treat or prevent an opportunistic  Toxoplasma gondii  infection. In another specific embodiment, Therapeutics of the invention are used in any combination with LEUCOVORIN™ and/or NEUPOGEN™ to prophylactically treat or prevent an opportunistic bacterial infection.  
     [1043] In a further embodiment, the Therapeutics of the invention are administered in combination with an antibiotic agent. Antibiotic agents that may be administered with the Therapeutics of the invention include, but are not limited to, amoxicillin, beta-lactamases, aminoglycosides, beta-lactam (glycopeptide), beta-lactamases, Clindamycin, chloramphenicol, cephalosporins, ciprofloxacin, ciprofloxacin, erythromycin, fluoroquinolones, macrolides, metronidazole, penicillins, quinolones, rapamycin, rifampin, streptomycin, sulfonamide, tetracyclines, trimethoprim, trimethoprim-sulfamthoxazole, and vancomycin.  
     [1044] In other embodiments, Therapeutics of the invention are administered in combination with immunosuppressive agents. Immunosuppressive agents that may be administered in combination with the Therapeutics of the invention include, but are not limited to, steroids, cyclosporine, cyclosporine analogs, cyclophosphamide methylprednisone, prednisone, azathioprine, FK-506, 15-deoxyspergualin, and other immunosuppressive agents that act by suppressing the function of responding T cells. Other immunosuppressive agents that may be administered in combination with the Therapeutics of the invention include, but are not limited to, prednisolone, methotrexate, thalidomide, methoxsalen, rapamycin, leflunomide, mizoribine (BREDININ™), brequinar, deoxyspergualin, and azaspirane (SKF 105685), ORTHOCLONE OKT® 3 (muromonab-CD3), SANDIMMUNE™, NEORAL™, SANGDYA™ (cyclosporine), PROGRAF® (FK506, tacrolimus), CELLCEPT® (mycophenolate motefil, of which the active metabolite is mycophenolic acid), IMURAN™ (azathioprine), glucocorticosteroids, adrenocortical steroids such as DELTASONE™ (prednisone) and HYDELTRASOL™ (prednisolone), FOLEX™ and MEXATE™ (methotrxate), OXSORALEN-ULTRA™ (methoxsalen) and RAPAMUNE™ (sirolimus). In a specific embodiment, immunosuppressants may be used to prevent rejection of organ or bone marrow transplantation.  
     [1045] In an additional embodiment, Therapeutics of the invention are administered alone or in combination with one or more intravenous immune globulin preparations. Intravenous immune globulin preparations that may be administered with the Therapeutics of the invention include, but not limited to, GAMMAR™, IVEEGAM™, SANDOGLOBULIN™, GAMMAGARD S/D™, ATGAM™ (antithymocyte glubulin), and GAMIMUNE™. In a specific embodiment, Therapeutics of the invention are administered in combination with intravenous immune globulin preparations in transplantation therapy (e.g., bone marrow transplant).  
     [1046] In certain embodiments, the Therapeutics of the invention are administered alone or in combination with an anti-inflammatory agent. Anti-inflammatory agents that may be administered with the Therapeutics of the invention include, but are not limited to, corticosteroids (e.g. betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, and triamcinolone), nonsteroidal anti-inflammatory drugs (e.g., diclofenac, diflunisal, etodolac, fenoprofen, floctafenine, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamate, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam, sulindac, tenoxicam, tiaprofenic acid, and tolmetin.), as well as antihistamines, aminoarylcarboxylic acid derivatives, arylacetic acid derivatives, arylbutyric acid derivatives, arylcarboxylic acids, arylpropionic acid derivatives, pyrazoles, pyrazolones, salicylic acid derivatives, thiazinecarboxamides, e-acetamidocaproic acid, S-adenosylmethionine, 3-amino-4-hydroxybutyric acid, amixetrine, bendazac, benzydamine, bucolome, difenpiramide, ditazol, emorfazone, guaiazulene, nabumetone, nimesulide, orgotein, oxaceprol, paranyline, perisoxal, pifoxime, proquazone, proxazole, and tenidap.  
     [1047] In an additional embodiment, the compositions of the invention are administered alone or in combination with an anti-angiogenic agent. Anti-angiogenic agents that may be administered with the compositions of the invention include, but are not limited to, Angiostatin (Entremed, Rockville, Md.), Troponin-1 (Boston Life Sciences, Boston, Mass.), anti-Invasive Factor, retinoic acid and derivatives thereof, paclitaxel (Taxol), Suramin, Tissue Inhibitor of Metalloproteinase-1, Tissue Inhibitor of Metalloproteinase-2, VEGI, Plasminogen Activator Inhibitor-1, Plasminogen Activator Inhibitor-2, and various forms of the lighter “d group” transition metals.  
     [1048] Lighter “d group” transition metals include, for example, vanadium, molybdenum, tungsten, titanium, niobium, and tantalum species. Such transition metal species may form transition metal complexes. Suitable complexes of the above-mentioned transition metal species include oxo transition metal complexes.  
     [1049] Representative examples of vanadium complexes include oxo vanadium complexes such as vanadate and vanadyl complexes. Suitable vanadate complexes include metavanadate and orthovanadate complexes such as, for example, ammonium metavanadate, sodium metavanadate, and sodium orthovanadate. Suitable vanadyl complexes include, for example, vanadyl acetylacetonate and vanadyl sulfate including vanadyl sulfate hydrates such as vanadyl sulfate mono- and trihydrates.  
     [1050] Representative examples of tungsten and molybdenum complexes also include oxo complexes. Suitable oxo tungsten complexes include tungstate and tungsten oxide complexes. Suitable tungstate complexes include ammonium tungstate, calcium tungstate, sodium tungstate dihydrate, and tungstic acid. Suitable tungsten oxides include tungsten (IV) oxide and tungsten (VI) oxide. Suitable oxo molybdenum complexes include molybdate, molybdenum oxide, and molybdenyl complexes. Suitable molybdate complexes include ammonium molybdate and its hydrates, sodium molybdate and its hydrates, and potassium molybdate and its hydrates. Suitable molybdenum oxides include molybdenum (VI) oxide, molybdenum (VI) oxide, and molybdic acid. Suitable molybdenyl complexes include, for example, molybdenyl acetylacetonate. Other suitable tungsten and molybdenum complexes include hydroxo derivatives derived from, for example, glycerol, tartaric acid, and sugars.  
     [1051] A wide variety of other anti-angiogenic factors may also be utilized within the context of the present invention. Representative examples include, but are not limited to, platelet factor 4; protamine sulphate; sulphated chitin derivatives (prepared from queen crab shells), (Murata et al., Cancer Res. 51:22-26, (1991)); Sulphated Polysaccharide Peptidoglycan Complex (SP-PG) (the function of this compound may be enhanced by the presence of steroids such as estrogen, and tamoxifen citrate); Staurosporine; modulators of matrix metabolism, including for example, proline analogs, cishydroxyproline, d,L-3,4-dehydroproline, Thiaproline, alpha,alpha-dipyridyl, aminopropionitrile fumarate; 4-propyl-5-(4-pyridinyl)-2(3H)-oxazolone; Methotrexate; Mitoxantrone; Heparin; Interferons; 2 Macroglobulin-serum; ChIMP-3 (Pavloff et al., J. Bio. Chem. 267:17321-17326, (1992)); Chymostatin (Toinkinson et al., Biochem J. 286:475-480, (1992)); Cyclodextrin Tetradecasulfate; Eponemycin; Camptothecin; Fumagillin (Ingber et al., Nature 348:555-557, (1990)); Gold Sodium Thiomalate (“GST”; Matsubara and Ziff, J. Clin. Invest. 79:1440-1446, (1987)); anticollagenase-serum; alpha2-antiplasmin (Holmes et al., J. Biol. Chem. 262(4):1659-1664, (1987)); Bisantrene (National Cancer Institute); Lobenzarit disodium (N-(2)-carboxyphenyl-4-chloroanthronilic acid disodium or “CCA”; (Takeuchi et al., Agents Actions 36:312-316, (1992)); and metalloproteinase inhibitors such as BB94.  
     [1052] Additional anti-angiogenic factors that may also be utilized within the context of the present invention include Thalidomide, (Celgene, Warren, N.J.); Angiostatic steroid; AGM-1470 (H. Brem and J. Folkman  J Pediatr. Surg.  28:445-51 (1993)); an integrin alpha v beta 3 antagonist (C. Storgard et al.,  J Clin. Invest.  103:47-54 (1999)); carboxynaminolmidazole; Carboxyamidotriazole (CAI) (National Cancer Institute, Bethesda, Md.); Conbretastatin A-4 (CA4P) (OXiGENE, Boston, Mass.); Squalamine (Magainin Pharmaceuticals, Plymouth Meeting, Pa.); TNP-470, (Tap Pharmaceuticals, Deerfield, Ill.); ZD-0101 AstraZeneca (London, UK); APRA (CT2584); Benefin, Byrostatin-1 (SC339555); CGP-41251 (PKC 412); CM101; Dexrazoxane (ICRF187); DMXAA; Endostatin; Flavopridiol; Genestein; GTE; ImmTher; Iressa (ZD1839); Octreotide (Somatostatin); Panretin; Penacillamine; Photopoint; PI-88; Prinomastat (AG-3340) Purlytin; Suradista (FCE26644); Tamoxifen (Nolvadex); Tazarotene; Tetrathiomolybdate; Xeloda (Capecitabine); and 5-Fluorouracil.  
     [1053] Anti-angiogenic agents that may be administed in combination with the compounds of the invention may work through a variety of mechanisms including, but not limited to, inhibiting proteolysis of the extracellular matrix, blocking the function of endothelial cell-extracellular matrix adhesion molecules, by antagonizing the function of angiogenesis inducers such as growth factors, and inhibiting integrin receptors expressed on proliferating endothelial cells. Examples of anti-angiogenic inhibitors that interfere with extraceilular matrix proteolysis and which may be administered in combination with the compositons of the invention include, but are not Imited to, AG-3340 (Agouron, La Jolla, Calif.), BAY-12-9566 (Bayer, West Haven, Conn.), BMS-275291 (Bristol Myers Squibb, Princeton, N.J.), CGS-27032A (Novartis, East Hanover, N.J.), Marimastat (British Biotech, Oxford, UK), and Metastat (Aeterna, St-Foy, Quebec). Examples of anti-angiogenic inhibitors that act by blocking the function of endothelial cell-extracellular matrix adhesion molecules and which may be administered in combination with the compositons of the invention include, but are not Imited to, EMD-121974 (Merck KcgaA Darmstadt, Germany) and Vitaxin (Ixsys, La Jolla, Calif./Medimmune, Gaithersburg, Md.). Examples of anti-angiogenic agents that act by directly antagonizing or inhibiting angiogenesis inducers and which may be administered in combination with the compositons of the invention include, but are not lmited to, Angiozyme (Ribozyme, Boulder, Colo.), Anti-VEGF antibody (Genentech, S. San Francisco, Calif.), PTK-787/ZK-225846 (Novartis, Basel, Switzerland), SU-101 (Sugen, S. San Francisco, Calif.), SU-5416 (Sugen/Pharmacia Upjohn, Bridgewater, N.J.), and SU-6668 (Sugen). Other anti-angiogenic agents act to indirectly inhibit angiogenesis. Examples of indirect inhibitors of angiogenesis which may be administered in combination with the compositons of the invention include, but are not limited to, IM-862 (Cytran, Kirkland, Wash.), Interferon-alpha, IL-12 (Roche, Nutley, N.J.), and Pentosan polysulfate (Georgetown University, Washington, D.C.).  
     [1054] In particular embodiments, the use of compositions of the invention in combination with anti-angiogenic agents is contemplated for the treatment, prevention, and/or amelioration of an autoimmune disease, such as for example, an autoimmune disease described herein.  
     [1055] In a particular embodiment, the use of compositions of the invention in combination with anti-angiogenic agents is contemplated for the treatment, prevention, and/or amelioration of arthritis. In a more particular embodiment, the use of compositions of the invention in combination with anti-angiogenic agents is contemplated for the treatment, prevention, and/or amelioration of rheumatoid arthritis.  
     [1056] In another embodiment, the polynucleotides encoding a polypeptide of the present invention are administered in combination with an angiogenic protein, or polynucteotides encoding an angiogenic protein. Examples of angiogenic proteins that may be administered with the compositions of the invention include, but are not limited to, acidic and basic fibroblast growth factors, VEGF-1, VEGF-2, VEGF-3, epidermal growth factor alpha and beta, platelet-derived endothelial cell growth factor, platelet-derived growth factor, tumor necrosis factor alpha, hepatocyte growth factor, insulin-like growth factor, colony stimulating factor, macrophage colony stimulating factor, granulocyte/macrophage colony stimulating factor, and nitric oxide synthase.  
     [1057] In additional embodiments, compostions of the invention are administered in combination with a chemotherapeutic agent. Chemotherapeutic agents that may be administered with the Therapeutics of the invention include, but are not limited to alkylating agents such as nitrogen mustards (for example, Mechlorethamine, cyclophosphamide, Cyclophosphamide Ifosfamide, Melphalan (L-sarcolysin), and Chlorambucil), ethylenimines and methylmelamines (for example, Hexamethylmelamine and Thiotepa), alkyl sulfonates (for example, Busulfan), nitrosoureas (for example, Carmustine (BCNU), Lomustine (CCNU), Semustine (methyl-CCNU), and Streptozocin (streptozotocin)), triazenes (for example, Dacarbazine (DTIC; dimethyltriazenoimidazolecarboxamide)), folic acid analogs (for example, Methotrexate (amethopterin)), pyrimidine analogs (for example, Fluorouacil (5-fluorouracil; 5-FU), Floxuridine (fluorodeoxyuridine; FudR), and Cytarabine (cytosine arabinoside)), purine analogs and related inhibitors (for example, Mercaptopurine (6-mercaptopurine; 6-MP), Thioguanine (6-thioguanine; TG), and Pentostatin (2′-deoxycoformycin)), vinca alkaloids (for example, Vinblastine (VLB, vinblastine sulfate) and Vincristine (vincristine sulfate)), epipodophyllotoxins (for example, Etoposide and Teniposide), antibiotics (for example, Dactinomycin (actinomycin D), Daunorubicin (daunomycin; rubidomycin), Doxorubicin, Bleomycin, Plicamycin (mithramycin), and Mitomycin (mitomycin C), enzymes (for example, L-Asparaginase), biological response modifiers (for example, Interferon-alpha and interferon-alpha-2b), platinum coordination compounds (for example, Cisplatin (cis-DDP) and Carboplatin), anthracenedione (Mitoxantrone), substituted ureas (for example, Hydroxyurea), methylhydrazine derivatives (for example, Procarbazine (N-methyihydrazine; MIH), adrenocorticosteroids (for example, Prednisone), progestins (for example, Hydroxyprogesterone caproate, Medroxyprogesterone, Medroxyprogesterone acetate, and Megestrol acetate), estrogens (for example, Diethylstilbestrol (DES), Diethyistilbestrol diphosphate, Estradiol, and Ethinyl estradiol), antiestrogens (for example, Tamoxifen), androgens (Testosterone proprionate, and Fluoxymesterone), antiandrogens (for example, Flutamide), gonadotropin-releasing horomone analogs (for example, Leuprolide), other hormones and hormone analogs (for example, methyltestosterone, estramustine, estramustine phosphate sodium, chlorotrianisene, and testolactone), and others (for example, dicarbazine, glutamic acid, and mitotane).  
     [1058] In one embodiment, the compositions of the invention are administered in combination with one or more of the following drugs: infliximab (also known as Remicade™ Centocor, Inc.), Trocade (Roche, RO-32-3555), Leflunomide (also known as Arava™ from Hoechst Marion Roussel), Kineret™ (an IL-1 Receptor antagonist also known as Anakinra from Amgen, Inc.).  
     [1059] In a specific embodiment, compositions of the invention are administered in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or combination of one or more of the components of CHOP. In one embodiment, the compositions of the invention are administered in combination with anti-CD20 antibodies, human monoclonal anti-CD20 antibodies. In another embodiment, the compositions of the invention are administered in combination with anti-CD20 antibodies and CHOP, or anti-CD20 antibodies and any combination of one or more of the components of CHOP, particularly cyclophosphamide and/or prednisone. In a specific embodiment, compositions of the invention are administered in combination with Rituximab. In a further embodiment, compositions of the invention are administered with Rituximab and CHOP, or Rituximab and any combination of one or more of the components of CHOP, particularly cyclophosphamide and/or prednisone. In a specific embodiment, compositions of the invention are administered in combination with tositumomab. In a further embodiment, compositions of the invention are administered with tositumomab and CHOP, or tositumomab and any combination of one or more of the components of CHOP, particularly cyclophosphamide and/or prednisone. The anti-CD20 antibodies may optionally be associated with radioisotopes, toxins or cytotoxic prodrugs.  
     [1060] In another specific embodiment, the compositions of the invention are administered in combination Zevalin™. In a further embodiment, compositions of the invention are administered with Zevalin™ and CHOP, or Zevalin™ and any combination of one or more of the components of CHOP, particularly cyclophosphamide and/or prednisone. Zevalin™ may be associated with one or more radisotopes. Particularly preferred isotopes are  90 Y and  111 In.  
     [1061] In an additional embodiment, the Therapeutics of the invention are administered in combination with cytokines. Cytokines that may be administered with the Therapeutics of the invention include, but are not limited to, IL2, IL3, IL4, IL5, IL6, IL7, IL10, IL12, IL13, IL15, anti-CD40, CD40L, IFN-gamma and TNF-alpha. In another embodiment, Therapeutics of the invention may be administered with any interleukin, including, but not limited to, IL-1alpha, IL-1beta, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-19, IL-20, and IL-21.  
     [1062] In one embodiment, the Therapeutics of the invention are administered in combination with members of the TNF family. TNF, TNF-related or TNF-like molecules that may be administered with the Therapeutics of the invention include, but are not limited to, soluble forms of TNF-alpha, tymphotoxin-alpha (LT-alpha, also known as TNF-beta), LT-beta (found in complex heterotrimer LT-alpha2-beta), OPGL, FasL, CD27L, CD30L, CD40L, 4-IBBL, DcR3, OX40L, TNF-gamma (International Publication No. WO 96/14328), AIM-I (International Publication No. WO 97/33899), endokine-alpha (International Publication No. WO 98/07880), OPG, and neutrokine-alpha (International Publication No. WO 98/18921, OX40, and nerve growth factor (NGF), and soluble forms of Fas, CD30, CD27, CD40 and 4-IBB, TR2 (International Publication No. WO 96/34095), DR3 (International Publication No. WO 97/33904), DR4 (International Publication No. WO 98/32856), TR5 (International Publication No. WO 98/30693), TRANK, TR9 (International Publication No. WO 98/56892),TR10 (International Publication No. WO 98/54202), 312C2 (International Publication No. WO 98/06842), and TR12, and soluble forms CD154, CD70, and CD153.  
     [1063] In an additional embodiment, the Therapeutics of the invention are administered in combination with angiogenic proteins. Angiogenic proteins that may be administered with the Therapeutics of the invention include, but are not limited to, Glioma Derived Growth Factor (GDGF), as disclosed in European Patent Number EP-399816; Platelet Derived Growth Factor-A (PDGF-A), as disclosed in European Patent Number EP-682110; Platelet Derived Growth Factor-B (PDGF-B), as disclosed in European Patent Number EP-282317; Placental Growth Factor (PlGF), as disclosed in International Publication Number WO 92/06194; Placental Growth Factor-2 (PIGF-2), as disclosed in Hauser et al., Growth Factors, 4:259-268 (1993); Vascular Endothelial Growth Factor (VEGF), as disclosed in International Publication Number WO 90/13649; Vascular Endothelial Growth Factor-A (VEGF-A), as disclosed in European Patent Number EP-506477; Vascular Endothelial Growth Factor-2 (VEGF-2), as disclosed in International Publication Number WO 96/39515; Vascular Endothelial Growth Factor B (VEGF-3); Vascular Endothelial Growth Factor B-186 (VEGF-B186), as disclosed in International Publication Number WO 96/26736; Vascular Endothelial Growth Factor-D (VEGF-D), as disclosed in International Publication Number WO 98/02543; Vascular Endothelial Growth Factor-D (VEGF-D), as disclosed in International Publication Number WO 98/07832; and Vascular Endothelial Growth Factor-E (VEGF-E), as disclosed in German Patent Number DE19639601. The above mentioned references are herein incorporated by reference in their entireties.  
     [1064] In an additional embodiment, the Therapeutics of the invention are administered in combination with Fibroblast Growth Factors. Fibroblast Growth Factors that may be administered with the Therapeutics of the invention include, but are not limited to, FGF-1, FGF-2, FGF-3, FGF-4, FGF-5, FGF-6, FGF-7, FGF-8, FGF-9, FGF-10, FGF-11, FGF-12, FGF-13, FGF-14, and FGF-15.  
     [1065] In an additional embodiment, the Therapeutics of the invention are administered in combination with hematopoietic growth factors. Hematopoietic growth factors that may be administered with the Therapeutics of the invention include, but are not limited to, granulocyte macrophage colony stimulating factor (GM-CSF) (sargramostim, LEUKINE™, PROKINE™), granulocyte colony stimulating factor (G-CSF) (filgrastim, NEUPOGEN™), macrophage colony stimulating factor (M-CSF, CSF-1) erythropoietin (epoetin alfa, EPOGEN™, PROCRIT™), stem cell factor (SCF, c-kit ligand, steel factor), megakaryocyte colony stimulating factor, PIXY321 (a GMCSF/IL-3 fusion protein), interleukins, especially any one or more of IL-1 through IL-1 2, interferon-gamma, or thrombopoietin.  
     [1066] In certain embodiments, Therapeutics of the present invention are administered in combination with adrenergic blockers, such as, for example, acebutolol, atenolol, betaxolol, bisoprolol, carteolol, labetalol, metoprolol, nadolol, oxprenolol, penbutolol, pindolol, propranolol, sotalol, and timolol.  
     [1067] In another embodiment, the Therapeutics of the invention are administered in combination with an antiarrhythmic drug (e.g., adenosine, amidoarone, bretylium, digitalis, digoxin, digitoxin, diliazem, disopyramide, esmolol, flecainide, lidocaine, mexiletine, moricizine, phenytoin, procainamide, N-acetyl procainamide, propafenone, propranolol, quinidine, sotalol, tocainide, and verapamil).  
     [1068] In another embodiment, the Therapeutics of the invention are administered in combination with diuretic agents, such as carbonic anhydrase-inhibiting agents (e.g., acetazolamide, dichlorphenamide, and methazolamide), osmotic diuretics (e.g., glycerin, isosorbide, mannitol, and urea), diuretics that inhibit Na + —K + -2Cl −  symport (e.g., furosemide, bumetanide, azosemide, piretanide, tripamide, ethacrynic acid, muzolimine, and torsemide), thiazide and thiazide-like diuretics (e.g., bendroflumethiazide, benzthiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, trichormethiazide, chlorthalidone, indapamide, metolazone, and quinethazone), potassium sparing diuretics (e.g., amiloride and triamterene), and mineralcorticoid receptor antagonists (e.g., spironolactone, canrenone, and potassium canrenoate).  
     [1069] In one embodiment, the Therapeutics of the invention are administered in combination with treatments for endocrine and/or hormone imbalance disorders. Treatments for endocrine and/or hormone imbalance disorders include, but are not limited to,  127 I, radioactive isotopes of iodine such as  131 I and  123 I; recombinant growth hormone, such as HUMATROPE™ (recombinant somatropin); growth hormone analogs such as PROTROPIN™ (somatrem); dopamine agonists such as PARLODEL™ (bromocriptine); somatostatin analogs such as SANDOSTATIN™ (octreotide); gonadotropin preparations such as PREGNYL™, A.P.L.™ and PROFASI™ (chorionic gonadotropin (CG)), PERGONAL™ (menotropins), and METRODIN™ (urofollitropin (uFSH)); synthetic human gonadotropin releasing hormone preparations such as FACTREL™ and LUTREPULSE™ (gonadorelin hydrochloride); synthetic gonadotropin agonists such as LUPRON™ (leuprolide acetate), SUPPRELIN™ (histrelin acetate), SYNAREL™ (nafarelin acetate), and ZOLADEX™ (goserelin acetate); synthetic preparations of thyrotropin-releasing hormone such as RELEFACT TRH™ and THYPINONE™ (protirelin); recombinant human TSH such as THYROGEN™; synthetic preparations of the sodium salts of the natural isomers of thyroid hormones such as L-T 4 ™, SYNTHROID™ and LEVOTHROID™ (levothyroxine sodium), L-T 3 ™, CYTOMEL™ and TRIOSTAT™ (liothyroine sodium), and THYROLAR™ (liotrix); antithyroid compounds such as 6-n-propylthiouracil (propylthiouracil), 1-methyl-2-mercaptoimidazole and TAPAZOLE™ (methimazole), NEO-MERCAZOLE™ (carbimazole); beta-adrenergic receptor antagonists such as propranolol and esmolol; Ca 2+  channel blockers; dexamethasone and iodinated radiological contrast agents such as TELEPAQUE™ (iopanoic acid) and ORAGRAFIN™ (sodium ipodate); estrogens or congugated estrogens such as ESTRACE™ (estradiol), ESTINYL™ (ethinyl estradiol), PREMARIN™, ESTRATAB™, ORTHO-EST™, OGEN™ and estropipate (estrone), ESTROVIS™ (quinestrol), ESTRADERM™ (estradiol), DELESTROGEN™ and VALERGEN™ (estradiol valerate), DEPO-ESTRADIOL CYPIONATE™ and ESTROJECT LA™ (estradiol cypionate); antiestrogens such as NOLVADEX™ (tamoxifen), SEROPHENE™ and CLOMID™ (clomiphene); progestins such as DURALUTIN™ (hydroxyprogesterone caproate), MPA™ and DEPO-PROVERA™ (medroxyprogesterone acetate), PROVERA™ and CYCRIN™ (MPA), MEGACE™ (megestrol acetate), NORLUTIN™ (norethindrone), and NORLUTATE™ and AYGESTIN™ (norethindrone acetate); progesterone implants such as NORPLANT SYSTEM™ (subdermal implants of norgestrel); antiprogestins such as RU 486™ (mifepristone); hormonal contraceptives such as ENOVID™ (norethynodrel plus mestranol), PROGESTASERT™ (intrauterine device that releases progesterone), LOESTRIN™, BREVICON™, MODICON™, GENORA™, NELONA™, NORINYL™, OVACON-35™ and OVACON-50™ (ethinyl estradiol/norethindrone), LEVLEN™, NORDETTE™, TRI-LEVLEN™ and TRIPHASIL-21™ (ethinyl estradiol/levonorgestrel) LO/OVRAL™ and OVRAL™ (ethinyl estradiol/norgestrel), DEMULEN™ (ethinyl estradiol/ethynodiol diacetate), NORINYL™, ORTHO-NOVUM™, NORETHIN™, GENORA™, and NELOVA™ (norethindrone/mestranol), DESOGEN™ and ORTHO-CEPT™ (ethinyl estradiol/desogestrel), ORTHO-CYCLEN™ and ORTHO-TRICYCLEN™ (ethinyl estradiol/norgestimate), MICRONOR™ and NOR-QD™ (norethindrone), and OVRETTE™ (norgestrel); testosterone esters such as methenolone acetate and testosterone undecanoate; parenteral and oral androgens such as TESTOJECT-50™ (testosterone), TESTEX™ (testosterone propionate), DELATESTRYL™ (testosterone enanthate), DEPO-TESTOSTERONE™ (testosterone cypionate), DANOCRINE™ (danazol), HALOTESTIN™ (fluoxymesterone), ORETON METHYL™, TESTRED™ and VIRILON™ (methyltestosterone), and OXANDRIN™ (oxandrolone); testosterone transdermal systems such as TESTODERM™; androgen receptor antagonist and 5-alpha-reductase inhibitors such as ANDROCUR™ (cyproterone acetate), EULEXIN™ (flutamide), and PROSCAR™ (finasteride); adrenocorticotropic hormone preparations such as CORTROSYN™ (cosyntropin); adrenocortical steroids and their synthetic analogs such as ACLOVATE™ (alclometasone dipropionate), CYCLOCORT™ (amcinonide), BECLOVENT™ and VANCERIL™ (beclomethasone dipropionate), CELESTONE™ (betamethasone), BENISONE™ and UTICORT™ (betamethasone benzoate), DIPROSONE™ (betamethasone dipropionate), CELESTONE PHOSPHATE™ (betamethasone sodium phosphate), CELESTONE SOLUSPAN™ (betamethasone sodium phosphate and acetate), BETA-VAL™ and VALISONE™ (betamethasone valerate), TEMOVATE™ (clobetasol propionate), CLODERM™ (clocortolone pivalate), CORTEF™ and HYDROCORTONE™ (cortisol (hydrocortisone)), HYDROCORTONE ACETATE™ (cortisol (hydrocortisone) acetate), LOCOID™ (cortisol (hydrocortisone) butyrate), HYDROCORTONE PHOSPHATE™ (cortisol (hydrocortisone) sodium phosphate), A-HYDROCORT™ and SOLU CORTEF™ (cortisol (hydrocortisone) sodium succinate), WESTCORT™ (cortisol (hydrocortisone) valerate), CORTISONE ACETATE™ (cortisone acetate), DESOWEN™ and TRIDESILON™ (desonide), TOPICORT™ (desoximetasone), DECADRON™ (dexamethasone), DECADRON LA™ (dexamethasone acetate), DECADRON PHOSPHATE™ and HEXADROL PHOSPHATE™ (dexamethasone sodium phosphate), FLORONE™ and MAXIFLOR™ (diflorasone diacetate), FLORINEF ACETATE™ (fludrocortisone acetate), AEROBID™ and NASALIDE™ (flunisolide), FLUONID™ and SYNALAR™ (fluocinolone acetonide), LIDEX™ (fluocinonide), FLUOR-OP™ and FML™ (fluorometholone), CORDRAN™ (flurandrenolide), HALOG™ (halcinonide), HMS LIZUTFILM™ (medrysone), MEDROL™ (methylprednisolone), DEPO-MEDROL™ and MEDROL ACETATE™ (methylprednisone acetate), A-METHAPRED™ and SOLUMEDROL™ (methylprednisolone sodium succinate), ELOCON™ (mometasone furoate), HALDRONE™ (paramethasone acetate), DELTA-CORTEF™ (prednisolone), ECONOPRED™ (prednisolone acetate), HYDELTRASOL™ (prednisolone sodium phosphate), HYDELTRA-T.B.A™ (prednisolone tebutate), DELTASONE™ (prednisone), ARISTOCORT™ and KENACORT™ (triamcinolone), KENALOG™ (triamcinolone acetonide), ARISTOCORT™ and KENACORT DIACETATE™ (triamcinolone diacetate), and ARISTOSPAN™ (triamcinolone hexacetonide); inhibitors of biosynthesis and action of adrenocortical steroids such as CYTADREN™ (aminoglutethimide), NIZORAL™ (ketoconazole), MODRASTANE™ (trilostane), and METOPIRONE™ (metyrapone); bovine, porcine or human insulin or mixtures thereof; insulin analogs; recombinant human insulin such as HUMULIN™ and NOVOLIN™; oral hypoglycemic agents such as ORAMIDE™ and ORINASE™ (tolbutamide), DIABINESE™ (chlorpropamide), TOLAMIDE™ and TOLINASE™ (tolazamide), DYMELOR™ (acetohexamide), glibenclamide, MICRONASE™, DIBETA™ and GLYNASE™ (glyburide), GLUCOTROL™ (glipizide), and DIAMICRON™ (gliclazide), GLUCOPHAGE™ (metformin), ciglitazone, pioglitazone, and alpha-glucosidase inhibitors; bovine or porcine glucagon; somatostatins such as SANDOSTATIN™ (octreotide); and diazoxides such as PROGLYCEM™ (diazoxide).  
     [1070] In one embodiment, the Therapeutics of the invention are administered in combination with treatments for uterine motility disorders. Treatments for uterine motility disorders include, but are not limited to, estrogen drugs such as conjugated estrogens (e.g., PREMARIN® and ESTRATAB®), estradiols (e.g., CLIMARA® and ALORA®), estropipate, and chlorotrianisene; progestin drugs (e.g., AMEN® (medroxyprogesterone), MICRONOR® (norethidrone acetate), PROMETRIUM® progesterone, and megestrol acetate); and estrogen/progesterone combination therapies such as, for example, conjugated estrogens/medroxyprogesterone (e.g., PREMPRO™ and PREMPHASE®) and norethindrone acetate/ethinyl estsradiol (e.g., FEMHRT™).  
     [1071] In an additional embodiment, the Therapeutics of the invention are administered in combination with drugs effective in treating iron deficiency and hypochromic anemias, including but not limited to, ferrous sulfate (iron sulfate, FEOSOL™), ferrous fumarate (e.g., FEOSTAT™), ferrous gluconate (e.g., FERGON™), polysaccharide-iron complex (e.g., NIFEREX™), iron dextran injection (e.g., INFED™), cupric sulfate, pyroxidine, riboflavin, Vitamin B 12 , cyancobalamin injection (e.g., REDISOL™, RUBRAMIN PC™), hydroxocobalamin, folic acid (e.g., FOLVITE™), leucovorin (folinic acid, 5-CHOH4PteGlu, citrovorum factor) or WELLCOVORIN (Calcium salt of leucovorin), transferrin or ferritin.  
     [1072] In certain embodiments, the Therapeutics of the invention are administered in combination with agents used to treat psychiatric disorders. Psychiatric drugs that may be administered with the Therapeutics of the invention include, but are not limited to, antipsychotic agents (e.g., chlorpromazine, chlorprothixene, clozapine, fluphenazine, haloperidol, loxapine, mesoridazine, molindone, olanzapine, perphenazine, pimozide, quetiapine, risperidone, thioridazine, thiothixene, trifluoperazine, and triflupromazine), antimanic agents (e.g., carbamazepine, divalproex sodium, lithium carbonate, and lithium citrate), antidepressants (e.g., amitriptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin, fluvoxamine, fluoxetine, imipramine, isocarboxazid, maprotiline, mirtazapine, nefazodone, nortriptyline, paroxetine, phenelzine, protriptyline, sertraline, tranylcypromine, trazodone, trimipramine, and venlafaxine), antianxiety agents (e.g., alprazolam, buspirone, chlordiazepoxide, clorazepate, diazepam, halazepam, lorazepam, oxazepam, and prazepam), and stimulants (e.g., d-amphetamine, methylphenidate, and pemoline).  
     [1073] In other embodiments, the Therapeutics of the invention are administered in combination with agents used to treat neurological disorders. Neurological agents that may be administered with the Therapeutics of the invention include, but are not limited to, antiepileptic agents (e.g., carbamazepine, clonazepam, ethosuximide, phenobarbital, phenytoin, primidone, valproic acid, divalproex sodium, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, zonisamide, diazepam, lorazepam, and clonazepam), antiparkinsonian agents (e.g., levodopa/carbidopa, selegiline, amantidine, bromocriptine, pergolide, ropinirole, pramipexole, benztropine; biperiden; ethopropazine; procyclidine; trihexyphenidyl, tolcapone), and ALS therapeutics (e.g. riluzole).  
     [1074] In another embodiment, Therapeutics of the invention are administered in combination with vasodilating agents and/or calcium channel blocking agents. Vasodilating agents that may be administered with the Therapeutics of the invention include, but are not limited to, Angiotensin Converting Enzyme (ACE) inhibitors (e.g., papaverine, isoxsuprine, benazepril, captopril, cilazapril, enalapril, enalaprilat, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, spirapril, trandolapril, and nylidrin), and nitrates (e.g., isosorbide dinitrate, isosorbide mononitrate, and nitroglycerin). Examples of calcium channel blocking agents that may be administered in combination with the Therapeutics of the invention include, but are not limited to amlodipine, bepridil, diltiazem, felodipine, flunarizine, isradipine, nicardipine, nifedipine, nimodipine, and verapamil.  
     [1075] In additional embodiments, the Therapeutics of the invention are administered in combination with other therapeutic or prophylactic regimens, such as, for example, radiation therapy.  
     Example 14  
     Method of Treating Decreased Levels of the Polypeptide  
     [1076] The present invention relates to a method for treating an individual in need of an increased level of a polypeptide of the invention in the body comprising administering to such an individual a composition comprising a therapeutically effective amount of an agonist of the invention (including potypeptides of the invention). Moreover, it will be appreciated that conditions caused by a decrease in the standard or normal expression level of a polypeptide of the present invention in an individual can be treated by administering the agonist or antagonist of the present invention. Thus, the invention also provides a method of treatment of an individual in need of an increased level of the polypeptide comprising administering to such an individual a Therapeutic comprising an amount of the agonist or antagonist to increase the activity level of the polypeptide in such an individual.  
     [1077] For example, a patient with decreased levels of a polypeptide receives a daily dose 0.1-100 ug/kg of the agonist or antagonist for six consecutive days. The exact details of the dosing scheme, based on administration and formulation, are provided in Example 13.  
     Example 15  
     Method of Treating Increased Levels of the Polypeptide  
     [1078] The present invention also relates to a method of treating an individual in need of a decreased level of a polypeptide of the invention in the body comprising administering to such an individual a composition comprising a therapeutically effective amount of an antagonist of the invention (including polypeptides and antibodies of the invention).  
     [1079] In one example, antisense technology is used to inhibit production of a polypeptide of the present invention. This technology is one example of a method of decreasing levels of a polypeptide, due to a variety of etiologies, such as cancer.  
     [1080] For example, a patient diagnosed with abnormally increased levels of a polypeptide is administered intravenously antisense polynucleotides at 0.5, 1.0, 1.5, 2.0 and 3.0 mg/kg day for 21 days. This treatment is repeated after a 7-day rest period if the treatment was well tolerated. The formulation of the antisense polynucleotide is provided in Example 13.  
     Example 16  
     Method of Treatment Using Gene Therapy-Ex Vivo  
     [1081] One method of gene therapy transplants fibroblasts, which are capable of expressing a polypeptide, onto a patient. Generally, fibroblasts are obtained from a subject by skin biopsy. The resulting tissue is placed in tissue-culture medium and separated into small pieces. Small chunks of the tissue are placed on a wet surface of a tissue culture flask, approximately ten pieces are placed in each flask. The flask is turned upside down, closed tight and left at room temperature over night. After 24 hours at room temperature, the flask is inverted and the chunks of tissue remain fixed to the bottom of the flask and fresh media (e.g., Ham&#39;s F12 media, with 10% FBS, penicillin and streptomycin) is added. The flasks are then incubated at 37 degree C. for approximately one week.  
     [1082] At this time, fresh media is added and subsequently changed every several days. After an additional two weeks in culture, a monolayer of fibroblasts emerge. The monolayer is trypsinized and scaled into larger flasks.  
     [1083] pMV-7 (Kirschmeier, P. T. et al., DNA, 7:219-25 (1988)), flanked by the long terminal repeats of the Moloney murine sarcoma virus, is digested with EcoRI and HindIlI and subsequently treated with calf intestinal phosphatase. The linear vector is fractionated on agarose gel and purified, using glass beads.  
     [1084] The cDNA encoding a polypeptide of the present invention can be amplified using PCR primers which correspond to the 5′ and 3′ end sequences respectively as set forth in Example 1 using primers and having appropriate restriction sites and initiation/stop codons, if necessary. Preferably, the 5′ primer contains an EcoRI site and the 3′ primer includes a HindIIl site. Equal quantities of the Moloney murine sarcoma virus linear backbone and the amplified EcoRI and HindIII fragment are added together, in the presence of T4 DNA ligase. The resulting mixture is maintained under conditions appropriate for ligation of the two fragments. The ligation mixture is then used to transform bacteria HB101, which are then plated onto agar containing kanamycin for the purpose of confirming that the vector has the gene of interest properly inserted.  
     [1085] The amphotropic pA317 or GP+am12 packaging cells are grown in tissue culture to confluent density in Dulbecco&#39;s Modified Eagles Medium (DMEM) with 10% calf serum (CS), penicillin and streptomycin. The MSV vector containing the gene is then added to the media and the packaging cells transduced with the vector. The packaging cells now produce infectious viral particles containing the gene (the packaging cells are now referred to as producer cells).  
     [1086] Fresh media is added to the transduced producer cells, and subsequently, the media is harvested from a 10 cm plate of confluent producer cells. The spent media, containing the infectious viral particles, is filtered through a millipore filter to remove detached producer cells and this media is then used to infect fibroblast cells. Media is removed from a sub-confluent plate of fibroblasts and quickly replaced with the media from the producer cells. This media is removed and replaced with fresh media. If the titer of virus is high, then virtually all fibroblasts will be infected and no selection is required. If the titer is very low, then it is necessary to use a retroviral vector that has a selectable marker, such as neo or his. Once the fibroblasts have been efficiently infected, the fibroblasts are analyzed to determine whether protein is produced.  
     [1087] The engineered fibroblasts are then transplanted onto the host, either alone or after having been grown to confluence on cytodex 3 microcarrier beads.  
     Example 17  
     Gene Therapy Using Endogenous Genes Corresponding To Polynucleotides of the Invention  
     [1088] Another method of gene therapy according to the present invention involves operably associating the endogenous polynucleotide sequence of the invention with a promoter via homologous recombination as described, for example, in U.S. Pat. NO: 5,641,670, issued Jun. 24, 1997; International Publication NO: WO 96/29411, published Sep. 26, 1996; International Publication NO: WO 94/12650, published Aug. 4, 1994; Koller et al.,  Proc. Natl. Acad. Sci. USA,  86:8932-8935 (1989); and Zijlstra et al.,  Nature,  342:435-438 (1989). This method involves the activation of a gene which is present in the target cells, but which is not expressed in the cells, or is expressed at a lower level than desired.  
     [1089] Polynucleotide constructs are made which contain a promoter and targeting sequences, which are homologous to the 5′ non-coding sequence of endogenous polynucleotide sequence, flanking the promoter. The targeting sequence will be sufficiently near the 5′ end of the polynucleotide sequence so the promoter will be operably linked to the endogenous sequence upon homologous recombination. The promoter and the targeting sequences can be amplified using PCR. Preferably, the amplified promoter contains distinct restriction enzyme sites on the 5′ and 3′ ends. Preferably, the 3′ end of the first targeting sequence contains the same restriction enzyme site as the 5′ end of the amplified promoter and the 5′ end of the second targeting sequence contains the same restriction site as the 3′ end of the amplified promoter.  
     [1090] The amplified promoter and the amplified targeting sequences are digested with the appropriate restriction enzymes and subsequently treated with calf intestinal phosphatase. The digested promoter and digested targeting sequences are added together in the presence of T4 DNA ligase. The resulting mixture is maintained under conditions appropriate for ligation of the two fragments. The construct is size fractionated on an agarose gel, then purified by phenol extraction and ethanol precipitation.  
     [1091] In this Example, the polynucleotide constructs are administered as naked polynucleotides via electroporation. However, the polynucleotide constructs may also be administered with transfection-facilitating agents, such as liposomes, viral sequences, viral particles, precipitating agents, etc. Such methods of delivery are known in the art.  
     [1092] Once the cells are transfected, homologous recombination will take place which results in the promoter being operably linked to the endogenous polynucleotide sequence. This results in the expression of polynucleotide corresponding to the polynucleotide in the cell. Expression may be detected by immunological staining, or any other method known in the art.  
     [1093] Fibroblasts are obtained from a subject by skin biopsy. The resulting tissue is placed in DMEM+10% fetal calf serum. Exponentially growing or early stationary phase fibroblasts are trypsinized and rinsed from the plastic surface with nutrient medium. An aliquot of the cell suspension is removed for counting, and the remaining cells are subjected to centrifugation. The supernatant is aspirated and the pellet is resuspended in 5 ml of electroporation buffer (20 mM HEPES pH 7.3, 137 mM NaCl, 5 mM KCl, 0.7 mM Na 2  HPO 4,  6 mM dextrose). The cells are recentrifuged, the supernatant aspirated, and the cells resuspended in electroporation buffer containing 1 mg/ml acetylated bovine serum albumin. The final cell suspension contains approximately 3×10 6  cells/ml. Electroporation should be performed immediately following resuspension.  
     [1094] Plasmid DNA is prepared according to standard techniques. For example, to construct a plasmid for targeting to the locus corresponding to the polynucleotide of the invention, plasmid pUC18 (MBI Fermentas, Amherst, N.Y.) is digested with HindIII. The CMV promoter is amplified by PCR with an XbaI site on the 5′ end and a BamHI site on the 3′ end. Two non-coding sequences are amplified via PCR: one non-coding sequence (fragment 1) is amplified with a HindIII site at the 5′ end and an Xba site at the 3′ end; the other non-coding sequence (fragment 2) is amplified with a BamHI site at the 5′ end and a HindIII site at the 3′ end. The CMV promoter and the fragments (1 and 2) are digested with the appropriate enzymes (CMV promoter—XbaI and BamHI; fragment 1—XbaI; fragment 2—BamHI) and ligated together. The resulting ligation product is digested with HindIII, and ligated with the HindIII-digested pUC18 plasmid.  
     [1095] Plasmid DNA is added to a sterile cuvette with a 0.4 cm electrode gap (Bio-Rad). The final DNA concentration is generally at least 120 μg/ml. 0.5 ml of the cell suspension (containing approximately 1.5.×10 6  cells) is then added to the cuvette, and the cell suspension and DNA solutions are gently mixed. Electroporation is performed with a Gene-Pulser apparatus (Bio-Rad). Capacitance and voltage are set at 960 μF and 250-300 V, respectively. As voltage increases, cell survival decreases, but the percentage of surviving cells that stably incorporate the introduced DNA into their genome increases dramatically. Given these parameters, a pulse time of approximately 14-20 mSec should be observed.  
     [1096] Electroporated cells are maintained at room temperature for approximately 5 min, and the contents of the cuvette are then gently removed with a sterile transfer pipette. The cells are added directly to 10 ml of prewarmed nutrient media (DMEM with 15% calf serum) in a 10 cm dish and incubated at 37 degree C. The following day, the media is aspirated and replaced with 10 ml of fresh media and incubated for a further 16-24 hours.  
     [1097] The engineered fibroblasts are then injected into the host, either alone or after having been grown to confluence on cytodex 3 microcarrier beads. The fibroblasts now produce the protein product. The fibroblasts can then be introduced into a patient as described above.  
     Example 18  
     Method of Treatment Using Gene Therapy—In Vivo  
     [1098] Another aspect of the present invention is using in vivo gene therapy methods to treat disorders, diseases and conditions. The gene therapy method relates to the introduction of naked nucleic acid (DNA, RNA, and antisense DNA or RNA) sequences into an animal to increase or decrease the expression of the polypeptide. The polynucleotide of the present invention may be operatively linked to (i.e., associated with) a promoter or any other genetic elements necessary for the expression of the polypeptide by the target tissue. Such gene therapy and delivery techniques and methods are known in the art, see, for example, WO90/11092, WO98/11779; U.S. Pat. Nos. 5693622, 5705151, 5580859; Tabata et al., Cardiovasc. Res. 35(3):470-479 (1997); Chao et al., Pharmacol. Res. 35(6):517-522 (1997); Wolff, Neuromuscul. Disord. 7(5):314-318 (1997); Schwartz et al., Gene Ther. 3(5):405-411 (1996); Tsurumi et al., Circulation 94(12):3281-3290 (1996) (incorporated herein by reference).  
     [1099] The polynucleotide constructs may be delivered by any method that delivers injectable materials to the cells of an animal, such as, injection into the interstitial space of tissues (heart, muscle, skin, lung, liver, intestine and the like). The polynucleotide constructs can be delivered in a pharmaceutically acceptable liquid or aqueous carrier.  
     [1100] The term “naked” polynucleotide, DNA or RNA, refers to sequences that are free from any delivery vehicle that acts to assist, promote, or facilitate entry into the cell, including viral sequences, viral particles, liposome formulations, lipofectin or precipitating agents and the like. However, the polynucleotides of the present invention may also be delivered in liposome formulations (such as those taught in Felgner P. L. et al. (1995) Ann. NY Acad. Sci. 772:126-139 and Abdallah B. et al. (1995) Biol. Cell 85(1):1-7) which can be prepared by methods well known to those skilled in the art.  
     [1101] The polynucleotide vector constructs used in the gene therapy method are preferably constructs that will not integrate into the host genome nor will they contain sequences that allow for replication. Any strong promoter known to those skilled in the art can be used for driving the expression of DNA. Unlike other gene therapy techniques, one major advantage of introducing naked nucleic acid sequences into target cells is the transitory nature of the polynucleotide synthesis in the cells. Studies have shown that non-replicating DNA sequences can be introduced into cells to provide production of the desired polypeptide for periods of up to six months.  
     [1102] The polynucleotide construct can be delivered to the interstitial space of tissues within an animal, including muscle, skin, brain, lung, liver, spleen, bone marrow, thymus, heart, lymph, blood, bone, cartilage, pancreas, kidney, gall bladder, stomach, intestine, testis, ovary, uterus, rectum, nervous system, eye, gland, and connective tissue. Interstitial space of the tissues comprises the intercellular fluid, mucopolysaccharide matrix among the reticular fibers of organ tissues, elastic fibers in the walls of vessels or chambers, collagen fibers of fibrous tissues, or that same matrix within connective tissue ensheathing muscle cells or in the lacunae of bone. It is similarly the space occupied by the plasma of the circulation and the lymph fluid of the lymphatic channels. Delivery to the interstitial space of muscle tissue is preferred for the reasons discussed below. They may be conveniently delivered by injection into the tissues comprising these cells. They are preferably delivered to and expressed in persistent, non-dividing cells which are differentiated, although delivery and expression may be achieved in non-differentiated or less completely differentiated cells, such as, for example, stem cells of blood or skin fibroblasts. In vivo muscle cells are particularly competent in their ability to take up and express polynucleotides.  
     [1103] For the naked polynucleotide injection, an effective dosage amount of DNA or RNA will be in the range of from about 0.05 g/kg body weight to about 50 mg/kg body weight. Preferably the dosage will be from about 0.005 mg/kg to about 20 mg/kg and more preferably from about 0.05 mg/kg to about 5 mg/kg. Of course, as the artisan of ordinary skill will appreciate, this dosage will vary according to the tissue site of injection. The appropriate and effective dosage of nucleic acid sequence can readily be determined by those of ordinary skill in the art and may depend on the condition being treated and the route of administration. The preferred route of administration is by the parenteral route of injection into the interstitial space of tissues. However, other parenteral routes may also be used, such as, inhalation of an aerosol formulation particularly for delivery to lungs or bronchial tissues, throat or mucous membranes of the nose. In addition, naked polynucleotide constructs can be delivered to arteries during angioplasty by the catheter used in the procedure.  
     [1104] The dose response effects of injected polynucleotide in muscle in vivo is determined as follows. Suitable template DNA for production of mRNA coding for polypeptide of the present invention is prepared in accordance with a standard recombinant DNA methodology. The template DNA, which may be either circular or linear, is either used as naked DNA or complexed with liposomes. The quadriceps muscles of mice are then injected with various amounts of the template DNA.  
     [1105] Five to six week old female and male Balb/C mice are anesthetized by intraperitoneal injection with 0.3 ml of 2.5% Avertin. A 1.5 cm incision is made on the anterior thigh, and the quadriceps muscle is directly visualized. The template DNA is injected in 0.1 ml of carrier in a 1 cc syringe through a 27 gauge needle over one minute, approximately 0.5 cm from the distal insertion site of the muscle into the knee and about 0.2 cm deep. A suture is placed over the injection site for future localization, and the skin is closed with stainless steel clips.  
     [1106] After an appropriate incubation time (e.g., 7 days) muscle extracts are prepared by excising the entire quadriceps. Every fifth 15 um cross-section of the individual quadriceps muscles is histochemically stained for protein expression. A time course for protein expression may be done in a similar fashion except that quadriceps from different mice are harvested at different times. Persistence of DNA in muscle following injection may be determined by Southern blot analysis after preparing total cellular DNA and HIRT supernatants from injected and control mice. The results of the above experimentation in mice can be used to extrapolate proper dosages and other treatment parameters in humans and other animals using naked DNA.  
     Example 19  
     Transgenic Animals  
     [1107] The polypeptides of the invention can also be expressed in transgenic animals. Animals of any species, including, but not limited to, mice, rats, rabbits, hamsters, guinea pigs, pigs, micro-pigs, goats, sheep, cows and non-human primates, e.g., baboons, monkeys, and chimpanzees may be used to generate transgenic animals. In a specific embodiment, techniques described herein or otherwise known in the art, are used to express polypeptides of the invention in humans, as part of a gene therapy protocol.  
     [1108] Any technique known in the art may be used to introduce the transgene (i.e., polynucleotides of the invention) into animals to produce the founder lines of transgenic animals. Such techniques include, but are not limited to, pronuclear microinjection (Paterson et al., Appl. Microbiol. Biotechnol. 40:691-698 (1994); Carver et al., Biotechnology (NY) 11:1263-1270 (1993); Wright et al., Biotechnology (NY) 9:830-834 (1991); and Hoppe et al., U.S. Pat. No. 4,873,191 (1989)); retrovirus mediated gene transfer into germ lines (Van der Putten et al., Proc. Natl. Acad. Sci., USA 82:6148-6152 (1985)), blastocysts or embryos; gene targeting in embryonic stem cells (Thompson et al., Cell 56:313-321 (1989)); electroporation of cells or embryos (Lo, 1983, Mol Cell. Biol. 3:1803-1814 (1983)); introduction of the polynucleotides of the invention using a gene gun (see, e.g., Ulmer et al., Science 259:1745 (1993); introducing nucleic acid constructs into embryonic pleuripotent stem cells and transferring the stem cells back into the blastocyst; and sperm-mediated gene transfer (Lavitrano et al., Cell 57:717-723 (1989); etc. For a review of such techniques, see Gordon, “Transgenic Animals,” Intl. Rev. Cytol. 115:171-229 (1989), which is incorporated by reference herein in its entirety.  
     [1109] Any technique known in the art may be used to produce transgenic clones containing polynucleotides of the invention, for example, nuclear transfer into enucleated oocytes of nuclei from cultured embryonic, fetal, or adult cells induced to quiescence (Campell et al., Nature 380:64-66 (1996); Wilmut et al., Nature 385:810-813 (1997)).  
     [1110] The present invention provides for transgenic animals that carry the transgene in all their cells, as well as animals which carry the transgene in some, but not all their cells, i.e., mosaic animals or chimeric. The transgene may be integrated as a single transgene or as multiple copies such as in concatamers, e.g., head-to-head tandems or head-to-tail tandems. The transgene may also be selectively introduced into and activated in a particular cell type by following, for example, the teaching of Lasko et al. (Lasko et al., Proc. Natl. Acad. Sci. USA 89:6232-6236 (1992)). The regulatory sequences required for such a cell-type specific activation will depend upon the particular cell type of interest, and will be apparent to those of skill in the art. When it is desired that the polynucleotide transgene be integrated into the chromosomal site of the endogenous gene, gene targeting is preferred. Briefly, when such a technique is to be utilized, vectors containing some nucleotide sequences homologous to the endogenous gene are designed for the purpose of integrating, via homologous recombination with chromosomal sequences, into and disrupting the function of the nucleotide sequence of the endogenous gene. The transgene may also be selectively introduced into a particular cell type, thus inactivating the endogenous gene in only that cell type, by following, for example, the teaching of Gu et al. (Gu et al., Science 265:103-106 (1994)). The regulatory sequences required for such a cell-type specific inactivation will depend upon the particular cell type of interest, and will be apparent to those of skill in the art.  
     [1111] Once transgenic animals have been generated, the expression of the recombinant gene may be assayed utilizing standard techniques. Initial screening may be accomplished by Southern blot analysis or PCR techniques to analyze animal tissues to verify that integration of the transgene has taken place. The level of mRNA expression of the transgene in the tissues of the transgenic animals may also be assessed using techniques which include, but are not limited to, Northern blot analysis of tissue samples obtained from the animal, in situ hybridization analysis, and reverse transcriptase-PCR (rt-PCR). Samples of transgenic gene-expressing tissue may also be evaluated immunocytochemically or immunohistochemically using antibodies specific for the transgene product.  
     [1112] Once the founder animals are produced, they may be bred, inbred, outbred, or crossbred to produce colonies of the particular animal. Examples of such breeding strategies include, but are not limited to: outbreeding of founder animals with more than one integration site in order to establish separate linies; inbreeding of separate lines in order to produce compound transgenics that express the transgene at higher levels because of the effects of additive expression of each transgene; crossing of heterozygous transgenic animals to produce animals homozygous for a given integration site in order to both augment expression and eliminate the need for screening of animals by DNA analysis; crossing of separate homozygous lines to produce compound heterozygous or homozygous lines; and breeding to place the transgene on a distinct background that is appropriate for an experimental model of interest.  
     [1113] Transgenic animals of the invention have uses which include, but are not limited to, animal model systems useful in elaborating the biological function of potypeptides of the present invention, studying conditions and/or disorders associated with aberrant expression, and in screening for compounds effective in ameliorating such conditions and/or disorders.  
     Example 20  
     Knock-Out Animals  
     [1114] Endogenous gene expression can also be reduced by inactivating or “knocking out” the gene and/or its promoter using targeted homologous recombination. (See e.g., Smithies et al., Nature 317:230-234 (1985); Thomas &amp; Capecchi, Cell 51:503-512 (1987); Thompson et al., Cell 5:313-321 (1989); each of which is incorporated by reference herein in its entirety.) For example, a mutant, non-functional polynucleotide of the invention (or a completely unrelated DNA sequence) flanked by DNA homologous to the endogenous polynucleotide sequence (either the coding regions or regulatory regions of the gene) can be used, with or without a selectable marker and/or a negative selectable marker, to transfect cells that express polypeptides of the invention in vivo. In another embodiment, techniques known in the art are used to generate knockouts in cells that contain, but do not express the gene of interest. Insertion of the DNA construct, via targeted homologous recombination, results in inactivation of the targeted gene. Such approaches are particularly suited in research and agricultural fields where modifications to embryonic stem cells can be used to generate animal offspring with an inactive targeted gene (e.g., see Thomas &amp; Capecchi 1987 and Thompson 1989, supra). However this approach can be routinely adapted for use in humans provided the recombinant DNA constructs are directly administered or targeted to the required site in vivo using appropriate viral vectors that will be apparent to those of skill in the art.  
     [1115] In further embodiments of the invention, cells that are genetically engineered to express the polypeptides of the invention, or alternatively, that are genetically engineered not to express the polypeptides of the invention (e.g., knockouts) are administered to a patient in vivo. Such cells may be obtained from the patient (i.e., animal, including human) or an MHC compatible donor and can include, but are not limited to fibroblasts, bone marrow cells, blood cells (e.g., lymphocytes), adipocytes, muscle cells, endothelial cells etc. The cells are genetically engineered in vitro using recombinant DNA techniques to introduce the coding sequence of polypeptides of the invention into the cells, or alternatively, to disrupt the coding sequence and/or endogenous regulatory sequence associated with the polypeptides of the invention, e.g., by transduction (using viral vectors, and preferably vectors that integrate the transgene into the cell genome) or transfection procedures, including, but not limited to, the use of plasmids, cosmids, YACs, naked DNA, electroporation, liposomes, etc. The coding sequence of the polypeptides of the invention can be placed under the control of a strong constitutive or inducible promoter or promoter/enhancer to achieve expression, and preferably secretion, of the polypeptides of the invention. The engineered cells which express and preferably secrete the polypeptides of the invention can be introduced into the patient systemically, e.g., in the circulation, or intraperitoneally.  
     [1116] Alternatively, the cells can be incorporated into a matrix and implanted in the body, e.g., genetically engineered fibroblasts can be implanted as part of a skin graft; genetically engineered endothelial cells can be implanted as part of a lymphatic or vascular graft. (See, for example, Anderson et al. U.S. Pat. No. 5,399,349; and Mulligan &amp; Wilson, U.S. Pat. No. 5,460,959 each of which is incorporated by reference herein in its entirety).  
     [1117] When the cells to be administered are non-autologous or non-MHC compatible cells, they can be administered using well known techniques which prevent the development of a host immune response against the introduced cells. For example, the cells may be introduced in an encapsulated form which, while allowing for an exchange of components with the immediate extracetlular environment, does not allow the introduced cells to be recognized by the host immune system.  
     [1118] Transgenic and “knock-out” animals of the invention have uses which include, but are not limited to, animal model systems useful in elaborating the biological function of polypeptides of the present invention, studying conditions and/or disorders associated with aberrant expression, and in screening for compounds effective in ameliorating such conditions and/or disorders.  
     Example 21  
     Assays Detecting Stimulation or Inhibition of B cell Proliferation and Differentiation  
     [1119] Generation of functional humoral immune responses requires both soluble and cognate signaling between B-lineage cells and their microenvironment. Signals may impart a positive stimulus that allows a B-lineage cell to continue its programmed development, or a negative stimulus that instructs the cell to arrest its current developmental pathway. To date, numerous stimulatory and inhibitory signals have been found to influence B cell responsiveness including IL-2, IL-4, IL-5, IL-6, IL-7, IL10, IL-13, IL-14 and IL-15. Interestingly, these signals are by themselves weak effectors but can, in combination with various co-stimulatory proteins, induce activation, proliferation, differentiation, homing, tolerance and death among B cell populations.  
     [1120] One of the best studied classes of B-cell co-stimulatory proteins is the TNF-superfamily. Within this family CD40, CD27, and CD30 along with their respective ligands CD154, CD70, and CD153 have been found to regulate a variety of immune responses. Assays which allow for the detection and/or observation of the proliferation and differentiation of these B-cell populations and their precursors are valuable tools in determining the effects various proteins may have on these B-cell populations in terms of proliferation and differentiation. Listed below are two assays designed to allow for the detection of the differentiation, proliferation, or inhibition of B-cell populations and their precursors.  
     [1121] In vitro Assay—Agonists or antagonists of the invention can be assessed for its ability to induce activation, proliferation, differentiation or inhibition and/or death in B-cell populations and their precursors. The activity of the agonists or antagonists of the invention on purified human tonsillar B cells, measured qualitatively over the dose range from 0.1 to 10,000 ng/mL, is assessed in a standard B-lymphocyte co-stimulation assay in which purified tonsillar B cells are cultured in the presence of either formalin-fixed  Staphylococcus aureus  Cowan I (SAC) or immobilized anti-human IgM antibody as the priming agent. Second signals such as IL-2 and IL-15 synergize with SAC and IgM crosslinking to elicit B cell proliferation as measured by tritiated-thymidine incorporation. Novel synergizing agents can be readily identified using this assay. The assay involves isolating human tonsillar B cells by magnetic bead (MACS) depletion of CD3-positive cells. The resulting cell population is greater than 95% B cells as assessed by expression of CD45R(B220).  
     [1122] Various dilutions of each sample are placed into individual wells of a 96-well plate to which are added 10 5  B-cells suspended in culture medium (RPMI 1640 containing 10% FBS, 5×10 −5  M 2ME, 100 U/ml penicillin, 10 ug/ml streptomycin, and 10 −5  dilution of SAC) in a total volume of 150 ul. Proliferation or inhibition is quantitated by a 20 h pulse (luCi/well) with 3H-thymidine (6.7 Ci/mM) beginning 72 h post factor addition. The positive and negative controls are IL2 and medium respectively.  
     [1123] In Vivo Assay—BALB/c mice are injected (i.p.) twice per day with buffer only, or 2 mg/Kg of agonists or antagonists of the invention, or truncated forms thereof. Mice receive this treatment for 4 consecutive days, at which time they are sacrificed and various tissues and serum collected for analyses. Comparison of H&amp;E sections from normal spleens and spleens treated with agonists or antagonists of the invention identify the results of the activity of the agonists or antagonists on spleen cells, such as the diffusion of peri-arterial lymphatic sheaths, and/or significant increases in the nucleated cellularity of the red pulp regions, which may indicate the activation of the differentiation and proliferation of B-cell populations. Immunohistochemical studies using a B cell marker, anti-CD45R(B220), are used to determine whether any physiological changes to splenic cells, such as splenic disorganization, are due to increased B-cell representation within loosely defined B-cell zones that infiltrate established T-cell regions.  
     [1124] Flow cytometric analyses of the spleens from mice treated with agonist or antagonist is used to indicate whether the agonists or antagonists specifically increases the proportion of ThB+, CD45R(B220)dull B cells over that which is observed in control mice.  
     [1125] Likewise, a predicted consequence of increased mature B-cell representation in vivo is a relative increase in serum Ig titers. Accordingly, serum IgM and IgA levels are compared between buffer and agonists or antagonists-treated mice.  
     [1126] The studies described in this example tested activity of agonists or antagonists of the invention. However, one skilled in the art could easily modify the exemplified studies to test the activity of polynucleotides or polypeptides of the invention (e.g., gene therapy).  
     Example 22  
     T Cell Proliferation Assay  
     [1127] A CD3-induced proliferation assay is performed on PBMCs and is measured by the uptake of  3 H-thymidine. The assay is performed as follows. Ninety-six well plates are coated with 100 μl/well of mAb to CD3 (HIT3a, Pharmingen) or isotype-matched control mAb (B33.1) overnight at 4 degrees C. (1 μg/mnl in 0.05M bicarbonate buffer, pH 9.5), then washed three times with PBS. PBMC are isolated by F/H gradient centrifugation from human peripheral blood and added to quadruplicate wells (5×10 4 /well) of mAb coated plates in RPMI containing 10% FCS and P/S in the presence of varying concentrations of agonists or antagonists of the invention (total volume 200 ul). Relevant protein buffer and medium alone are controls. After 48 hr. culture at 37 degrees C., plates are spun for 2 min. at 1000 rpm and 100 μl of supernatant is removed and stored −20 degrees C. for measurement of IL-2 (or other cytokines) if effect on proliferation is observed. Wells are supplemented with 100 ul of medium containing 0.5 uCi of  3 H-thymidine and cultured at 37 degrees C. for 18-24 hr. Wells are harvested and incorporation of  3 H-thymidine used as a measure of proliferation. Anti-CD3 alone is the positive control for proliferation. IL-2 (100 U/ml) is also used as a control which enhances proliferation. Control antibody which does not induce proliferation of T cells is used as the negative control for the effects of agonists or antagonists of the invention.  
     [1128] The studies described in this example tested activity of agonists or antagonists of the invention. However, one skilled in the art could easily modify the exemplified studies to test the activity of polynucleotides or polypeptides of the invention (e.g., gene therapy).  
     Example 23  
     Effect of Agonists or Antagonists of the Invention on the Expression ofMHC Class II, Costimulatory and Adhesion Molecules and Cell Differentiation of Monocytes and Monocyte-Derived Human Dendritic Cells  
     [1129] Dendritic cells are generated by the expansion of proliferating precursors found in the peripheral blood: adherent PBMC or elutriated monocytic fractions are cultured for 7-10 days with GM-CSF (50 ng/ml) and IL-4 (20 ng/ml). These dendritic cells have the characteristic phenotype of immature cells (expression of CD1, CD80, CD86, CD40 and MHC class II antigens). Treatment with activating factors, such as TNF-α, causes a rapid change in surface phenotype (increased expression of MHC class I and II, costimulatory and adhesion molecules, downregulation of FCγRII, upregulation of CD83). These changes correlate with increased antigen-presenting capacity and with functional maturation of the dendritic cells.  
     [1130] FACS analysis of surface antigens is performed as follows. Cells are treated 1-3 days with increasing concentrations of agonist or antagonist of the invention or LPS (positive control), washed with PBS containing 1% BSA and 0.02 mM sodium azide, and then incubated with 1:20 dilution of appropriate FITC- or PE-labeled monoclonal antibodies for 30 minutes at 4 degrees C. After an additional wash, the labeled cells are analyzed by flow cytometry on a FACScan (Becton Dickinson).  
     [1131] Effect on the production of cytokines. Cytokines generated by dendritic cells, in particular IL-12, are important in the initiation of T-cell dependent immune responses. IL-12 strongly influences the development of Thl helper T-cell immune response, and induces cytotoxic T and NK cell function. An ELISA is used to measure the IL-12 release as follows. Dendritic cells (10 6 /ml) are treated with increasing concentrations of agonists or antagonists of the invention for 24 hours. LPS (100 ng/ml) is added to the cell culture as positive control. Supernatants from the cell cultures are then collected and analyzed for IL-12 content using commercial ELISA kit (e.g., R&amp;D Systems (Minneapolis, Minn.)). The standard protocols provided with the kits are used.  
     [1132] Effect on the expression of MHC Class II. costimulatory and adhesion molecules. Three major families of cell surface antigens can be identified on monocytes: adhesion molecules, molecules involved in antigen presentation, and Fc receptor. Modulation of the expression of MHC class II antigens and other costimulatory molecules, such as B7 and ICAM-1, may result in changes in the antigen presenting capacity of monocytes and ability to induce T cell activation. Increased expression of Fc receptors may correlate with improved monocyte cytotoxic activity, cytokine release and phagocytosis.  
     [1133] FACS analysis is used to examine the surface antigens as follows. Monocytes are treated 1-5 days with increasing concentrations of agonists or antagonists of the invention or LPS (positive control), washed with PBS containing 1% BSA and 0.02 mM sodium azide, and then incubated with 1:20 dilution of appropriate FITC- or PE-labeled monoclonal antibodies for 30 minutes at 4 degrees C. After an additional wash, the labeled cells are analyzed by flow cytometry on a FACScan (Becton Dickinson).  
     [1134] Monocyte activation and/or increased survival. Assays for molecules that activate (or alternatively, inactivate) monocytes and/or increase monocyte survival (or alternatively, decrease monocyte survival) are known in the art and may routinely be applied to determine whether a molecule of the invention functions as an inhibitor or activator of monocytes. Agonists or antagonists of the invention can be screened using the three assays described below. For each of these assays, Peripheral blood mononuclear cells (PBMC) are purified from single donor leukopacks (American Red Cross, Baltimore, Md.) by centrifugation through a Histopaque gradient (Sigma). Monocytes are isolated from PBMC by counterflow centrifugal elutriation.  
     [1135] Monocyte Survival Assay. Human peripheral blood monocytes progressively lose viability when cultured in absence of serum or other stimuli. Their death results from internally regulated processes (apoptosis). Addition to the culture of activating factors, such as TNF-alpha dramatically improves cell survival and prevents DNA fragmentation. Propidium iodide (PI) staining is used to measure apoptosis as follows. Monocytes are cultured for 48 hours in polypropylene tubes in serum-free medium (positive control), in the presence of 100 ng/ml TNF-alpha (negative control), and in the presence of varying concentrations of the compound to be tested. Cells are suspended at a, concentration of 2×10 6 /ml in PBS containing PI at a final concentration of 5 μg/ml, and then incubated at room temperature for 5 minutes before FACScan analysis. PI uptake has been demonstrated to correlate with DNA fragmentation in this experimental paradigm.  
     [1136] Effect on cytokine release. An important function of monocytes/macrophages is their regulatory activity on other cellular populations of the immune system through the release of cytokines after stimulation. An ELISA to measure cytokine release is performed as follows. Human monocytes are incubated at a density of 5×10 5  cells/ml with increasing concentrations of agonists or antagonists of the invention and under the same conditions, but in the absence of agonists or antagonists. For IL-12 production, the cells are primed overnight with IFN (100 U/ml) in the presence of agonist or antagonist of the invention. LPS (10 ng/ml) is then added. Conditioned media are collected after 24 h and kept frozen until use. Measurement of TNF-alpha, IL-10, MCP-1 and IL-8 is then performed using a commercially available ELISA kit (e.g., R&amp;D Systems (Minneapolis, Minn.)) and applying the standard protocols provided with the kit.  
     [1137] Oxidative burst. Purified monocytes are plated in 96-w plate at 2-1×10 5  cell/well. Increasing concentrations of agonists or antagonists of the invention are added to the wells in a total volume of 0.2 ml culture medium (RPMI 1640+10% FCS, glutamine and antibiotics). After 3 days incubation, the plates are centrifuged and the medium is removed from the wells. To the macrophage monolayers, 0.2 ml per well of phenol red solution (140 mM NaCl, 10 mM potassium phosphate buffer pH 7.0, 5.5 mM dextrose, 0.56 mM phenol red and 19 U/ml of HRPO) is added, together with the stimulant (200 nM PMA). The plates are incubated at 37° C. for 2 hours and the reaction is stopped by adding 20 μl 1N NaOH per well. The absorbance is read at 610 nm. To calculate the amount of H 2 O 2  produced by the macrophages, a standard curve of a H 2 O 2  solution of known molarity is performed for each experiment.  
     [1138] The studies described in this example tested activity of agonists or antagonists of the invention. However, one skilled in the art could easily modify the exemplified studies to test the activity of polynucleotides or polypeptides of the invention (e.g., gene therapy).  
     Example 24  
     Biological Effects of Agonists or Antagonists of the Invention  
     [1139] Astrocyte and Neuronal Assays  
     [1140] Agonists or antagonists of the invention, expressed in  Escherichia coli  and purified as described above, can be tested for activity in promoting the survival, neurite outgrowth, or phenotypic differentiation of cortical neuronal cells and for inducing the proliferation of glial fibrillary acidic protein immunopositive cells, astrocytes. The selection of cortical cells for the bioassay is based on the prevalent expression of FGF-1 and FGF-2 in cortical structures and on the previously reported enhancement of cortical neuronal survival resulting from FGF-2 treatment. A thymidine incorporation assay, for example, can be used to elucidate an agonist or antagonist of the invention&#39;s activity on these cells.  
     [1141] Moreover, previous reports describing the biological effects of FGF-2 (basic FGF) on cortical or hippocampal neurons in vitro have demonstrated increases in both neuron survival and neurite outgrowth (Walicke et al., “Fibroblast growth factor promotes survival of dissociated hippocampal neurons and enhances neurite extension.”  Proc. Natl. Acad. Sci. USA  83:3012-3016. (1986), assay herein incorporated by reference in its entirety). However, reports from experiments done on PC-12 cells suggest that these two responses are not necessarily synonymous and may depend on not only which FGF is being tested but also on which receptor(s) are expressed on the target cells. Using the primary cortical neuronal culture paradigm, the ability of an agonist or antagonist of the invention to induce neurite outgrowth can be compared to the response achieved with FGF-2 using, for example, a thymidine incorporation assay.  
     [1142] Fibroblast and Endothelial Cell Assays  
     [1143] Human lung fibroblasts are obtained from Clonetics (San Diego, Calif.) and maintained in growth media from Clonetics. Dermal microvascular endothelial cells are obtained from Cell Applications (San Diego, Calif.). For proliferation assays, the human lung fibroblasts and dermal microvascular endothelial cells can be cultured at 5,000 cells/well in a 96-well plate for one day in growth medium. The cells are then incubated for one day in 0.1% BSA basal medium. After replacing the medium with fresh 0.1% BSA medium, the cells are incubated with the test proteins for 3 days. Alamar Blue (Alamar Biosciences, Sacramento, Calif.) is added to each well to a final concentration of 10%. The cells are incubated for 4 hr. Cell viability is measured by reading in a CytoFluor fluorescence reader. For the PGE 2  assays, the human lung fibroblasts are cultured at 5,000 cells/well in a 96-well plate for one day. After a medium change to 0.1% BSA basal medium, the cells are incubated with FGF-2 or agonists or antagonists of the invention with or-without IL-1α for 24 hours. The supernatants are collected and assayed for PGE 2  by EIA kit (Cayman, Ann Arbor, Mich.). For the IL-6 assays, the human lung fibroblasts are cultured at 5,000 cells/well in a 96-well plate for one day. After a medium change to 0.1% BSA basal medium, the cells are incubated with FGF-2 or with or without agonists or antagonists of the invention IL-1α for 24 hours. The supernatants are collected and assayed for IL-6 by ELISA kit (Endogen, Cambridge, Mass.).  
     [1144] Human lung fibroblasts are cultured with FGF-2 or agonists or antagonists of the invention for 3 days in basal medium before the addition of Alamar Blue to assess effects on growth of the fibroblasts. FGF-2 should show a stimulation at 10-2500 ng/ml which can be used to compare stimulation with agonists or antagonists of the invention.  
     [1145] Parkinson Models.  
     [1146] The loss of motor function in Parkinson&#39;s disease is attributed to a deficiency of striatal dopamine resulting from the degeneration of the nigrostriatal dopaminergic projection neurons. An animal model for Parkinson&#39;s that has been extensively characterized involves the systemic administration of 1-methyl-4 phenyl 1,2,3,6-tetrahydropyridine (MPTP). In the CNS, MPTP is taken-up by astrocytes and catabolized by monoamine oxidase B to 1-methyl-4-phenyl pyridine (MPP + ) and released. Subsequently, MPP +  is actively accumulated in dopaminergic neurons by the high-affinity reuptake transporter for dopamine. MPP +  is then concentrated in mitochondria by the electrochemical gradient and selectively inhibits nicotidamide adenine disphosphate: ubiquinone oxidoreductionase (complex I), thereby interfering with electron transport and eventually generating oxygen radicals.  
     [1147] It has been demonstrated in tissue culture paradigms that FGF-2 (basic FGF) has trophic activity towards nigral dopaminergic neurons (Ferrari et al., Dev. Biol. 1989). Recently, Dr. Unsicker&#39;s group has demonstrated that administering FGF-2 in gel foam implants in the striatum results in the near complete protection of nigral dopaminergic neurons from the toxicity associated with MPTP exposure (Otto and Unsicker, J. Neuroscience, 1990).  
     [1148] Based on the data with FGF-2, agonists or antagonists of the invention can be evaluated to determine whether it has an action similar to that of FGF-2 in enhancing dopaminergic neuronal survival in vitro and it can also be tested in vivo for protection of dopaminergic neurons in the striatum from the damage associated with MPTP treatment. The potential effect of an agonist or antagonist of the invention is first examined in vitro in a dopaminergic neuronal cell culture paradigm. The cultures are prepared by dissecting the midbrain floor plate from gestation day 14 Wistar rat embryos. The tissue is dissociated with trypsin and seeded at a density of 200,000 cells/cm 2  on polyorthinine-laminin coated glass coverslips. The cells are maintained in Dulbecco&#39;s Modified Eagle&#39;s medium and F12 medium containing hormonal supplements (N1). The cultures are fixed with paraformaldehyde after 8 days in vitro and are processed for tyrosine hydroxylase, a specific marker for dopaminergic neurons, immunohistochemical staining. Dissociated cell cultures are prepared from embryonic rats. The culture medium is changed every third day and the factors are also added at that time.  
     [1149] Since the dopaminergic neurons are isolated from animals at gestation day 14, a developmental time which is past the stage when the dopaminergic precursor cells are proliferating, an increase in the number of tyrosine hydroxylase immunopositive neurons would represent an increase in the number of dopaminergic neurons surviving in vitro. Therefore, if an agonist or antagonist of the invention acts to prolong the survival of dopaminergic neurons, it would suggest that the agonist or antagonist may be involved in Parkinson&#39;s Disease.  
     [1150] The studies described in this example tested activity of agonists or antagonists of the invention. However, one skilled in the art could easily modify the exemplified studies to test the activity of polynucleotides or polypeptides of the invention (e.g., gene therapy).  
     Example 25  
     The Effect of Agonists or Antagonists of the Invention on the Growth of Vascular Endothelial Cells  
     [1151] On day 1, human umbilical vein endothelial cells (HUVEC) are seeded at 2-5×10 4  cells/35 mm dish density in M199 medium containing 4% fetal bovine serum (FBS), 16 units/ml heparin, and 50 units/ml endothelial cell growth supplements (ECGS, Biotechnique, Inc.). On day 2, the medium is replaced with M199 containing 10% FBS, 8 units/ml heparin. An agonist or antagonist of the invention, and positive controls, such as VEGF and basic FGF (bFGF) are added, at varying concentrations. On days 4 and 6, the medium is replaced. On day 8, cell number is determined with a Coulter Counter.  
     [1152] An increase in the number of HUVEC cells indicates that the compound of the invention may proliferate vascular endothelial cells, while a decrease in the number of HUVEC cells indicates that the compound of the invention inhibits vascular endothelial cells.  
     [1153] The studies described in this example tested activity of a polypeptide of the invention. However, one skilled in the art could easily modify the exemplified studies to test the activity of polynucleotides (e.g., gene therapy), agonists, and/or antagonists of the invention.  
     Example 26  
     Rat Corneal Wound Healing Model  
     [1154] This animal model shows the effect of an agonist or antagonist of the invention on neovascularization. The experimental protocol includes:  
     [1155] Making a 1-1.5 mm long incision from the center of cornea into the stromal layer.  
     [1156] Inserting a spatula below the lip of the incision facing the outer corner of the eye.  
     [1157] Making a pocket (its base is 1-1.5 mm form the edge of the eye).  
     [1158] Positioning a pellet, containing 50 ng-5 ug of an agonist or antagonist of the invention, within the pocket.  
     [1159] Treatment with an agonist or antagonist of the invention can also be applied topically to the corneal wounds in a dosage range of 20 mg-500mg (daily treatment for five days).  
     [1160] The studies described in this example tested activity of agonists or antagonists of the invention. However, one skilled in the art could easily modify the exemplified studies to test the activity of polynucleotides or polypeptides of the invention (e.g., gene therapy).  
     Example 27  
     Diabetic Mouse and Glucocorticoid-Impaired Wound Healing Models  
     [1161] Diabetic db+/db+Mouse Model.  
     [1162] To demonstrate that an agonist or antagonist of the invention accelerates the healing process, the genetically diabetic mouse model of wound healing is used. The full thickness wound healing model in the db+/db+ mouse is a well characterized, clinically relevant and reproducible model of impaired wound healing. Healing of the diabetic wound is dependent on formation of granulation tissue and re-epithelialization rather than contraction (Gartner, M. H. et al.,  J. Surg. Res.  52:389 (1992); Greenhalgh, D. G. et al.,  Am. J. Pathol.  136:1235 (1990)).  
     [1163] The diabetic animals have many of the characteristic features observed in Type II diabetes mellitus. Homozygous (db+/db+) mice are obese in comparison to their normal heterozygous (db+/+m) littermates. Mutant diabetic (db+/db+) mice have a single autosomal recessive mutation on chromosome 4 (db+) (Coleman et al.  Proc. Natl. Acad. Sci. USA  77:283-293 (1982)). Animals show polyphagia, polydipsia and polyuria. Mutant diabetic mice (db+/db+) have elevated blood glucose, increased or normal insulin levels, and suppressed cell-mediated immunity (Mandel et al.,  J. Immunol.  120:1375 (1978); Debray-Sachs, M. et al.,  Clin. Exp. Immunol.  51(1):1-7 (1983); Leiter et al.,  Am. J. of Pathol.  114:46-55 (1985)). Peripheral neuropathy, myocardial complications, and microvascular lesions, basement membrane thickening and glomerular filtration abnormalities have been described in these animals (Norido, F. et al.,  Exp. Neurol.  83(2):221-232 (1984); Robertson et al.,  Diabetes  29(1):60-67 (1980); Giacomelli et al.,  Lab Invest.  40(4):460-473 (1979); Coleman, D. L.,  Diabetes  31 ( Suppl ):1-6 (1982)). These homozygous diabetic mice develop hyperglycemia that is resistant to insulin analogous to human type II diabetes (Mandel et al.,  J. Immunol.  120:1375-1377 (1978)).  
     [1164] The characteristics observed in these animals suggests that healing in this model may be similar to the healing observed in human diabetes (Greenhalgh, et al.,  Am. J. of Pathol.  136:1235-1246 (1990)).  
     [1165] Genetically diabetic female C57BL/KsJ (db+/db+) mice and their non-diabetic (db+/+m) heterozygous littermates are used in this study (Jackson Laboratories). The animals are purchased at 6 weeks of age and are 8 weeks old at the beginning of the study. Animals are individually housed and received food and water ad libitum. All manipulations are performed using aseptic techniques. The experiments are conducted according to the rules and guidelines of Human Genome Sciences, Inc. Institutional Animal Care and Use Committee and the Guidelines for the Care and Use of Laboratory Animals.  
     [1166] Wounding protocol is performed according to previously reported methods (Tsuboi, R. and Rifkin, D. B.,  J. Exp. Med.  172:245-251 (1990)). Briefly, on the day of wounding, animals are anesthetized with an intraperitoneal injection of Avertin (0.01 mg/mL), 2,2,2-tribromoethanol and 2-methyl-2-butanol dissolved in deionized water. The dorsal region of the animal is shaved and the skin washed with 70% ethanol solution and iodine. The surgical area is dried with sterile gauze prior to wounding. An 8 mm full-thickness wound is then created using a Keyes tissue punch. Immediately following wounding, the surrounding skin is gently stretched to eliminate wound expansion. The wounds are left open for the duration of the experiment. Application of the treatment is given topically for 5 consecutive days commencing on the day of wounding. Prior to treatment, wounds are gently cleansed with sterile saline and gauze sponges.  
     [1167] Wounds are visually examined and photographed at a fixed distance at the day of surgery and at two day intervals thereafter. Wound closure is determined by daily measurement on days 1-5 and on day 8. Wounds are measured horizontally and vertically using a calibrated Jameson caliper. Wounds are considered healed if granulation tissue is no longer visible and the wound is covered by a continuous epithelium.  
     [1168] An agonist or antagonist of the invention is administered using at a range different doses, from 4 mg to 500 mg per wound per day for 8 days in vehicle. Vehicle control groups received 50 mL of vehicle solution.  
     [1169] Animals are euthanized on day 8 with an intraperitoneal injection of sodium pentobarbital (300 mg/kg). The wounds and surrounding skin are then harvested for histology and immunohistochemistry. Tissue specimens are placed in 10% neutral buffered formalin in tissue cassettes between biopsy sponges for further processing.  
     [1170] Three groups of 10 animals each (5 diabetic and 5 non-diabetic controls) are evaluated: 1) Vehicle placebo control, 2) untreated group, and 3) treated group.  
     [1171] Wound closure is analyzed by measuring the area in the vertical and horizontal axis and obtaining the total square area of the wound. Contraction is then estimated by establishing the differences between the initial wound area (day 0) and that of post treatment (day 8). The wound area on day 1 is 64 mm 2 , the corresponding size of the dermal punch. Calculations are made using the following formula:  
     [Open area on day 8]−[Open area on day 1]/[Open area on day 1] 
     [1172] Specimens are fixed in 10% buffered formalin and paraffin embedded blocks are sectioned perpendicular to the wound surface (5 mm) and cut using a Reichert-Jung microtome. Routine hematoxylin-eosin (H&amp;E) staining is performed on cross-sections of bisected wounds. Histologic examination of the wounds are used to assess whether the healing process and the morphologic appearance of the repaired skin is altered by treatment with an agonist or antagonist of the invention. This assessment included verification of the presence of cell accumulations inflammatory cells, capillaries, fibroblasts, reepithelialization and epidermal maturity (Greenhalgh, D. G. et al.,  Am. J. Pathol.  136:1235 (1990)). A calibrated lens micrometer is used by a blinded observer.  
     [1173] Tissue sections are also stained immunohistochemically with a polyclonal rabbit anti-human keratin antibody using ABC Elite detection system. Human skin is used as a positive tissue control while non-immune IgG is used as a negative control. Keratinocyte growth is determined by evaluating the extent of reepithelialization of the wound using a calibrated lens micrometer.  
     [1174] Proliferating cell nuclear antigen/cyclin (PCNA) in skin specimens is demonstrated by using anti-PCNA antibody (1:50) with an ABC Elite detection system. Human colon cancer served as a positive tissue control and human brain tissue is used as a negative tissue control. Each specimen included a section with omission of the primary antibody and substitution with non-immune mouse IgG. Ranking of these sections is based on the extent of proliferation on a scale of 0-8, the lower side of the scale reflecting slight proliferation to the higher side reflecting intense proliferation.  
     [1175] Experimental data are analyzed using an unpaired t test. A p value of &lt;0.05 is considered significant.  
     [1176] Steroid Impaired Rat Model  
     [1177] The inhibition of wound healing by steroids has been well documented in various in vitro and in vivo systems (Wahl, Glucocorticoids and Wound healing. In: Anti-Inflammatory Steroid Action: Basic and Clinical Aspects. 280-302 (1989); Wahlet al.,  J. Immunol.  115: 476-481 (1975); Werb et al.,  J. Exp. Med.  147:1684-1694 (1978)). Glucocorticoids retard wound healing by inhibiting angiogenesis, decreasing vascular permeability (Ebert et al.,  An. Intern. Med.  37:701-705 (1952)), fibroblast proliferation, and collagen synthesis (Beck et al.,  Growth Factors.  5: 295-304 (1991); Haynes et al.,  J. Clin. Invest.  61: 703-797 (1978)) and producing a transient reduction of circulating monocytes (Haynes et al.,  J. Clin. Invest.  61: 703-797 (1978); Wahl, “Glucocorticoids and wound healing”, In: Antiinflammatory Steroid Action: Basic and Clinical Aspects, Academic Press, New York, pp. 280-302 (1989)). The systemic administration of steroids to impaired wound healing is a well establish phenomenon in rats (Beck et al.,  Growth Factors.  5: 295-304 (1991); Haynes et al.,  J. Clin. Invest.  61: 703-797 (1978); Wahl, “Glucocorticoids and wound healing”, In: Antiinflammatory Steroid Action: Basic and Clinical Aspects, Academic Press, New York, pp. 280-302 (1989); Pierce et al.,  Proc. Natl. Acad. Sci. USA  86: 2229-2233 (1989)).  
     [1178] To demonstrate that an agonist or antagonist of the invention can accelerate the healing process, the effects of multiple topical applications of the agonist or antagonist on full thickness excisional skin wounds in rats in which healing has been impaired by the systemic administration of methylprednisolone is assessed.  
     [1179] Young adult male Sprague Dawley rats weighing 250-300 g (Charles River Laboratories) are used in this example. The animals are purchased at 8 weeks of age and are 9 weeks old at the beginning of the study. The healing response of rats is impaired by the systemic administration of methylprednisolone (17 mg/kg/rat intramuscularly) at the time of wounding. Animals are individually housed and received food and water ad libitum. All manipulations are performed using aseptic techniques. This study is conducted according to the rules and guidelines of Human Genome Sciences, Inc. Institutional Animal Care and Use Committee and the Guidelines for the Care and Use of Laboratory Animals.  
     [1180] The wounding protocol is followed according to section A, above. On the day of wounding, animals are anesthetized with an intramuscular injection of ketamine (50 mg/kg) and xylazine (5 mg/kg). The dorsal region of the animal is shaved and the skin washed with 70% ethanol and iodine solutions. The surgical area is dried with sterile gauze prior to wounding. An 8 mm full-thickness wound is created using a Keyes tissue punch. The wounds are left open for the duration of the experiment. Applications of the testing materials are given topically once a day for 7 consecutive days commencing on the day of wounding and subsequent to methylprednisolone administration. Prior to treatment, wounds are gently cleansed with sterile saline and gauze sponges.  
     [1181] Wounds are visually examined and photographed at a fixed distance at the day of wounding and at the end of treatment. Wound closure is determined by daily measurement on days 1-5 and on day 8. Wounds are measured horizontally and vertically using a calibrated Jameson caliper. Wounds are considered healed if granulation tissue is no longer visible and the wound is covered by a continuous epithelium.  
     [1182] The agonist or antagonist of the invention is administered using at a range different doses, from 4 mg to 500 mg per wound per day for 8 days in vehicle. Vehicle control groups received 50 mL of vehicle solution.  
     [1183] Animals are euthanized on day 8 with an intraperitoneal injection of sodium pentobarbital (300 mg/kg). The wounds and surrounding skin are then harvested for histology. Tissue specimens are placed in 10% neutral buffered formalin in tissue cassettes between biopsy sponges for further processing.  
     [1184] Three groups of 10 animals each (5 with methylprednisolone and 5 without glucocorticoid) are evaluated: 1) Untreated group 2) Vehicle placebo control 3) treated groups.  
     [1185] Wound closure is analyzed by measuring the area in the vertical and horizontal axis and obtaining the total area of the wound. Closure is then estimated by establishing the differences between the initial wound area (day 0) and that of post treatment (day 8). The wound area on day I is 64 mm 2 , the corresponding size of the dermal punch. Calculations are made using the following formula:  
     [Open area on day 8]−[Open area on day 1]/[Open area on day 1] 
     [1186] Specimens are fixed in 10% buffered formalin and paraffin embedded blocks are sectioned perpendicular to the wound surface (5 mm) and cut using an Olympus microtome. Routine hematoxylin-eosin (H&amp;E) staining is performed on cross-sections of bisected wounds. Histologic examination of the wounds allows assessment of whether the healing process and the morphologic appearance of the repaired skin is improved by treatment with an agonist or antagonist of the invention. A calibrated lens micrometer is used by a blinded observer to determine the distance of the wound gap.  
     [1187] Experimental data are analyzed using an unpaired t test. A p value of &lt;0.05 is considered significant.  
     [1188] The studies described in this example tested activity of agonists or antagonists of the invention. However, one skilled in the art could easily modify the exemplified studies to test the activity of polynucleotides or polypeptides of the invention (e.g., gene therapy).  
     Example 28  
     Lymphadema Animal Model  
     [1189] The purpose of this experimental approach is to create an appropriate and consistent lymphedema model for testing the therapeutic effects of an agonist or antagonist of the invention in lymphangiogenesis and re-establishment of the lymphatic circulatory system in the rat hind limb. Effectiveness is measured by swelling volume of the affected limb, quantification of the amount of lymphatic vasculature, total blood plasma protein, and histopathology. Acute lymphedema is observed for 7-10 days. Perhaps more importantly, the chronic progress of the edema is followed for up to 3-4 weeks.  
     [1190] Prior to beginning surgery, blood sample is drawn for protein concentration analysis. Male rats weighing approximately ˜350 g are dosed with Pentobarbital. Subsequently, the right legs are shaved from knee to hip. The shaved area is swabbed with gauze soaked in 70% EtOH. Blood is drawn for serum total protein testing. Circumference and volumetric measurements are made prior to injecting dye into paws after marking 2 measurement levels (0.5 cm above heel, at mid-pt of dorsal paw). The intradermal dorsum of both right and left paws are injected with 0.05 ml of 1% Evan&#39;s Blue. Circumference and volumetric measurements are then made following injection of dye into paws.  
     [1191] Using the knee joint as a landmark, a mid-leg inguinal incision is made circumferentially allowing the femoral vessels to be located. Forceps and hemostats are used to dissect and separate the skin flaps. After locating the femoral vessels, the lymphatic vessel that runs along side and underneath the vessel(s) is located. The main lymphatic vessels in this area are then electrically coagulated or suture ligated.  
     [1192] Using a microscope, muscles in back of the leg (near the semitendinosis and adductors) are bluntly dissected. The popliteal lymph node is then located. The 2 proximal and 2 distal lymphatic vessels and distal blood supply of the popliteal node are then ligated by suturing. The popliteal lymph node, and any accompanying adipose tissue, is then removed by cutting connective tissues.  
     [1193] Care is taken to control any mild bleeding resulting from this procedure. After lymphatics are occluded, the skin flaps are sealed by using liquid skin (Vetbond) (A J Buck). The separated skin edges are sealed to the underlying muscle tissue while leaving a gap of ˜0.5 cm around the leg. Skin also may be anchored by suturing to underlying muscle when necessary.  
     [1194] To avoid infection, animals are housed individually with mesh (no bedding). Recovering animals are checked daily through the optimal edematous peak, which typically occurred by day 5-7. The plateau edematous peak are then observed. To evaluate the intensity of the lymphedema, the circumference and volumes of 2 designated places on each paw before operation and daily for 7 days are measured. The effect of plasma proteins on lymphedema is determined and whether protein analysis is a useful testing perimeter is also investigated. The weights of both control and edematous limbs are evaluated at 2 places. Analysis is performed in a blind manner.  
     [1195] Circumference Measurements: Under brief gas anesthetic to prevent limb movement, a cloth tape is used to measure limb circumference. Measurements are done at the ankle bone and dorsal paw by 2 different people and those 2 readings are averaged. Readings are taken from both control and edematous limbs.  
     [1196] Volumetric Measurements: On the day of surgery, animals are anesthetized with Pentobarbital and are tested prior to surgery. For daily volumetrics animals are under brief halothane anesthetic (rapid immobilization and quick recovery), and both legs are shaved and equally marked using waterproof marker on legs. Legs are first dipped in water, then dipped into instrument to each marked level, then measured by Buxco edema software(Chen/Victor). Data is recorded by one person, while the other is dipping the limb to marked area.  
     [1197] Blood-plasma protein measurements: Blood is drawn, spun, and serum separated prior to surgery and then at conclusion for total protein and Ca2 +  comparison.  
     [1198] Limb Weight Comparison: After drawing blood, the animal is prepared for tissue collection. The limbs are amputated using a quillitine, then both experimental and control legs are cut at the ligature and weighed. A second weighing is done as the tibio-cacaneal joint is disarticulated and the foot is weighed.  
     [1199] Histological Preparations: The transverse muscle located behind the knee (popliteal) area is dissected and arranged in a metal mold, filled with freezegel, dipped into cold methylbutane, placed into labeled sample bags at −80EC until sectioning. Upon sectioning, the muscle is observed under fluorescent microscopy for lymphatics..  
     [1200] The studies described in this example tested activity of agonists or antagonists of the invention. However, one skilled in the art could easily modify the exemplified studies to test the activity of polynucleotides or polypeptides of the invention (e.g., gene therapy).  
     Example 29  
     Suppression of TNF Alpha-induced Adhesion Molecule Expression by a Agonist or Antagonist of the Invention  
     [1201] The recruitment of lymphocytes to areas of inflammation and angiogenesis involves specific receptor-ligand interactions between cell surface adhesion molecules (CAMs) on lymphocytes and the vascular endothelium. The adhesion process, in both normal and pathological settings, follows a multi-step cascade that involves intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and endothelial leukocyte adhesion molecule-1 (E-selectin) expression on endothelial cells (EC). The expression of these molecules and others on the vascular endothelium determines the efficiency with which leukocytes may adhere to the local vasculature and extravasate into the local tissue during the development of an inflammatory response. The local concentration of cytokines and growth factor participate in the modulation of the expression of these CAMs.  
     [1202] Tumor necrosis factor alpha (TNF-a), a potent proinflammatory cytokine, is a stimulator of all three CAMs on endothelial cells and may be involved in a wide variety of inflammatory responses, often resulting in a pathological outcome.  
     [1203] The potential of an agonist or antagonist of the invention to mediate a suppression of TNF-a induced CAM expression can be examined. A modified ELISA assay which uses ECs as a solid phase absorbent is employed to measure the amount of CAM expression on TNF-a treated ECs when co-stimulated with a member of the FGF family of proteins.  
     [1204] To perform the experiment, human umbilical vein endothelial cell (HUVEC) cultures are obtained from pooled cord harvests and maintained in growth medium (EGM-2; Clonetics, San Diego, Calif.) supplemented with 10% FCS and 1% penicillin/streptomycin in a 37 degree C. humidified incubator containing 5% CO 2 . HUVECs are seeded in 96-well plates at concentrations of 1×10 4  cells/well in EGM medium at 37 degree C. for 18-24 hrs or until confluent. The monolayers are subsequently washed 3 times with a serum-free solution of RPMI-1640 supplemented with 100 U/ml penicillin and 100 mg/ml streptomycin, and treated with a given cytokine and/or growth factor(s) for 24 h at 37 degree C. Following incubation, the cells are then evaluated for CAM expression.  
     [1205] Human Umbilical Vein Endothelial cells (HUVECs) are grown in a standard 96 well plate to confluence. Growth medium is removed from the cells and replaced with 90 ul of 199 Medium (10% FBS). Samples for testing and positive or negative controls are added to the plate in triplicate (in 10 ul volumes). Plates are incubated at 37 degree C. for either 5 h (selectin and integrin expression) or 24 h (integrin expression only). Plates are aspirated to remove medium and 100 μl of 0.1% paraformaldehyde-PBS(with Ca++ and Mg++) is added to each well. Plates are held at 4° C. for 30 min.  
     [1206] Fixative is then removed from the wells and wells are washed 1× with PBS(+Ca,Mg)+0.5% BSA and drained. Do not allow the wells to dry. Add 10 μl of diluted primary antibody to the test and control wells. Anti-ICAM-1-Biotin, Anti-VCAM-1-Biotin and Anti-E-selectin-Biotin are used at a concentration of 10 μg/ml (1:10 dilution of 0.1 mg/ml stock antibody). Cells are incubated at 37° C. for 30 min. in a humidified environment. Wells are washed ×3 with PBS(+Ca,Mg)+0.5% BSA.  
     [1207] Then add 20 μl of diluted ExtrAvidin-Alkaline Phosphotase (1:5,000 dilution) to each well and incubated at 37° C. for 30 min. Wells are washed ×3 with PBS(+Ca,Mg)+0.5% BSA. 1 tablet of p-Nitrophenol Phosphate pNPP is dissolved in 5 ml of glycine buffer (pH 10.4). 100 μl of pNPP substrate in glycine buffer is added to each test well. Standard wells in triplicate are prepared from the working dilution of the ExtrAvidin-Alkaline Phosphotase in glycine buffer: 1:5,000 (10 0 )&gt;10 −0.5 &gt;10 −1 &gt;10 −15 0.5 μl of each dilution is added to triplicate wells and the resulting AP content in each well is 5.50 ng, 1.74 ng, 0.55 ng, 0.18 ng. 100 μl of pNNP reagent must then be added to each of the standard wells. The plate must be incubated at 37° C. for 4 h. A volume of 50 μl of 3M NaOH is added to all wells. The results are quantified on a plate reader at 405 nm. The background subtraction option is used on blank wells filled with glycine buffer only. The template is set up to indicate the concentration of AP-conjugate in each standard well [5.50 ng; 1.74 ng; 0.55 ng; 0.18 ng]. Results are indicated as amount of bound AP-conjugate in each sample.  
     [1208] The studies described in this example tested activity of agonists or antagonists of the invention. However, one skilled in the art could easily modify the exemplified studies to test the activity of polynucleotides or polypeptides of the invention (e.g., gene therapy).  
     Example 30  
     Production Of Polypeptide of the Invention For High-Throughput Screening Assays  
     [1209] The following protocol produces a supernatant containing polypeptide of the present invention to be tested. This supernatant can then be used in the Screening Assays described in Examples 32-41.  
     [1210] First, dilute Poly-D-Lysine (644 587 Boehringer-Mannheim) stock solution (1 mg/ml in PBS) 1:20 in PBS (w/o calcium or magnesium 17-516F Biowhittaker) for a working solution of 50 ug/ml. Add 200 ul of this solution to each well (24 well plates) and incubate at RT for 20 minutes. Be sure to distribute the solution over each well (note: a 12-channel pipetter may be used with tips on every other-channel). Aspirate off the Poly-D-Lysine solution and rinse with 1 ml PBS (Phosphate Buffered Saline). The PBS should remain in the well until just prior to plating the cells and plates may be poly-lysine coated in advance for up to two weeks.  
     [1211] Plate 293T cells (do not carry cells past P+20) at 2×10 5  cells/well in 0.5 ml DMEM(Dulbecco&#39;s Modified Eagle Medium)(with 4.5 G/L glucose and L-glutamine (12-604F Biowhittaker))/10% heat inactivated FBS(14-503F Biowhittaker)/1× Penstrep(17-602E Biowhittaker). Let the cells grow overnight.  
     [1212] The next day, mix together in a sterile solution basin: 300 ul Lipofectamine (18324-012 Gibco/BRL) and 5 ml Optimem I (31985070 Gibco/BRL)/96-well plate. With a small volume multi-channel pipetter, aliquot approximately 2 ug of an expression vector containing a polynucleotide insert, produced by the methods described in Examples 8-10, into an appropriately labeled 96-well round bottom plate. With a multi-channel pipetter, add 50 ul of the Lipofectamine/Optimem I mixture to each well. Pipette up and down gently to mix. Incubate at RT 15-45 minutes. After about 20 minutes, use a multi-channel pipetter to add 150 ul Optimem I to each well. As a control, one plate of vector DNA lacking an insert should be transfected with each set of transfections.  
     [1213] Preferably, the transfection should be performed by tag-teaming the following tasks. By tag-teaming, hands on time is cut in half, and the cells do not spend too much time on PBS. First, person A aspirates off the media from four 24-well plates of cells, and then person B rinses each well with 0.5-1 ml PBS. Person A then aspirates off PBS rinse, and person B, using a 12-channel pipetter with tips on every other channel, adds the 200 ul of DNA/Lipofectamine/Optimem I complex to the odd wells first, then to the even wells, to each row on the 24-well plates. Incubate at 37 degree C. for 6 hours.  
     [1214] While cells are incubating, prepare appropriate media, either 1% BSA in DMEM with 1× penstrep, or HGS CHO-5 media (116.6 mg/L of CaCl2 (anhyd); 0.00130 mg/L CuSO 4 —5H 2 O; 0.050 mg/L of Fe(NO 3 ) 3 —9H 2 O; 0.417 mg/L of FeSO 4 —7H 2 O; 311.80 mg/L of Kcl; 28.64 mg/L of MgCl 2 ; 48.84 mg/L of MgSO 4 ; 6995.50 mg/L of NaCl; 2400.0 mg/L of NaHCO 3 ; 62.50 mg/L of NaH 2 PO 4 —H 2 O; 71.02 mg/L of Na 2 HPO4; 0.4320 mg/L of ZnSO 4 —7H 2 O; 0.002 mg/L of Arachidonic Acid ; 1.022 mg/L of Cholesterol; 0.070 mg/L of DL-alpha-Tocopherol-Acetate; 0.0520 mg/L of Linoleic Acid; 0.010 mg/L of Linolenic Acid; 0.010 mg/L of Myristic Acid; 0.010 mg/L of Oleic Acid; 0.010 mg/L of Palmitric Acid; 0.010 mg/L of Palmitic Acid; 100 mg/L of Pluronic F-68; 0.010 mg/L of Stearic Acid; 2.20 mg/L of Tween 80; 4551 mg/L of D-Glucose; 130.85 mg/ml of L-Alanine; 147.50 mg/ml of L-Arginine-HCL; 7.50 mg/ml of L-Asparagine-H 2 O; 6.65 mg/ml of L-Aspartic Acid; 29.56 mg/ml of L-Cystine-2HCL—H 2 O; 31.29 mg/ml of L-Cystine-2HCL; 7.35 mg/ml of L-Glutamic Acid; 365.0 mg/ml of L-Glutamine; 18.75 mg/ml of Glycine; 52.48 mg/ml of L-Histidine-HCL—H 2 O; 106.97 mg/ml of L-Isoleucine; 111.45 mg/ml of L-Leucine; 163.75 mg/ml of L-Lysine HCL; 32.34 mg/ml of L-Methionine; 68.48 mg/ml of L-Phenylalainine; 40.0 mg/ml of L-Proline; 26.25 mg/ml of L-Serine; 101.05 mg/ml of L-Threonine; 19.22 mg/ml of L-Tryptophan; 91.79 mg/ml of L-Tryrosine-2Na—2H 2 O; and 99.65 mg/ml of L-Valine; 0.0035 mg/L of Biotin; 3.24 mg/L of D-Ca Pantothenate; 11.78 mg/L of Choline Chloride; 4.65 mg/L of Folic Acid; 15.60 mg/L of i-Inositol; 3.02 mg/L of Niacinamide; 3.00 mg/L of Pyridoxal HCL; 0.031 mg/L of Pyridoxine HCL; 0.319 mg/L of Riboflavin; 3.17 mg/L of Thiamine HCL; 0.365 mg/L of Thymidine; 0.680 mg/L of Vitamin B 12 ; 25 mM of HEPES Buffer; 2.39 mg/L of Na Hypoxanthine; 0.105 mg/L of Lipoic Acid; 0.081 mg/L of Sodium Putrescine-2HCL; 55.0 mg/L of Sodium Pyruvate; 0.0067 mg/L of Sodium Selenite; 20 uM of Ethanolamine; 0.122 mg/L of Ferric Citrate; 41.70 mg/L of Methyl-B-Cyclodextrin complexed with Linoleic Acid; 33.33 mg/L of Methyl-B-Cyclodextrin complexed with Oleic Acid; 10 mg/L of Methyl-B-Cyclodextrin comptexed with Retinal Acetate. Adjust osmolarity to 327 mOsm) with 2 mm glutamine and 1× penstrep. (BSA (81-068-3 Bayer) 100 gm dissolved in 1L DMEM for a 10% BSA stock solution). Filter the media and collect 50 ul for endotoxin assay in 15 ml polystyrene conical.  
     [1215] The transfection reaction is terminated, preferably by tag-teaming, at the end of the incubation period. Person A aspirates off the transfection media, while person B adds 1.5 ml appropriate media to each well. Incubate at 37 degree C. for 45 or 72 hours depending on the media used: 1% BSA for 45 hours or CHO-5 for 72 hours.  
     [1216] On day four, using a 300 ul multichannel pipetter, aliquot 600 ul in one 1 ml deep well plate and the remaining supernatant into a 2 ml deep well. The supernatants from each well can then be used in the assays described in Examples 32-39.  
     [1217] It is specifically understood that when activity is obtained in any of the assays described below using a supernatant, the activity originates from either the polypeptide of the present invention directly (e.g., as a secreted protein) or by polypeptide of the present invention inducing expression of other proteins, which are then secreted into the supernatant. Thus, the invention further provides a method of identifying the protein in the supernatant characterized by an activity in a particular assay.  
     Example 31  
     Construction of GAS Reporter Construct  
     [1218] One signal transduction pathway involved in the differentiation and proliferation of cells is called the Jaks-STATs pathway. Activated proteins in the Jaks-STATs pathway bind to gamma activation site “GAS” elements or interferon-sensitive responsive element (“ISRE”), located in the promoter of many genes. The binding of a protein to these elements alter the expression of the associated gene.  
     [1219] GAS and ISRE elements are recognized by a class of transcription factors called Signal Transducers and Activators of Transcription, or “STATs.” There are six members of the STATs family. Stat1 and Stat3 are present in many cell types, as is Stat2 (as response to IFN-alpha is widespread). Stat4 is more restricted and is not in many cell types though it has been found in T helper class I, cells after treatment with IL-12. Stat5 was originally called mammary growth factor, but has been found at higher concentrations in other cells including myeloid cells. It can be activated in tissue culture cells by many cytokines.  
     [1220] The STATs are activated to translocate from the cytoplasm to the nucleus upon tyrosine phosphorylation by a set of kinases known as the Janus Kinase (“Jaks”) family. Jaks represent a distinct family of soluble tyrosine kinases and include Tyk2, Jak1, Jak2, and Jak3. These kinases display significant sequence similarity and are generally catalytically inactive in resting cells.  
     [1221] The Jaks are activated by a wide range of receptors summarized in the Table below. (Adapted from review by Schidler and Dalnell, Ann. Rev. Biochem. 64:621-51 (1995).) A cytokine receptor family, capable of activating Jaks, is divided into two groups: (a) Class 1 includes receptors for IL-2, IL-3, IL-4, IL-6, IL-7, IL-9, IL-11, IL-12, IL-15, Epo, PRL, GH, G-CSF, GM-CSF, LIF, CNTF, and thrombopoietin; and (b) Class 2 includes IFN-a, IFN-g, and IL-10. The Class 1 receptors share a conserved cysteine motif (a set of four conserved cysteines and one tryptophan) and a WSXWS motif (a membrane proximal region encoding Trp-Ser-Xaa-Trp-Ser(SEQ ID NO: 2)).  
     [1222] Thus, on binding of a ligand to a receptor, Jaks are activated, which in turn activate STATs, which then translocate and bind to GAS elements. This entire process is encompassed in the Jaks-STATs signal transduction pathway.  
     [1223] Therefore, activation of the Jaks-STATs pathway, reflected by the binding of the GAS or the ISRE element, can be used to indicate proteins involved in the proliferation and differentiation of cells. For example, growth factors and cytokines are known to activate the Jaks-STATs pathway. (See Table below.) Thus, by using GAS elements linked to reporter molecules, activators of the Jaks-STATs pathway can be identified.  
                                                  JAKs                                             Ligand   tyk2   Jak1   Jak2   Jak3   STATS   GAS (elements) or ISRE               IFN family                               IFN-a/B   +   +   −   −   1, 2, 3   ISRE       IFN-g       +   +   −   1   GAS (IRF1 &gt; Lys6 &gt; IFP)       Il-10   +   ?   ?   −   1, 3       gp130 family       IL-6 (Pleiotropic)+   +   +   ?       1, 3   GAS (IRF1 &gt; Lys6 &gt; IFP)       Il-11(Pleiotropic)?   +   ?   ?       1, 3       OnM(Pleiotropic)?   +   +   ?       1, 3       LIF(Pleiotropic)?   +   +   ?       1, 3       CNTF(Pleiotropic)   −/+   +   +   ?   1, 3       G-CSF(Pleiotropic)   ?   +   ?   ?   1, 3       IL-12(Pleiotropic)   +   −   +   +   1, 3       g-C family       IL-2 (lymphocytes)   −   +   −   +   1, 3, 5   GAS       IL-4 (lymph/myeloid)   −   +   −   +   6   GAS (IRF1 = IFP &gt;&gt; Ly6)(IgH)       IL-7 (lymphocytes)   −   +   −   +   5   GAS       IL-9 (lymphocytes)   −   +   −   +   5   GAS       IL-13 (lymphocyte)   −   +   ?   ?   6   GAS       IL-15   ?   +   ?   +   5   GAS       gp140 family       IL-3 (myeloid)   −   −   +   −   5   GAS (IRF1 &gt; IFP &gt;&gt; Ly6)       IL-5 (myeloid)   −   −   +   −   5   GAS       GM-CSF (myeloid)   −   −   +   −   5   GAS       Growth hormone family       GH   ?   −   +   −   5       PRL   ?   +/−   +   −   1, 3, 5       EPO   ?   −   +   −   5   GAS (B-CAS &gt; IRF1 = IFP &gt;&gt; Ly6)       Receptor Tyrosine Kinases       EGF   ?   +   +   −   1, 3   GAS (IRF1)       PDGF   ?   +   +   −   1, 3       CSF-1   ?   +   +   −   1, 3   GAS (not IRF1)                  
 
     [1224] To construct a synthetic GAS containing promoter element, which is used in the Biological Assays described in Examples 32-33, a PCR based strategy is employed to generate a GAS-SV40 promoter sequence. The 5′ primer contains four tandem copies of the GAS binding site found in the IRF1 promoter and previously demonstrated to bind STATs upon induction with a range of cytokines (Rothman et al., Immunity 1:457-468 (1994).), although other GAS or ISRE elements can be used instead. The 5′ primer also contains 18 bp of sequence complementary to the SV40 early promoter sequence and is flanked with an XhoI site. The sequence of the 5′ primer is:  
                              5′:GCGCCTCGAGATTTCCCCGAAATCTAGATTTCCCCGAAATGATTTCCCCG   (SEQ ID NO: 3)                   AAATGATTTCCCCGAAATATCTGCCATCTCAATTAG:3′          
 
     [1225] The downstream primer is complementary to the SV40 promoter and is flanked with a Hind III site: 5′:GCGGCAAGCTTTTTGCAAAGCCTAGGC:3′ (SEQ ID NO: 4)  
     [1226] PCR amplification is performed using the SV40 promoter template present in the B-gal:promoter plasmid obtained from Clontech. The resulting PCR fragment is digested with XhoI/Hind III and subcloned into BLSK2-. (Stratagene.) Sequencing with forward and reverse primers confirms that the insert contains the following sequence:  
                              5′: CTCGAG ATTTCCCCGAAATCTAGATTTCCCCGAAATGATTTCCCCGAAAT   (SEQ ID NO: 5)                   GATTTCCCCGAAATATCTGCCATCTCAATTAGTCAGCAACCATAGTCCCGC               CCCTAACTCCGCCCATCCCGCCCCTAACTCCGCCCAGTTCCGCCCATTCTCC               GCCCCATGGCTGACTAATTTTTTTTATTTATGCAGAGGCCGAGGCCGCCTC               GGCCTCTGAGCTATTCCAGAAGTAGTGAGGAGGCTTTTTTGGAGGCCTAGG               CTTTTGCAAA AAGCTT :3′          
 
     [1227] With this GAS promoter element linked to the SV40 promoter, a GAS:SEAP2 reporter construct is next engineered. Here, the reporter molecule is a secreted alkaline phosphatase, or “SEAP.” Clearly, however, any reporter molecule can be used instead of SEAP, in this or in any of the other Examples. Well known reporter molecules that can be used instead of SEAP include chloramphenicol acetyltransferase (CAT), luciferase, alkaline phosphatase, B-galactosidase, green fluorescent protein (GFP), or any protein detectable by an antibody.  
     [1228] The above sequence confirmed synthetic GAS-SV40 promoter element is subcloned into the pSEAP-Promoter vector obtained from Clontech using HindIII and XhoI, effectively replacing the SV40 promoter with the amplified GAS:SV40 promoter element, to create the GAS-SEAP vector. However, this vector does not contain a neomycin resistance gene, and therefore, is not preferred for mammalian expression systems.  
     [1229] Thus, in order to generate mammalian stable cell lines expressing the GAS-SEAP reporter, the GAS-SEAP cassette is removed from the GAS-SEAP vector using SalI and NotI, and inserted into a backbone vector containing the neomycin resistance gene, such as pGFP-1 (Clontech), using these restriction sites in the multiple cloning site, to create the GAS-SEAP/Neo vector. Once this vector is transfected into mammalian cells, this vector can then be used as a reporter molecule for GAS binding as described in Examples 32-33.  
     [1230] Other constructs can be made using the above description and replacing GAS with a different promoter sequence. For example, construction of reporter molecules containing NFK-B and EGR promoter sequences are described in Examples 34 and 35. However, many other promoters can be substituted using the protocols described in these Examples. For instance, SRE, IL-2, NFAT, or Osteocalcin promoters can be substituted, alone or in combination (e.g., GAS/NF-KB/EGR, GAS/NF-KB, Il-2/NFAT, or NF-KB/GAS). Similarly, other cell lines can be used to test reporter construct activity, such as HELA (epithelial), HUVEC (endothelial), Reh (B-cell), Saos-2 (osteoblast), HUVAC (aortic), or Cardiomyocyte.  
     Example 32  
     High-Throughput Screening Assay for T-cell Activity  
     [1231] The following protocol is used to assess T-cell activity by identifying factors, and determining whether supemate containing a polypeptide of the invention proliferates and/or differentiates T-cells. T-cell activity is assessed using the GAS/SEAP/Neo construct produced in Example 31. Thus, factors that increase SEAP activity indicate the ability to activate the Jaks-STATS signal transduction pathway. The T-cell used in this assay is Jurkat T-cells (ATCC Accession No. TIB-152), although Molt-3 cells (ATCC Accession No. CRL-1552) and Molt-4 cells (ATCC Accession No. CRL-1582) cells can also be used.  
     [1232] Jurkat T-cells are lymphoblastic CD4+ Th1 helper cells. In order to generate stable cell lines, approximately 2 million Jurkat cells are transfected with the GAS-SEAP/neo vector using DMRIE-C (Life Technologies)(transfection procedure described below). The transfected cells are seeded to a density of approximately 20,000 cells per well and transfectants resistant to 1 mg/ml genticin selected. Resistant colonies are expanded and then tested for their response to increasing concentrations of interferon gamma. The dose response of a selected clone is demonstrated.  
     [1233] Specifically, the following protocol will yield sufficient cells for 75 wells containing 200 ul of cells. Thus, it is either scaled up, or performed in multiple to generate sufficient cells for multiple 96 well plates. Jurkat cells are maintained in RPMI+10% serum with 1% Pen-Strep. Combine 2.5 mls of OPTI-MEM (Life Technologies) with 10 ug of plasmid DNA in a T25 flask. Add 2.5 ml OPTI-MEM containing 50 ul of DMRIE-C and incubate at room temperature for 15-45 mins.  
     [1234] During the incubation period, count cell concentration, spin down the required number of cells (10 7  per transfection), and resuspend in OPTI-MEM to a final concentration of 10 7  cells/ml. Then add 1 ml of 1×10 7  cells in OPTI-MEM to T25 flask and incubate at 37 degree C. for 6 hrs. After the incubation, add 10 ml of RPMI+15% serum.  
     [1235] The Jurkat:GAS-SEAP stable reporter lines are maintained in RPMI+10% serum, 1 mg/ml Genticin, and 1% Pen-Strep. These cells are treated with supernatants containing polypeptide of the present invention or polypeptide of the present invention induced polypeptides as produced by the protocol described in Example 30.  
     [1236] On the day of treatment with the supernatant, the cells should be washed and resuspended in fresh RPMI+10% serum to a density of 500,000 cells per ml. The exact number of cells required will depend on the number of supernatants being screened. For one 96 well plate, approximately 10 million cells (for 10 plates, 100 million cells) are required.  
     [1237] Transfer the cells to a triangular reservoir boat, in order to dispense the cells into a 96 well dish, using a 12 channel pipette. Using a 12 channel pipette, transfer 200 ul of cells into each well (therefore adding 100, 000 cells per well).  
     [1238] After all the plates have been seeded, 50 ul of the supernatants are transferred directly from the 96 well plate containing the supernatants into each well using a 12 channel pipette. In addition, a dose of exogenous interferon gamma (0.1, 1.0, 10 ng) is added to wells H9, H10, and H11 to serve as additional positive controls for the assay.  
     [1239] The 96 well dishes containing Jurkat cells treated with supernatants are placed in an incubator for 48 hrs (note: this time is variable between 48-72 hrs). 35 ul samples from each well are then transferred to an opaque 96 well plate using a 12 channel pipette. The opaque plates should be covered (using sellophene covers) and stored at −20 degree C. until SEAP assays are performed according to Example 36. The plates containing the remaining treated cells are placed at 4 degree C. and serve as a source of material for repeating the assay on a specific well if desired.  
     [1240] As a positive control, 100 Unit/ml interferon gamma can be used which is known to activate Jurkat T cells. Over 30 fold induction is typically observed in the positive control wells.  
     [1241] The above protocol may be used in the generation of both transient, as well as stable, transfected cells, which would be apparent to those of skill in the art.  
     Example 33  
     High-Throughput Screening Assay Identifying Myeloid Activity  
     [1242] The following protocol is used to assess myeloid activity of polypeptide of the present invention by determining whether polypeptide of the present invention proliferates and/or differentiates myeloid cells. Myeloid cell activity is assessed using the GAS/SEAP/Neo construct produced in Example 31. Thus, factors that increase SEAP activity indicate the ability to activate the Jaks-STATS signal transduction pathway. The myeloid cell used in this assay is U937, a pre-monocyte cell line, although TF-1, HL60, or KG1 can be used.  
     [1243] To transiently transfect U937 cells with the GAS/SEAP/Neo construct produced in Example 31, a DEAE-Dextran method (Kharbanda et. al., 1994, Cell Growth &amp; Differentiation, 5:259-265) is used. First, harvest 2×10 7  U937 cells and wash with PBS. The U937 cells are usually grown in RPMI 1640 medium containing 10% heat-inactivated fetal bovine serum (FBS) supplemented with 100 units/ml penicillin and 100 mg/ml streptomycin.  
     [1244] Next, suspend the cells in 1 ml of 20 mM Tris-HCl (pH 7.4) buffer containing 0.5 mg/ml DEAE-Dextran, 8 ug GAS-SEAP2 plasmid DNA, 140 mM NaCl, 5 mM KCl, 375 uM Na 2 HPO 4 .7H 2 O, 1 mM MgCl 2 , and 675 uM CaCl 2 . Incubate at 37 degrees C. for 45 min.  
     [1245] Wash the cells with RPMI 1640 medium containing 10% FBS and then resuspend in 10 ml complete medium and incubate at 37 degree C. for 36 hr.  
     [1246] The GAS-SEAP/U937 stable cells are obtained by growing the cells in 400 ug/ml G418. The G418-free medium is used for routine growth but every one to two months, the cells should be re-grown in 400 ug/ml G418 for couple of passages.  
     [1247] These cells are tested by harvesting 1×10 8  cells (this is enough for ten 96-well plates assay) and wash with PBS. Suspend the cells in 200 ml above described growth medium, with a final density of 5×10 5  cells/ml. Plate 200 ul cells per well in the 96-well plate (or 1×10 5  cells/well).  
     [1248] Add 50 ul of the supernatant prepared by the protocol described in Example 30. Incubate at 37 degee C. for 48 to 72 hr. As a positive control, 100 Unit/ml interferon gamma can be used which is known to activate U937 cells. Over 30 fold induction is typically observed in the positive control wells. SEAP assay the supernatant according to the protocol described in Example 36.  
     Example 34  
     High-Throughput Screening Assay Identifying Neuronal Activity  
     [1249] When cells undergo differentiation and proliferation, a group of genes are activated through many different signal transduction pathways. One of these genes, EGR1 (early growth response gene 1), is induced in various tissues and cell types upon activation. The promoter of EGR1 is responsible for such induction. Using the EGR1 promoter linked to reporter molecules, activation of cells can be assessed by polypeptide of the present invention.  
     [1250] Particularly, the following protocol is used to assess neuronal activity in PC12 cell lines. PC12 cells (rat phenochromocytoma cells) are known to proliferate and/or differentiate by activation with a number of mitogens, such as TPA (tetradecanoyl phorbol acetate), NGF (nerve growth factor), and EGF (epidermal growth factor). The EGR1 gene expression is activated during this treatment. Thus, by stably transfecting PC12 cells with a construct containing an EGR promoter linked SEAP reporter, activation of PC12 cells by polypeptide of the present invention can be assessed.  
     [1251] The EGR/SEAP reporter construct can be assembled by the following protocol. The EGR-1 promoter sequence (−633 to +1)(Sakamoto K et al., Oncogene 6:867-871 (1991)) can be PCR amplified from human genomic DNA using the following primers:  
                              (SEQ ID NO: 6)                                     5′ GCGCTCGAGGGATGACAGCGATAGAACCCCGG-3′                                         (SEQ ID NO: 7)                                     5′ GCGAAGCTTCGCGACTCCCCGGATCCGCCTC-3′              
 
     [1252] Using the GAS:SEAP/Neo vector produced in Example 31, EGR1 amplified product can then be inserted into this vector. Linearize the GAS:SEAP/Neo vector using restriction enzymes XhoI/HindIII, removing the GAS/SV40 stuffer. Restrict the EGR1 amplified product with these same enzymes. Ligate the vector and EGR1 promoter.  
     [1253] To prepare 96 well-plates for cell culture, two mls of a coating solution (1:30 dilution of collagen type-I (Upstate Biotech Inc. Cat#08-115) in 30% ethanol (filter sterilized)) is added per one 10 cm plate or 50 ml per well of the 96-well plate, and allowed to air dry for 2 hr.  
     [1254] PC12 cells are routinely grown in RPMI-1640 medium (Bio Whittaker) ining 10% horse serum (JRH BIOSCIENCES, Cat. # 12449-78P), 5% heat-inactivated fetal bovine serum (FBS) supplemented with 100 units/ml penicillin and 100 ug/ml streptomycin on a precoated 10 cm tissue culture dish. One to four split is done every three to four days. Cells are removed from the plates by scraping and resuspended with pipetting up and down for more than 15 times.  
     [1255] Transfect the EGR/SEAP/Neo construct into PC12 using the Lipofectamine protocol described in Example 30. EGR-SEAP/PC12 stable cells are obtained by growing the cells in 300 ug/ml G418. The G418-free medium is used for routine growth but every one to two months, the cells should be re-grown in 300 ug/ml G418 for couple of passages.  
     [1256] To assay for neuronal activity, a 10 cm plate with cells around 70 to 80% confluent is screened by removing the old medium. Wash the cells once with PBS (Phosphate buffered saline). Then starve the cells in low serum medium (RPMI-1640 containing 1% horse serum and 0.5% FBS with antibiotics) overnight.  
     [1257] The next morning, remove the medium and wash the cells with PBS. Scrape off the cells from the plate, suspend the cells well in 2 ml low serum medium. Count the cell number and add more low serum medium to reach final cell density as 5×10 5  cells/ml.  
     [1258] Add 200 ul of the cell suspension to each well of 96-well plate (equivalent to 1×10 5  cells/well). Add 50 ul supernatant produced by Example 30, 37 degree C. for 48 to 72 hr. As a positive control, a growth factor known to activate PC12 cells through EGR can be used, such as 50 ng/ul of Neuronal Growth Factor (NGF). Over fifty-fold induction of SEAP is typically seen in the positive control wells. SEAP assay the supernatant according to Example 36.  
     Example 35  
     High-Throughput Screening Assay for T-cell Activity  
     [1259] NF-KB (Nuclear Factor KB) is a transcription factor activated by a wide variety of agents including the inflammatory cytokines IL-1 and TNF, CD30 and CD40, lymphotoxin-alpha and lymphotoxin-beta, by exposure to LPS or thrombin, and by expression of certain viral gene products. As a transcription factor, NF-KB regulates the expression of genes involved in immune cell activation, control of apoptosis (NF-KB appears to shield cells from apoptosis), B and T-cell development, anti-viral and antimicrobial responses, and multiple stress responses.  
     [1260] In non-stimulated conditions, NF-KB is retained in the cytoplasm with I-KB (Inhibitor KB). However, upon stimulation, I-KB is phosphorylated and degraded, causing NF-KB to shuttle to the nucleus, thereby activating transcription of target genes. Target genes activated by NF-KB include IL-2, IL-6, GM-CSF, ICAM-1 and class 1 MHC.  
     [1261] Due to its central role and ability to respond to a range of stimuli, reporter constructs utilizing the NF-KB promoter element are used to screen the supernatants produced in Example 30. Activators or inhibitors of NF-KB would be useful in treating, preventing, and/or diagnosing diseases. For example, inhibitors of NF-KB could be used to treat those diseases related to the acute or chronic activation of NF-KB, such as rheumatoid arthritis.  
     [1262] To construct a vector containing the NF-KB promoter element, a PCR. based strategy is employed. The upstream primer contains four tandem copies of the NF-KB binding site (GGGGACTTTCCC) (SEQ ID NO: 8), 18 bp of sequence complementary to the 5′ end of the SV40 early promoter sequence, and is flanked with an XhoI site:  
                              5′:GCGGCCTCGAGGGGACTTTCCCGGGGACTTTCCGGGGACTTTCCGGGAC   (SEQ ID NO: 9)                   TTTCCATCCTGCCATCTCAATTAG:3′          
 
     [1263] The downstream primer is complementary to the 3′ end of the SV40 promoter and is flanked with a Hind III site:  
     [1264] 5′:GCGGCAAGCTTTTTGCAAAGCCTAGGC:3′ (SEQ ID NO: 4)  
     [1265] PCR amplification is performed using the SV40 promoter template present in the pB-gal:promoter plasmid obtained from Clontech. The resulting PCR fragment is digested with XhoI and Hind III and subcloned into BLSK2-. (Stratagene) Sequencing with the T7 and T3 primers confirms the insert contains the following sequence:  
                          (SEQ ID NO: 10)                         5′:CTCGAGGGGACTTTCCCGGGGACTTTCCGGGGACTTTCCGGGACTTT                   CCATCTGCCATCTCAATTAGTCAGCAACCATAGTCCCGCCCCTAACTCCG               CCCATCCCGCCCCTAACTCCGCCCAGTTCCGCCCATTCTCCGCCCCATGG               CTGACTAATTTTTTTTATTTATGCAGAGGCCGAGGCCGCCTCGGCCTCTG               AGCTATTCCAGAAGTAGTGAGGAGGCTTTTTTGGAGGCCTAGGCTTTTGC               AAAAAGCTT:3′          
 
     [1266] Next, replace the SV40 minimal promoter element present in the pSEAP2-promoter plasmid (Clontech) with this NF-KB/SV40 fragment using XhoI and HindIII. However, this vector does not contain a neomycin resistance gene, and therefore, is not preferred for mammalian expression systems.  
     [1267] In order to generate stable mammalian cell lines, the NF-KB/SV40/SEAP cassette is removed from the above NF-KB/SEAP vector using restriction enzymes SalI and NotI, and inserted into a vector containing neomycin resistance. Particularly, the NF-KB/SV40/SEAP cassette was inserted into pGFP-1 (Clontech), replacing the GFP gene, after restricting pGFP-1 with SalI and NotI.  
     [1268] Once NF-KB/SV40/SEAP/Neo vector is created, stable Jurkat T-cells are created and maintained according to the protocol described in Example 32. Similarly, the method for assaying supematants with these stable Jurkat T-cells is also described in Example 32. As a positive control, exogenous TNF alpha (0.1,1, 10 ng) is added to wells H9, H10, and H11, with a 5-10 fold activation typically observed.  
     Example 36  
     Assay for SEAP Activity  
     [1269] As a reporter molecule for the assays described in Examples 32-35, SEAP activity is assayed using the Tropix Phospho-light Kit (Cat. BP-400) according to the following general procedure. The Tropix Phospho-light Kit supplies the Dilution, Assay, and Reaction Buffers used below.  
     [1270] Prime a dispenser with the 2.5×Dilution Buffer and dispense 15 ul of 2.5×dilution buffer into Optiplates containing 35 ul of a supernatant. Seal the plates with a plastic sealer and incubate at 65 degree C. for 30 min. Separate the Optiplates to avoid uneven heating.  
     [1271] Cool the samples to room temperature for 15 minutes. Empty the dispenser and prime with the Assay Buffer. Add 50 ml Assay Buffer and incubate at room temperature 5 min. Empty the dispenser and prime with the Reaction Buffer (see the Table below). Add 50 ul Reaction Buffer and incubate at room temperature for 20 minutes. Since the intensity of the chemiluminescent signal is time dependent, and it takes about 10 minutes to read 5 plates on a luminometer, thus one should treat 5 plates at each time and start the second set 10 minutes later.  
     [1272] Read the relative light unit in the luminometer. Set H12 as blank, and print the results. An increase in chemiluminescence indicates reporter activity.  
                              Reaction Buffer Formulation:                         # of plates   Rxn buffer diluent (ml)   CSPD (ml)                                 10   60   3       11   65   3.25       12   70   3.5       13   75   3.75       14   80   4       15   85   4.25       16   90   4.5       17   95   4.75       18   100   5       19   105   5.25       20   110   5.5       21   115   5.75       22   120   6       23   125   6.25       24   130   6.5       25   135   6.75       26   140   7       27   145   7.25       28   150   7.5       29   155   7.75       30   160   8       31   165   8.25       32   170   8.5       33   175   8.75       34   180   9       35   185   9.25       36   190   9.5       37   195   9.75       38   200   10       39   205   10.25       40   210   10.5       41   215   10.75       42   220   11       43   225   11.25       44   230   11.5       45   235   11.75       46   240   12       47   245   12.25       48   250   12.5       49   255   12.75       50   260   13                  
 
     Example 37  
     High-Throughput Screening Assay Identifying Changes in Small Molecule Concentration and Membrane Permeability  
     [1273] Binding of a ligand to a receptor is known to alter intracellular levels of small molecules, such as calcium, potassium, sodium, and pH, as well as alter membrane potential. These alterations can be measured in an assay to identify supernatants which bind to receptors of a particular cell. Although the following protocol describes an assay for calcium, this protocol can easily be modified to detect changes in potassium, sodium, pH, membrane potential, or any other small molecule which is detectable by a fluorescent probe.  
     [1274] The following assay uses Fluorometric Imaging Plate Reader (“FLIPR”) to measure changes in fluorescent molecules (Molecular Probes) that bind small molecules. Clearly, any fluorescent molecule detecting a small molecule can be used instead of the calcium fluorescent molecule, fluo-4 (Molecular Probes, Inc.; catalog no. F-14202), used here.  
     [1275] For adherent cells, seed the cells at 10,000-20,000 cells/well in a Co-star black 96-well plate with clear bottom. The plate is incubated in a CO 2  incubator for 20 hours. The adherent cells are washed two times in Biotek washer with 200 ul of HBSS (Hank&#39;s Balanced Salt Solution) leaving 100 ul of buffer after the final wash.  
     [1276] A stock solution of 1 mg/ml fluo-4 is made in 10% pluronic acid DMSO. To load the cells with fluo-4 , 50 ul of 12 ug/ml fluo-4 is added to each well. The plate is incubated at 37 degrees C. in a CO 2  incubator for 60 min. The plate is washed four times in the Biotek washer with HBSS leaving 100 ul of buffer.  
     [1277] For non-adherent cells, the cells are spun down from culture media. Cells are re-suspended to 2-5×10 6  cells/ml with HBSS in a 50-ml conical tube. 4 ul of 1 mg/ml fluo-4 solution in 10% pluronic acid DMSO is added to each ml of cell suspension. The tube is then placed in a 37 degrees C. water bath for 30-60 min. The cells are washed twice with HBSS, resuspended to1×10 6  cells/ml, and dispensed into a microplate, 100 ul/well. The plate is centrifuged at 1000 rpm for 5 min. The plate is then washed once in Denley Cell Wash with 200 ul, followed by an aspiration step to 100 ul final volume.  
     [1278] For a non-cell based assay, each well contains a fluorescent molecule, such as fluo-4 . The supernatant is added to the well, and a change in fluorescence is detected.  
     [1279] To measure the fluorescence of intracellular calcium, the FLIPR is set for the following parameters: (1) System gain is 300-800 mW; (2) Exposure time is 0.4 second; (3) Camera F/stop is F/2; (4) Excitation is 488 nm; (5) Emission is 530 nm; and (6) Sample addition is 50 ul. Increased emission at 530 nm indicates an extracellular signaling event caused by the a molecule, either polypeptide of the present invention or a molecule induced by polypeptide of the present invention, which has resulted in an increase in the intracellular Ca ++  concentration.  
     Example 38  
     High-Throughput Screening Assay Identifying Tyrosine Kinase Activity  
     [1280] The Protein Tyrosine Kinases (PTK) represent a diverse group of transmembrane and cytoplasmic kinases. Within the Receptor Protein Tyrosine Kinase RPTK) group are receptors for a range of mitogenic and metabolic growth factors including the PDGF, FGF, EGF, NGF, HGF and Insulin receptor subfamilies. In addition there are a large family of RPTKs for which the corresponding ligand is unknown. Ligands for RPTKs include mainly secreted small proteins, but also membrane-bound and extracellular matrix proteins.  
     [1281] Activation of RPTK by ligands involves ligand-mediated receptor dimerization, resulting in transphosphorylation of the receptor subunits and activation of the cytoplasmic tyrosine kinases. The cytoplasmic tyrosine kinases include receptor associated tyrosine kinases of the src-family (e.g., src, yes, lck, lyn, fyn) and non-receptor linked and cytosolic protein tyrosine kinases, such as the Jak family, members of which mediate signal transduction triggered by the cytokine superfamily of receptors (e.g., the Interleukins, Interferons, GM-CSF, and Leptin).  
     [1282] Because of the wide range of known factors capable of stimulating tyrosine kinase activity, identifying whether polypeptide of the present invention or a molecule induced by polypeptide of the present invention is capable of activating tyrosine kinase signal transduction pathways is of interest. Therefore, the following protocol is designed to identify such molecules capable of activating the tyrosine kinase signal transduction pathways.  
     [1283] Seed target cells (e.g., primary keratinocytes) at a density of approximately 25,000 cells per well in a 96 well Loprodyne Silent Screen Plates purchased from Nalge Nunc (Naperville, Ill.). The plates are sterilized with two 30 minute rinses with 100% ethanol, rinsed with water and dried overnight. Some plates are coated for 2 hr with 100 ml of cell culture grade type I collagen (50 mg/ml), gelatin (2% ) or polylysine (50 mg/ml), all of which can be purchased from Sigma Chemicals (St. Louis, Mo.) or 10% Matrigel purchased from Becton Dickinson (Bedford,Mass.), or calf serum, rinsed with PBS and stored at 4 degree C. Cell growth on these plates is assayed by seeding 5,000 cells/well in growth medium and indirect quantitation of cell number through use of alamarBlue as described by the manufacturer Alamar Biosciences, Inc. (Sacramento, Calif.) after 48 hr. Falcon plate covers #3071 from Becton Dickinson (Bedford,Mass.) are used to cover the Loprodyne Silent Screen Plates. Falcon Microtest III cell culture plates can also be used in some proliferation experiments.  
     [1284] To prepare extracts, A431 cells are seeded onto the nylon membranes of Loprodyne plates (20,000/200 ml/well) and cultured overnight in complete medium. Cells are quiesced by incubation in serum-free basal medium for 24 hr. After 5-20 minutes treatment with EGF (60 ng/ml) or 50 ul of the supernatant produced in Example 30, the medium was removed and 100 ml of extraction buffer ((20 mM HEPES pH 7.5, 0.15 M NaCl, 1% Triton X-100, 0.1% SDS, 2 mM Na3VO4, 2 mM Na4P207 and a cocktail of protease inhibitors (# 1836170) obtained from Boeheringer Mannheim (Indianapolis, Ind.)) is added to each well and the plate is shaken on a rotating shaker for 5 minutes at 4° C. The plate is then placed in a vacuum transfer manifold and the extract filtered through the 0.45 mm membrane bottoms of each well using house vacuum. Extracts are collected in a 96-well catch/assay plate in the bottom of the vacuum manifold and immediately placed on ice. To obtain extracts clarified by centrifugation, the content of each well, after detergent solubilization for 5 minutes, is removed and centrifuged for 15 minutes at 4 degree C. at 16,000×g.  
     [1285] Test the filtered extracts for levels of tyrosine kinase activity. Although many methods of detecting tyrosine kinase activity are known, one method is described here.  
     [1286] Generally, the tyrosine kinase activity of a supernatant is evaluated by determining its ability to phosphorylate a tyrosine residue on a specific substrate (a biotinylated peptide). Biotinylated peptides that can be used for this purpose include PSK1 (corresponding to amino acids 6-20 of the cell division kinase cdc2-p34) and PSK2 (corresponding to amino acids 1-17 of gastrin). Both peptides are substrates for a range of tyrosine kinases and are available from Boehringer Mannheim.  
     [1287] The tyrosine kinase reaction is set up by adding the following components in order. First, add 10 ul of 5 uM Biotinylated Peptide, then 10 ul ATP/Mg 2+  (5 mM ATP/50 mM MgCl 2 ), then 10 ul of 5× Assay Buffer (40 mM imidazole hydrochloride, pH7.3, 40 mM beta-glycerophosphate, 1 mM EGTA, 100 mM MgCl 2 , 5 mM MnCl 2 , 0.5 mg/ml BSA), then 5 ul of Sodium Vanadate (1 mM), and then 5 ul of water. Mix the components gently and preincubate the reaction mix at 30 degree C. for 2 min. Initial the reaction by adding 10 ul of the control enzyme or the filtered supernatant.  
     [1288] The tyrosine kinase assay reaction is then terminated by adding 10 ul of 120 mm EDTA and place the reactions on ice.  
     [1289] Tyrosine kinase activity is determined by transferring 50 ul aliquot of reaction mixture to a microtiter plate (MTP) module and incubating at 37 degree C. for 20 min. This allows the streptavidin coated 96 well plate to associate with the biotinylated peptide. Wash the MTP module with 300 ul/well of PBS four times. Next add 75 ul of anti-phospotyrosine antibody conjugated to horse radish peroxidase (anti-P-Tyr-POD(0.5 u/ml)) to each well and incubate at 37 degree C. for one hour. Wash the well as above.  
     [1290] Next add 100 ul of peroxidase substrate solution (Boehringer Mannheim) and incubate at room temperature for at least 5 mins (up to 30 min). Measure the absorbance of the sample at 405 nm by using ELISA reader. The level of bound peroxidase activity is quantitated using an ELISA reader and reflects the level of tyrosine kinase activity.  
     Example 39  
     High-Throutghput Screening Assay Identifying Phosphorylation Activity  
     [1291] As a potential alternative and/or complement to the assay of protein tyrosine kinase activity described in Example 38, an assay which detects activation (phosphorylation) of major intracellular signal transduction intermediates can also be used. For example, as described below one particular assay can detect tyrosine phosphorylation of the Erk-1 and Erk-2 kinases. However, phosphorylation of other molecules, such as Raf, JNK, p38 MAP, Map kinase kinase (MEK), MEK kinase, Src, Muscle specific kinase (MuSK), IRAK, Tec, and Janus, as well as any other phosphoserine, phosphotyrosine, or phosphothreonine molecule, can be detected by substituting these molecules for Erk-1 or Erk-2 in the following assay.  
     [1292] Specifically, assay plates are made by coating the wells of a 96-well ELISA plate with 0.1 ml of protein G (1 ug/ml) for 2 hr at room temp, (RT). The plates are then rinsed with PBS and blocked with 3% BSA/PBS for 1 hr at RT. The protein G plates are then treated with 2 commercial monoclonal antibodies (100 ng/well) against Erk-1 and Erk-2 (1 hr at, RT) (Santa Cruz Biotechnology). (To detect other molecules, this step can easily be modified by substituting a monoclonal antibody detecting any of the above described molecules.) After 3-5 rinses with PBS, the plates are stored at 4 degree C. until use.  
     [1293] A431 cells are seeded at 20,000/well in a 96-well Loprodyne filterplate and cultured overnight in growth medium. The cells are then starved for 48 hr in basal medium (DMEM) and then treated with EGF (6 ng/well) or 50 ul of the supernatants obtained in Example 30 for 5-20 minutes. The cells are then solubilized and extracts filtered directly into the assay plate.  
     [1294] After incubation with the extract for 1 hr at RT, the wells are again rinsed. As a positive control, a commercial preparation of MAP kinase (10 ng/well) is used in place of A431 extract. Plates are then treated with a commercial polyclonal (rabbit) antibody (1 ug/ml) which specifically recognizes the phosphorylated epitope of the Erk-1 and Erk-2 kinases (1 hr at RT). This antibody is biotinylated by standard procedures. The bound polyclonal antibody is then quantitated by successive incubations with Europium-streptavidin and Europium fluorescence enhancing reagent in the Wallac DELFIA instrument (time-resolved fluorescence). An increased fluorescent signal over background indicates a phosphorylation by polypeptide of the present invention or a molecule induced by polypeptide of the present invention.  
     Example 40  
     Assay for the Stimulation of Bone Marrow CD34+ Cell Proliferation  
     [1295] This assay is based on the ability of human CD34+ to proliferate in the presence of hematopoietic growth factors and evaluates the ability of isolated polypeptides expressed in mammalian cells to stimulate proliferation of CD34+ cells.  
     [1296] It has been previously shown that most mature precursors will respond to only a single signal. More immature precursors require at least two signals to respond. Therefore, to tests the effect of polypeptides on hematopoietic activity of a wide range of progenitor cells, the assay contains a given polypeptide in-the presence or absence of other hematopoietic growth factors. Isolated cells are cultured for 5 days in the presence of Stem Cell Factor (SCF) in combination with tested sample. SCF alone has a very limited effect on the proliferation of bone marrow (BM) cells, acting in such conditions only as a “survival” factor. However, combined with any factor exhibiting stimulatory effect on these cells (e.g., IL-3), SCF will cause a synergistic effect. Therefore, if the tested polypeptide has a stimulatory effect on hematopoietic progenitors, such activity can be easily detected. Since normal BM cells have a low level of cycling cells, it is likely that any inhibitory effect of a given polypeptide, or agonists or antagonists thereof, might not be detected. Accordingly, assays for an inhibitory effect on progenitors is preferably tested in cells that are first subjected to in vitro stimulation with SCF+IL+3, and then contacted with the compound that is being evaluated for inhibition of such induced proliferation.  
     [1297] Briefly, CD34+ cells are isolated using methods known in the art. The cells are thawed and resuspended in medium (QBSF 60 serum-free medium with 1% L-glutamine (500 ml ) Quality Biological, Inc., Gaithersburg, Md. Cat# 160-204-101). After several gentle centrifugation steps at 200× g, cells are allowed to rest for one hour. The cell count is adjusted to 2.5×10 5  cells/mt. During this time, 100 μl of sterile water is added to the peripheral wells of a 96-well plate. The cytokines that can be tested with a given polypeptide in this assay is rhSCF (R&amp;D Systems, Minneapolis, Minn., Cat# 255-SC) at 50 ng/ml alone and in combination with rhSCF and rhIL-3 (R&amp;D Systems, Minneapolis, Minn., Cat# 203-ML) at 30 ng/ml. After one hour, 10 μl of prepared cytokines, 50 μl of the supernatants prepared in Example 30 (supernatants at 1:2 dilution=50 μl) and 20 μl of diluted cells are added to the media which is already present in the wells to allow for a final total volume of 100 μl. The plates are then placed in a 37° C./5% CO 2  incubator for five days.  
     [1298] Eighteen hours before the assay is harvested, 0.5 μCi/well of [3H] Thymidine is added in a 10 μl volume to each well to determine the proliferation rate. The experiment is terminated by harvesting the cells from each 96-well plate to a filtermat using the Tomtec Harvester 96. After harvesting, the filtermats are dried, trimmed and placed into OmniFilter assemblies consisting of one OmniFilter plate and one OmnniFilter Tray. 60 μl Microscint is added to each well and the plate sealed with TopSeal-A press-on sealing film A bar code 15 sticker is affixed to the first plate for counting. The sealed plates are then loaded and the level of radioactivity determined via the Packard Top Count and the printed data collected for analysis. The level of radioactivity reflects the amount of cell proliferation.  
     [1299] The studies described in this example test the activity of a given polypeptide to stimulate bone marrow CD34+ cell proliferation. One skilled in the art could easily modify the exemplified studies to test the activity of polynucleotides (e.g., gene therapy), antibodies, agonists, and/or antagonists and fragments and variants thereof. As a nonlimiting example, potential antagonists tested in this assay would be expected to inhibit cell proliferation in the presence of cytokines and/or to increase the inhibition of cell proliferation in the presence of cytokines and a given polypeptide. In contrast, potential agonists tested in this assay would be expected to enhance cell proliferation and/or to decrease the inhibition of cell proliferation in the presence of cytokines and a given polypeptide.  
     [1300] The ability of a gene to stimulate the proliferation of bone marrow CD34+ cells indicates that polynucleotides and polypeptides corresponding to the gene are useful for the diagnosis and treatment of disorders affecting the immune system and hematopoiesis. Representative uses are described in the “Immune Activity” and “Infectious Disease” sections above, and elsewhere herein.  
     Example 41  
     Assay for Extracellular Matrix Enhanced Cell Response (EMECR)  
     [1301] The objective of the Extracellular Matrix Enhanced Cell Response (EMECR) assay is to identify gene products (e.g., isolated polypeptides) that act on the hematopoietic stem cells in the context of the extracellular matrix (ECM) induced signal.  
     [1302] Cells respond to the regulatory factors in the context of signal(s) received from the surrounding microenvironment. For example, fibroblasts, and endothelial and epithelial stem cells fail to replicate in the absence of signals from the ECM. Hematopoietic stem cells can undergo self-renewal in the bone marrow, but not in in vitro suspension culture. The ability of stem cells to undergo self-renewal in vitro is dependent upon their interaction with the stromal cells and the ECM protein fibronectin (fn). Adhesion of cells to fn is mediated by the α 5 .β 1  and α 4 .β 1  integrin receptors, which are expressed by human and mouse hematopoietic stem cells. The factor(s) which integrate with the ECM environment and are responsible for stimulating stem cell self-renewal have not yet been identified. Discovery of such factors should be of great interest in gene therapy and bone marrow transplant applications  
     [1303] Briefly, polystyrene, non tissue culture treated, 96-well plates are coated with fn fragment at a coating concentration of 0.2 μg/cm 2 . Mouse bone marrow cells are plated (1,000 cells/well ) in 0.2 ml of serum-free medium. Cells cultured in the presence of IL-3 ( 5 ng/ml )+SCF ( 50 ng/ml ) would serve as the positive control, conditions under which little self-renewal but pronounced differentiation of the stem cells is to be expected. Gene products of the invention (e.g., including, but not limited to, polynucleotides and polypeptides of the present invention, and supernatants produced in Example 30), are tested with appropriate negative controls in the presence and absence of SCF(5.0 ng/ml), where test factor supernatants represent 10% of the total assay volume. The plated cells are then allowed to grow by incubating in a low oxygen environment ( 5% CO 2 , 7% O 2 , and 88% N 2  ) tissue culture incubator for 7 days. The number of proliferating cells within the wells is then quantitated by measuring thymidine incorporation into cellular DNA. Verification of the positive hits in the assay will require phenotypic characterization of the cells, which can be accomplished by scaling up of the culture system and using appropriate antibody reagents against cell surface antigens and FACScan.  
     [1304] One skilled in the art could easily modify the exemplified studies to test the activity of polynucleotides (e.g., gene therapy), antibodies, agonists, and/or antagonists and fragments and variants thereof.  
     [1305] If a particular polypeptide of the present invention is found to be a stimulator of hematopoietic progenitors, polynucleotides and polypeptides corresponding to the gene encoding said polypeptide may be useful for the diagnosis and treatment of disorders affecting the immune system and hematopoiesis. Representative uses are described in the “Immune Activity” and “Infectious Disease” sections above, and elsewhere herein. The gene product may also be useful in the expansion of stem cells and committed progenitors of various blood lineages, and in the differentiation and/or proliferation of various cell types.  
     [1306] Additionally, the polynucleotides and/or polypeptides of the gene of interest and/or agonists and/or antagonists thereof, may also be employed to inhibit the proliferation and differentiation of hematopoietic cells and therefore may be employed to protect bone marrow stem cells from chemotherapeutic agents during chemotherapy. This antiproliferative effect may allow administration of higher doses of chemotherapeutic agents and, therefore, more effective chemotherapeutic treatment.  
     [1307] Moreover, polynucleotides and polypeptides corresponding to the gene of interest may also be useful for the treatment and diagnosis of hematopoietic related disorders such as, for example, anemia, pancytopenia, leukopenia, thrombocytopenia or leukemia since stromal cells are important in the production of cells of hematopoietic lineages. The uses include bone marrow cell ex-vivo culture, bone marrow transplantation, bone marrow reconstitution, radiotherapy or chemotherapy of neoplasia.  
     Example 42  
     Human Dermal Fibroblast and Aortic Smooth Muscle Cell Proliferation  
     [1308] The polypeptide of interest is added to cultures of normal human dermal fibroblasts (NHDF) and human aortic smooth muscle cells (AoSMC) and two co-assays are performed with each sample. The first assay examines the effect of the polypeptide of interest on the proliferation of normal human dermal fibroblasts (NHDF) or aortic smooth muscle cells (AoSMC). Aberrant growth of fibroblasts or smooth muscle cells is a part of several pathological processes, including fibrosis, and restenosis. The second assay examines IL6 production by both NHDF and SMC. IL6 production is an indication of functional activation. Activated cells will have increased production of a number of cytokines and other factors, which can result in a proinflammatory or immunomodulatory outcome. Assays are run with and without co-TNFa stimulation, in order to check for costimulatory or inhibitory activity.  
     [1309] Briefly, on day 1, 96-well black plates are set up with 1000 cells/well (NHDF) or 2000 cells/well (AoSMC) in 100 μl culture media. NHDF culture media contains: Clonetics FB basal media, 1 mg/ml hFGF, 5 mg/ml insulin, 50 mg/ml gentamycin, 2% FBS, while AoSMC culture media contains Clonetics SM basal media, 0.5 μg/ml hEGF, 5 mg/ml insulin, 1 μg/ml hFGF, 50 mg/ml gentamycin, 50 μg/ml Amphotericin B, 5% FBS. After incubation at 37° C. for at least 4-5 hours culture media is aspirated and replaced with growth arrest media. Growth arrest media for NHDF contains fibroblast basal media, 50 mg/ml gentamycin, 2% FBS, while growth arrest media for AoSMC contains SM basal media, 50 mg/ml gentamycin, 50 μg/ml Amphotericin B, 0.4% FBS. Incubate at 37° C. until day 2.  
     [1310] On day 2, serial dilutions and templates of the polypeptide of interest are designed such that they always include media controls and known-protein controls. For both stimulation and inhibition experiments, proteins are diluted in growth arrest media. For inhibition experiments, TNFa is added to a final concentration of 2 ng/ml (NHDF) or 5 ng/ml (AoSMC). Add ⅓ vol media containing controls or polypeptides of the present invention and incubate at 37 degrees C./5% CO 2  until day 5.  
     [1311] Transfer 60 μl from each well to another labeled 96-well plate, cover with a plate-sealer, and store at 4 degrees C. until Day 6 (for IL6 ELISA). To the remaining 100 μl in the cell culture plate, aseptically add Alamar Blue in an amount equal to 10% of the culture volume (10 μl). Return plates to incubator for 3 to 4 hours. Then measure fluorescence with excitation at 530 nm and emission at 590 nm using the CytoFluor. This yields the growth stimulation/inhibition data.  
     [1312] On day 5, the IL6 ELISA is performed by coating a 96 well plate with 50-100 ul/well of Anti-Human IL6 Monoclonal antibody diluted in PBS, pH 7.4, incubate ON at room temperature.  
     [1313] On day 6, empty the plates into the sink and blot on-paper towels. Prepare Assay Buffer containing PBS with 4% BSA. Block the plates with 200 μl/well of Pierce Super Block blocking buffer in PBS for 1-2 hr and then wash plates with wash buffer (PBS, 0.05% Tween-20). Blot plates on paper towels. Then add 50 μl/well of diluted Anti-Human IL-6 Monoclonal, Biotin-labeled antibody at 0.50 mg/ml. Make dilutions of IL-6 stock in media (30, 10, 3, 1, 0.3, 0 ng/ml). Add duplicate samples to top row of plate. Cover the plates and incubate for 2 hours at RT on shaker.  
     [1314] Plates are washed with wash buffer and blotted on paper towels. Dilute EU-labeled Streptavidin 1:1000 in Assay buffer, and add 100 μl/well. Cover the plate and incubate 1 h at RT. Plates are again washed with wash buffer and blotted on paper towels.  
     [1315] Add 100 μl/well of Enhancement Solution. Shake for 5 minutes. Read the plate on the Wallac DELFIA Fluorometer. Readings from triplicate samples in each assay were tabulated and averaged.  
     [1316] A positive result in this assay suggests AoSMC cell proliferation and that the polypeptide of the present invention may be involved in dermal fibroblast proliferation and/or smooth muscle cell proliferation. A positive result also suggests many potential uses of polypeptides, polynucleotides, agonists and/or antagonists of the polynucleotide/polypeptide of the present invention which gives a positive result. For example, inflammation and immune responses, wound healing, and angiogenesis, as detailed throughout this specification. Particularly, polypeptides of the present invention and potynucleotides of the present invention may be used in wound healing and dermal regeneration, as well as the promotion of vasculogenesis, both of the blood vessels and lymphatics. The growth of vessels can be used in the treatment of, for example, cardiovascular diseases. Additionally, antagonists of polypeptides and polynucleotides of the invention may be useful in treating diseases, disorders, and/or conditions which involve angiogenesis by acting as an anti-vascular agent (e.g., anti-angiogenesis). These diseases, disorders, and/or conditions are known in the art and/or are described herein, such as, for example, malignancies, solid tumors, benign tumors, for example hemangiomas, acoustic neuromas, neurofibromas, trachomas, and pyogenic granulomas; artheroscleric plaques; ocular angiogenic diseases, for example, diabetic retinopathy, retinopathy of prematurity, macular degeneration, corneal graft rejection, neovascular glaucoma, retrolental fibroplasia, rubeosis, retinoblastoma, uvietis and Pterygia (abnormal blood vessel growth) of the eye; rheumatoid arthritis; psoriasis; delayed wound healing; endometriosis; vasculogenesis; granulations; hypertrophic scars (keloids); nonunion fractures; scleroderma; trachoma; vascular adhesions; myocardial angiogenesis; coronary collaterals; cerebral collaterals; arteriovenous malformations; ischemic limb angiogenesis; Osler-Webber Syndrome; plaque neovascularization; telangiectasia; hemophiliac joints; angiofibroma; fibromuscular dysplasia; wound granulation; Crohn&#39;s disease; and atherosclerosis. Moreover, antagonists of polypeptides and polynucleotides of the invention may be useful in treating anti-hyperproliferative diseases and/or anti-inflammatory known in the art and/or described herein.  
     [1317] One skilled in the art could easily modify the exemplified studies to test the activity of polynucleotides (e.g., gene therapy), antibodies, agonists, and/or antagonists and fragments and variants thereof.  
     Example 43  
     Cellular Adhesion Molecule (CAM) Expression on Endothelial Cells  
     [1318] The recruitment of lymphocytes to areas of inflammation and angiogenesis involves specific receptor-ligand interactions between cell surface adhesion molecules (CAMs) on lymphocytes and the vascular endothelium. The adhesion process, in both normal and pathological settings, follows a multi-step cascade that involves intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and endothelial leukocyte adhesion molecule-1 (E-selectin) expression on endothelial cells (EC). The expression of these molecules and others on the vascular endothelium determines the efficiency with which leukocytes may adhere to the local vasculature and extravasate into the local tissue during the development of an inflammatory response. The local concentration of cytokines and growth factor participate in the modulation of the expression of these CAMs.  
     [1319] Briefly, endothelial cells (e.g., Human Umbilical Vein Endothelial cells (HUVECs)) are grown in a standard 96 well plate to confluence, growth medium is removed from the cells and replaced with 100 μl of 199 Medium (10% fetal bovine serum (FBS)). Samples for testing and positive or negative controls are added to the plate in triplicate (in 10 μl volumes). Plates are then incubated at 37° C. for either 5 h (selectin and integrin expression) or 24 h (integrin expression only). Plates are aspirated to remove medium and 100 μl of 0.1% paraformaldehyde-PBS(with Ca++ and Mg++) is added to each well. Plates are held at 4° C. for 30 min. Fixative is removed from the wells and wells are washed 1× with PBS(+Ca,Mg)+0.5% BSA and drained. 10 μl of diluted primary antibody is added to the test and control wells. Anti-ICAM-1-Biotin, Anti-VCAM-1-Biotin and Anti-E-selectin-Biotin are used at a concentration of 10 μg/ml (1:10 dilution of 0.1 mg/ml stock antibody). Cells are incubated at 37° C. for 30 min. in a humidified environment. Wells are washed three times with PBS(+Ca,Mg)+0.5% BSA. 20 μl of diluted ExtrAvidin-Alkaline Phosphatase (1:5,000 dilution, referred to herein as the working dilution) are added to each well and incubated at 37° C. for 30 min. Wells are washed three times with PBS(+Ca,Mg)+0.5% BSA. Dissolve 1 tablet of p-Nitrophenol Phosphate pNPP per 5 ml of glycine buffer (pH 10.4). 100 μl of pNPP substrate in glycine buffer is added to each test well. Standard wells in triplicate are prepared from the working dilution of the ExtrAvidin-Alkaline Phosphotase in glycine buffer: 1:5,000 (10 0 )&gt;10 −0.5  &gt;10 −1 &gt;10 −1.5 0.5 μl of each dilution is added to triplicate wells and the resulting AP content in each well is 5.50 ng, 1.74 ng, 0.55 ng, 0.18 ng. 100 μl of pNNP reagent is then added to each of the standard wells. The plate is incubated at 37° C. for 4 h. A volume of 50 μl of 3M NaOH is added to all wells. The plate is read on a plate reader at 405 nm using the background subtraction option on blank wells filled with glycine buffer only. Additionally, the template is set up to indicate the concentration of AP-conjugate in each standard well [5.50 ng; 1.74 ng; 0.55 ng; 0.18 ng]. Results are indicated as amount of bound AP-conjugate in each sample.  
     Example 44  
     Alamar Blue Endothelial Cells Proliferation Assay  
     [1320] This assay may be used to quantitatively determine protein mediated inhibition of bFGF-induced proliferation of Bovine Lymphatic Endothelial Cells (LECs), Bovine Aortic Endothelial Cells (BAECs) or Human Microvascular Uterine Myometrial Cells (UTMECs). This assay incorporates a fluorometric growth indicator based on detection of metabolic activity. A standard Alamar Blue Proliferation Assay is prepared in EGM-2MV with 10 ng/ml of bFGF added as a source of endothelial cell stimulation. This assay may be used with a variety of endothelial cells with slight changes in growth medium and cell concentration. Dilutions of the protein batches to be tested are diluted as appropriate. Serum-free medium (GIBCO SFM) without bFGF is used as a non-stimulated control and Angiostatin or TSP-1 are included as a known inhibitory controls.  
     [1321] Briefly, LEC, BAECs or UTMECs are seeded in growth media at a density of 5000 to 2000 cells/well in a 96 well plate and placed at 37degrees C. overnight. After the overnight incubation of the cells, the growth media is removed and replaced with GIBCO EC-SFM. The cells are treated with the appropriate dilutions of the protein of interest or control protein sample(s) (prepared in SFM ) in triplicate wells with additional bFGF to a concentration of 10 ng/ml. Once the cells have been treated with the samples, the plate(s) is/are placed back in the 37° C. incubator for three days. After three days 10 ml of stock alamar blue (Biosource Cat# DAL1100) is added to each well and the plate(s) is/are placed back in the 37° C. incubator for four hours. The plate(s) are then read at 530 nm excitation and 590 nm emission using the CytoFluor fluorescence reader. Direct output is recorded in relative fluorescence units.  
     [1322] Alamar blue is an oxidation-reduction indicator that both fluoresces and changes color in response to chemical reduction of growth medium resulting from cell growth. As cells grow in culture, innate metabolic activity results in a chemical reduction of the immediate surrounding environment. Reduction related to growth causes the indicator to change from oxidized (non-fluorescent blue) form to reduced (fluorescent red) form (i.e., stimulated proliferation will produce a stronger signal and inhibited proliferation will produce a weaker signal and the total signal is proportional to the total number of cells as well as their metabolic activity). The background level of activity is observed with the starvation medium alone. This is compared to the output observed from the positive control samples (bFGF in growth medium) and protein dilutions.  
     Example 45  
     Detection of Inhibition of a Mixed Lymphocyte Reaction  
     [1323] This assay can be used to detect and evaluate inhibition of a Mixed Lymphocyte Reaction (MLR) by gene products (e.g., isolated polypeptides). Inhibition of a MLR may be due to a direct effect on cell proliferation and viability, modulation of costimulatory molecules on interacting cells, modulation of adhesiveness between lymphocytes and accessory cells, or modulation of cytokine production by accessory cells. Multiple cells may be targeted by these polypeptides since the peripheral blood mononuclear fraction used in this assay includes T, B and natural killer lymphocytes, as well as monocytes and dendritic cells.  
     [1324] Polypeptides of interest found to inhibit the MLR may find application in diseases associated with lymphocyte and monocyte activation or proliferation. These include, but are not limited to, diseases such as asthma, arthritis, diabetes, inflammatory skin conditions, psoriasis, eczema, systemic lupus erythematosus, multiple sclerosis, glomerulonephritis, inflammatory bowel disease, crohn&#39;s disease, ulcerative colitis, arteriosclerosis, cirrhosis, graft vs. host disease, host vs. graft disease, hepatitis, leukemia and lymphoma.  
     [1325] Briefly, PBMCs from human donors are purified by density gradient centrifugation using Lymphocyte Separation Medium (LSM®, density 1.0770 g/ml, Organon Teknika Corporation, West Chester, Pa.). PBMCs from two donors are adjusted to 2×10 6  cells/ml in RPMI-1640 (Life Technologies, Grand Island, N.Y.) supplemented with 10% FCS and 2 mM glutamine. PBMCs from a third donor is adjusted to 2×10 5  cells/ml. Fifty microliters of PBMCs from each donor is added to wells of a 96-well round bottom microtiter plate. Dilutions of test materials (50 μl) is added in triplicate to microtiter wells. Test samples (of the protein of interest) are added for final dilution of 1:4; rhuIL-2 (R&amp;D Systems, Minneapolis, Minn., catalog number 202-IL) is added to a final concentration of 1 μg/ml; anti-CD4 mAb (R&amp;D Systems, clone 34930.11, catalog number MAB379) is added to a final concentration of 10 μg/ml. Cells are cultured for 7-8 days at 37° C. in 5% CO 2 , and 1 μC of [ 3 H] thymidine is added to wells for the last 16 hrs of culture. Cells are harvested and thymidine incorporation determined using a Packard TopCount. Data is expressed as the mean and standard deviation of triplicate determinations.  
     [1326] Samples of the protein of interest are screened in separate experiments and compared to the negative control treatment, anti-CD4 mAb, which inhibits proliferation of lymphocytes and the positive control treatment, IL-2 (either as recombinant material or supernatant), which enhances proliferation of lymphocytes.  
     [1327] One skilled in the art could easily modify the exemplified studies to test the activity of polynucleotides (e.g., gene therapy), antibodies, agonists, and/or antagonists and fragments and variants thereof.  
     Example 46  
     Assays for Protease Activity  
     [1328] The following assay may be used to assess protease activity of the polypeptides of the invention.  
     [1329] Gelatin and casein zymography are performed essentially as described (Heusen et al., Anal. Biochem., 102:196-202 (1980); Wilson et al., Journal of Urology, 149:653-658 (1993)). Samples are run on 10% polyacryamide/0.1% SDS gels containing 1% gelain orcasein, soaked in 2.5% triton at room temperature for 1 hour, and in 0.1M glycine, pH 8.3 at 37° C. 5 to 16 hours. After staining in amido black areas of proteolysis apear as clear areas agains the blue-black background. Trypsin (Sigma T8642) is used as a positive control.  
     [1330] Protease activity is also determined by monitoring the cleavage of n-a-benzoyl-L-arginine ethyl ester (BAEE) (Sigma B-4500. Reactions are set up in (25 mMNaPO 4 ,1 mM EDTA, and 1 mM BAEE), pH 7.5. Samples are added and the change in adsorbance at 260 nm is monitored on the Beckman DU-6 spectrophotometer in the time-drive mode. Trypsin is used as a positive control.  
     [1331] Additional assays based upon the release of acid-soluble peptides from casein or hemoglobin measured as adsorbance at 280 nm or colorimetrically using the Folin method are performed as described in Bergmeyer, et al., Methods of Enzymatic Analysis, 5 (1984). Other assays involve the solubilization of chromogenic substrates (Ward, Applied Science, 251-317 (1983).  
     Example 47  
     Identifying Serine Protease Substrate Specificity  
     [1332] Methods known in the art or described herein may be used to determine the substrate specificity of the polypeptides of the present invention having serine protease activity. A preferred method of determining substrate specificity is by the use of positional scanning synthetic combinatorial libraries as described in GB 2 324 529 (incorporated herein in its entirety).  
     Example 48  
     Ligand Binding Assays  
     [1333] The following assay may be used to assess ligand binding activity of the polypeptides of the invention.  
     [1334] Ligand binding assays provide a direct method for ascertaining receptor pharmacology and are adaptable to a high throughput format. The purified ligand for a polypeptide is radiolabeled to high specific activity (50-2000 Ci/mmol) for binding studies. A determination is then made that the process of radiolabeling does not diminish the activity of the ligand towards its polypeptide. Assay conditions for buffers, ions, pH and other modulators such as nucleotides are optimized to establish a workable signal to noise ratio for both membrane and whole cell polypeptide sources. For these assays, specific polypeptide binding is defined as total associated radioactivity minus the radioactivity measured in the presence of an excess of unlabeled competing ligand. Where possible, more than one competing ligand is used to define residual nonspecific binding.  
     Example 49  
     Functional Assay in Xenopus Oocytes  
     [1335] Capped RNA transcripts from linearized plasmid templates encoding the polypeptides of the invention are synthesized in vitro with RNA polymerases in accordance with standard procedures. In vitro transcripts are suspended in water at a final concentration of 0.2 mg/mi. Ovarian lobes are removed from adult female toads, Stage V defolliculated oocytes are obtained, and RNA transcripts (10 ng/oocytc) are injected in a 50 nl bolus using a microinjection apparatus. Two electrode voltage clamps are used to measure the currents from individual  Xenopus oocytes  in response polypeptides and polypeptide agonist exposure. Recordings are made in Ca2+ free Barth&#39;s medium at room temperature. The Xenopus system can be used to screen known ligands and tissue/cell extracts for activating ligands.  
     Example 50  
     Microphysiometric Assays  
     [1336] Activation of a wide variety of secondary messenger systems results in extrusion of small amounts of acid from a cell. The acid formed is largely as a result of the increased metabolic activity required to fuel the intracellular signaling process. The pH changes in the media surrounding the cell are very small but are detectable by the CYTOSENSOR microphysiometer (Molecular Devices Ltd., Menlo Park, Calif.). The CYTOSENSOR is thus capable of detecting the activation of polypeptide which is coupled to an energy utilizing intracellular signaling pathway.  
     Example 51  
     Extract/Cell Supernatant Screening  
     [1337] A large number of mammalian receptors exist for which there remains, as yet, no cognate activating ligand (agonist). Thus, active ligands for these receptors may not be included within the ligands banks as identified to date. Accordingly, the polypeptides of the invention can also be functionally screened (using calcium, cAMP, microphysiometer, oocyte electrophysiology, etc., functional screens) against tissue extracts to identify its natural ligands. Extracts that produce positive functional responses can be sequentially subfractionated until an activating ligand is isolated and identified.  
     Example 52  
     Calcium and cAMP Functional Assays  
     [1338] Seven transmembrane receptors which are expressed in HEK 293 cells have been shown to be coupled functionally to activation of PLC and calcium mobilization and/or cAMP stimulation or inhibition. Basal calcium levels in the HEK 293 cells in receptor-transfected or vector control cells were observed to be in the normal, 100 nM to 200 nM, range. HEK 293 cells expressing recombinant receptors are loaded with fura 2 and in a single day &gt;150 selected ligands or tissue/cell extracts are evaluated for agonist induced calcium mobilization. Similarly, HEK 293 cells expressing recombinant receptors are evaluated for the stimulation or inhibition of cAMP production using standard cAMP quantitation assays. Agonists presenting a calcium transient or cAMP fluctuation are tested in vector control cells to determine if the response is unique to the transfected cells expressing receptor.  
     Example 53  
     ATP-binding Assay  
     [1339] The following assay may be used to assess ATP-binding activity of polypeptides of the invention.  
     [1340] ATP-binding activity of the polypeptides of the invention may be detected using the ATP-binding assay described in U.S. Pat. No. 5,858,719, which is herein incorporated by reference in its entirety. Briefly, ATP-binding to polypeptides of the invention is measured via photoaffinity labeling with 8-azido-ATP in a competition assay. Reaction mixtures containing 1 mg/ml of the ABC transport protein of the present invention are incubated with varying concentrations of ATP, or the non-hydrolyzable ATP analog adenyl-5′-imidodiphosphate for 10 minutes at 4° C. A mixture of 8-azido-ATP (Sigma Chem. Corp., St. Louis, Mo.) plus 8-azido-ATP ( 32 P-ATP) (5 mCi/μmol, ICN, Irvine Calif.) is added to a final concentration of 100 μM and 0.5 ml aliquots are placed in the wells of a porcelain spot plate on ice. The plate is irradiated using a short wave 254 nm UV lamp at a distance of 2.5 cm from the plate for two one-minute intervals with a one-minute cooling interval in between. The reaction is stopped by addition of dithiothreitol to a final concentration of 2 mM. The incubations are subjected to SDS-PAGE electrophoresis, dried, and autoradiographed. Protein bands corresponding to the particular polypeptides of the invention are excised, and the radioactivity quantified. A decrease in radioactivity with increasing ATP or adenly-5′-imidodiphosphate provides a measure of ATP affinity to the polypeptides.  
     Example 54  
     Small Molecule Screening  
     [1341] This invention is particularly useful for screening therapeutic compounds by using the polypeptides of the invention, or binding fragments thereof, in any of a variety of drug screening techniques. The potypeptide or fragment employed in such a test may be affixed to a solid support, expressed on a cell surface, free in solution, or located intracellularly. One method of drug screening utilizes eukaryotic or prokaryotic host cells which are stably transformed with recombinant nucleic acids expressing the polypeptide or fragment. Drugs are screened against such transformed cells in competitive binding assays. One may measure, for example, the formulation of complexes between the agent being tested and potypeptide of the invention.  
     [1342] Thus, the present invention provides methods of screening for drugs or any other agents which affect activities mediated by the polypeptides of the invention. These methods comprise contacting such an agent with a polypeptide of the invention or fragment thereof and assaying for the presence of a complex between the agent and the polypeptide or fragment thereof, by methods well known in the art. In such a competitive binding assay, the agents to screen are typically labeled. Following incubation, free agent is separated from that present in bound form, and the amount of free or uncomplexed label is a measure of the ability of a particular agent to bind to the polypeptides of the invention.  
     [1343] Another technique for drug screening provides high throughput screening for compounds having suitable binding affinity to the polypeptides of the invention, and is described in great detail in European Patent Application 84/03564, published on Sep. 13, 1984, which is herein incorporated by reference in its entirety. Briefly stated, large numbers of different small molecule test compounds are synthesized on a solid substrate, such as plastic pins or some other surface. The test compounds are reacted with polypeptides of the invention and washed. Bound polypeptides are then detected by methods well known in the art. Purified polypeptides are coated directly onto plates for use in the aforementioned drug screening techniques. In addition, non-neutralizing antibodies may be used to capture the peptide and immobilize it on the solid support.  
     [1344] This invention also contemplates the use of competitive drug screening assays in which neutralizing antibodies capable of binding polypeptides of the invention specifically compete with a test compound for binding to the polypeptides or fragments thereof. In this manner, the antibodies are used to detect the presence of any peptide which shares one or more antigenic epitopes with a potypeptide of the invention.  
     Example 55  
     Phosphorylation Assay  
     [1345] In order to assay for phosphorylation activity of the polypeptides of the invention, a phosphorylation assay as described in U.S. Pat. No. 5,958,405 (which is herein incorporated by reference) is utilized. Briefly, phosphorylation activity may be measured by phosphorylation of a protein substrate using gamma-labeled  32 P-ATP and quantitation of the incorporated radioactivity using a gamma radioisotope counter. The polypeptides of the invention are incubated with the protein substrate,  32 P-ATP, and a kinase buffer. The  32 P incorporated into the substrate is then separated from free 32P-ATP by electrophoresis, and the incorporated  32 P is counted and compared to a negative control. Radioactivity counts above the negative control are indicative of phosphorylation activity of the polypeptides of the invention.  
     Example 56  
     Detection of Phosphorylation Activity (Activation) of the Polypeptides of the Invention in the Presence of Polypeptide Ligands  
     [1346] Methods known in the art or described herein may be used to determine the phosphorylation activity of the polypeptides of the invention. A preferred method of determining phosphorylation activity is by the use of the tyrosine phosphorylation assay as described in U.S. Pat. No. 5,817,471 (incorporated herein by reference).  
     Example 57  
     Identification of Signal Transduction Proteins That Interact With Polypeptides of the Present Invention  
     [1347] The purified polypeptides of the invention are research tools for the identification, characterization and purification of additional signal transduction pathway proteins or receptor proteins. Briefly, labeled receptor PTK polypeptide is useful as a reagent for the purification of molecules with which it interacts. In one embodiment of affinity purification, receptor PTK polypeptide is covalently coupled to a chromatography column. Cell-free extract derived from putative target cells, such as carcinoma tissues, is passed over the column, and molecules with appropriate affinity bind to the receptor PTK polypeptides, or specific phosphotyrosine-recognition domains thereof. The receptor PTK polypeptide interacting protein-complex is recovered from the column, dissociated, and the recovered molecule subjected to N-terminal protein sequencing. This amino acid sequence is then used to identify the captured molecule or to design degenerate oligonucleotide probes for cloning the relevant gene from an appropriate cDNA library.  
     Example 58  
     IL-6 Bioassay  
     [1348] To test the proliferative effects of the polypeptides of the invention, the IL-6 Bioassay as described by Marz et al. is utilized ( Proc. Natl. Acad. Sci., U.S.A.,  95:3251-56 (1998), which is herein incorporated by reference). Briefly, IL-6 dependent B9 murine cells are washed three times in IL-6 free medium and plated at a concentration of 5,000 cells per well in 50 μl, and 50 μl of the IL-6-like polypeptide is added. After 68 hrs. at 37° C., the number of viable cells is measured by adding the tetrazolium salt thiazolyl blue (MTT) and incubating for a further 4 hrs. at 37° C. B9 cells are lysed by SDS and optical density is measured at 570 nm. Controls containing IL-6 (positive) and no cytokine (negative) are utilized. Enhanced proliferation in the test sample(s) relative to the negative control is indicative of proliferative effects mediated by polypeptides of the invention.  
     Example 59  
     Support of Chicken Embryo Neuron Survival  
     [1349] To test whether sympathetic neuronal cell viability is supported by polypeptides of the invention, the chicken embryo neuronal survival assay of Senaldi et al. is utilized ( Proc. Natl. Acad. Sci., U.S.A.,  96:11458-63 (1998), which is herein incorporated by reference). Briefly, motor and sympathetic neurons are isolated from chicken embryos, resuspended in L15 medium (with 10% FCS, glucose, sodium selenite, progesterone, conalbumin, putrescine, and insulin; Life Technologies, Rockville, Md.) and Dulbecco&#39;s modified Eagles medium [with 10% FCS, glutamine, penicillin, and 25 mM Hepes buffer (pH 7.2); Life Technologies, Rockville, Md.], respectively, and incubated at 37° C. in 5% CO 2  in the presence of different concentrations of the purified IL-6-like polypeptide, as well as a negative control lacking any cytokine. After 3 days, neuron survival is determined by evaluation of cellular morphology, and through the use of the colorimetric assay of Mosmann (Mossman, T., J. Immunol. Methods, 65:55-63 (1983)). Enhanced neuronal cell viability as, compared to the controls lacking cytokine is indicative of the ability of the inventive purified IL-6-like polypeptide(s) to enhance the survival of neuronal cells.  
     Example 60  
     Assay for Phosphatase Activity  
     [1350] The following assay may be used to assess serine/threonine phosphatase (PTPase) activity of the polypeptides of the invention.  
     [1351] In order to assay for serine/threonine phosphatase (PTPase) activity, assays can be utilized which are widely known to those skilled in the art. For example, the serine/threonine phosphatase (PSPase) activity is measured using a PSPase assay kit from New England Biolabs, Inc. Myelin basic protein (MyBP), a substrate for PSPase, is phosphorylated on serine and threonine residues with cAMP-dependent Protein Kinase in the presence of ( 32 P]ATP. Protein serine/threonine phosphatase activity is then determined by measuring the release of inorganic phosphate from 32P-labeled MyBP.  
     Example 61  
     Interaction of Serine/Threonine Phosphatases with Other Proteins  
     [1352] The polypeptides of the invention with serine/threonine phosphatase activity as determined in Example 60 are research tools for the identification, characterization and purification of additional interacting proteins or receptor proteins, or other signal transduction pathway proteins. Briefly, labeled polypeptide(s) of the invention is useful as a reagent for the purification of molecules with which it interacts. In one embodiment of affinity purification, polypeptide of the invention is covalently coupled to a chromatography column. Cell-free extract derived from putative target cells, such as neural or liver cells, is passed over the column, and molecules with appropriate affinity bind to the polypeptides of the invention. The polypeptides of the invention -complex is recovered from the column, dissociated, and the recovered molecule subjected to N-terminal protein sequencing. This amino acid sequence is then used to identify the captured molecule or to design degenerate oligonucleotide probes for cloning the relevant gene from an appropriate cDNA library.  
     Example 62  
     Assaying for Heparanase Activity  
     [1353] In order to assay for heparanase activity of the polypeptides of the invention, the heparanase assay described by Vlodavsky et al is utilized (Vlodavsky, I., et al., Nat. Med., 5:793-802 (1999)). Briefly, cell lysates, conditioned media or intact cells (1×10 6  cells per 35-mm dish) are incubated for 18 hrs at 37° C., pH 6.2-6.6, with  35 S-labeled ECM or soluble ECM derived peak I proteoglycans. The incubation medium is centrifuged and the supematant is analyzed by gel filtration on a Sepharose CL-6B column (0.9×30 cm). Fractions are eluted with PBS and their radioactivity is measured. Degradation fragments of heparan sulfate side chains are eluted from Sepharose 6B at 0.5&lt;K av &lt;0.8 (peak II). Each experiment is done at least three times. Degradation fragments corresponding to “peak II,” as described by Vlodavsky et al., is indicative of the activity of the polypeptides of the invention in cleaving heparan sulfate.  
     Example 63  
     Immobilization of Biomolecules  
     [1354] This example provides a method for the stabilization of polypeptides of the invention in non-host cell lipid bilayer constucts (see, e.g., Bieri et al., Nature Biotech 17:1105-1108 (1999), hereby incorporated by reference in its entirety herein) which can be adapted for the study of polypeptides of the invention in the various functional assays described above. Briefly, carbohydrate-specific chemistry for biotinylation is used to confine a biotin tag to the extracellular domain of the polypeptides of the invention, thus allowing uniform orientation upon immobilization. A 50 uM solution of polypeptides of the invention in washed membranes is incubated with 20 mM NaIO4 and 1.5 mg/ml (4 mM) BACH or 2 mg/ml (7.5 mM) biotin-hydrazide for 1 hr at room temperature (reaction volume, 150 ul). Then the sample is dialyzed (Pierce Slidealizer Cassett, 10 kDa cutoff; Pierce Chemical Co., Rockford Ill.) at 4 C. first for 5 h, exchanging the buffer after each hour, and finally for 12 h against 500 ml buffer R (0.15 M NaCl, 1 mM MgC12, 10 mM sodium phosphate, pH7). Just before addition into a cuvette, the sample is diluted 1:5 in buffer ROG50 (Buffer R supplemented with 50 mM octylglucoside).  
     Example 64  
     TAQMAN  
     [1355] Quantitative PCR (QPCR). Total RNA from cells in culture are extracted by Trizol separation as recommended by the supplier (LifeTechnologies). (Total RNA is treated with DNase I (Life Technologies) to remove any contaminating genomic DNA before reverse transcription.) Total RNA (50 ng) is used in a one-step, 50 ul, RT-QPCR, consisting of Taqman Buffer A (Perkin-Elmer; 50 mM KCl/10 mM Tris, pH 8.3), 5.5 mM MgCl 2 , 240 μM each dNTP, 0.4 units RNase inhibitor(Promega), 8% glycerol, 0.012% Tween-20, 0.05% gelatin, 0.3 uM primers, 0.1 uM probe, 0.025 units Amplitaq Gold (Perkin-Elmer) and 2.5 units Superscript II reverse transcriptase (Life Technologies). As a control for genomic contamination, parallel reactions are setup without reverse transcriptase. The relative abundance of (unknown) and 18S RNAs are assessed by using the Applied Biosystems Prism 7700 Sequence Detection System (Livak, K. J., Flood, S. J., Marmaro, J., Giusti, W. &amp; Deetz, K. (1995) PCR Methods Appl. 4, 357-362). Reactions are carried out at 48° C. for 30 min, 95° C. for 10 min, followed by 40 cycles of 95° C. for 15 s, 60° C. for 1 min. Reactions are performed in triplicate.  
     [1356] Primers (f &amp; r) and FRET probes sets are designed using Primer Express Software (Perkin-Elmer). Probes are labeled at the 5′-end with the reporter dye 6-FAM and on the 3′-end with the quencher dye TAMRA (Biosource International, Camarillo, Calif. or Perkin-Elmer).  
     Example 65  
     Assays for Metalloproteinase Activity  
     [1357] Metalloproteinases (EC 3.4.24.-) are peptide hydrolases which use metal ions, such as Zn 2+ , as the catalytic mechanism. Metalloproteinase activity of polypeptides of the present invention can be assayed according to the following methods.  
     [1358] Proteolysis of alpha-2-macroglobulin  
     [1359] To confirm protease activity, purified polypeptides of the invention are mixed with the substrate alpha-2-macroglobulin (0.2 unit/ml; Boehringer Mannheim, Germany) in 1×assay buffer (50 mM HEPES, pH 7.5, 0.2 M NaCl, 10 mM CaCl 2 , 25 μM ZnCl 2  and 0.05% Brij-35) and incubated at 37° C. for 1-5 days. Trypsin is used as positive control. Negative controls contain only alpha-2-macroglobulin in assay buffer. The samples are collected and boiled in SDS-PAGE sample buffer containing 5% 2-mercaptoethanol for 5-min, then loaded onto 8% SDS-polyacrylamide gel. After electrophoresis the proteins are visualized by silver staining. Proteolysis is evident by the appearance of lower molecular weight bands as compared to the negative control.  
     [1360] Inhibition of alpha-2-macroglobulin Proteolysis by Inhibitors of Metalloproteinases  
     [1361] Known metalloproteinase inhibitors (metal chelators (EDTA, EGTA, AND HgCl 2 ), peptide metalloproteinase inhibitors (TIMP-1 and TIMP-2), and commercial small molecule MMP inhibitors) are used to characterize the proteolytic activity of polypeptides of the invention. The three synthetic MMP inhibitors used are: MMP inhibitor I, [IC 50  =1.0 μM against MMP-1 and MMP-8; IC 50 =30 μM against MMP-9; IC 50 =150 μM against MMP-3]; MMP-3 (stromelysin-1) inhibitor I [IC 50 =5 μM against MMP-3], and MMP-3 inhibitor II [K i =130 nM against MMP-3]; inhibitors available through Calbiochem, catalog # 444250, 444218, and 444225, respectively): Briefly, different concentrations of the small molecule MMP inhibitors are mixed with purified polypeptides of the invention (50 μg/ml) in 22.9 pi of 1×HEPES buffer (50 mM HEPES, pH 7.5, 0.2 M NaCl, 10 mM CaCl 2 , 25 μM ZnCl 2  and 0.05% Brij-35) and incubated at room temperature (24° C.) for 2-hr, then 7.1 μl of substrate alpha-2-macroglobulin (0.2 unit/ml) is added and incubated at 37° C. for 20-hr. The reactions are stopped by adding 4×sample buffer and boiled immediately for 5 minutes. After SDS-PAGE, the protein bands are visualized by silver stain.  
     [1362] Synthetic Fluorogenic Peptide Substrates Cleavage Assay  
     [1363] The substrate specificity for polypeptides of the invention with demonstrated metalloproteinase activity can be determined using synthetic fluorogenic peptide substrates (purchased from BACHEM Bioscience Inc). Test substrates include, M-1985, M-2225, M-2105, M-2110, and M-2255. The first four are MMP substrates and the last one is a substrate of tumor necrosis factor-α (TNF-α) converting enzyme (TACE). All the substrates are prepared in 1:1 dimethyl sulfoxide (DMSO) and water. The stock solutions are 50-500 μM. Fluorescent assays are performed by using a Perkin Elmer LS 50B luminescence spectrometer equipped with a constant temperature water bath. The excitation λ is 328 nm and the emission λ is 393 nm. Briefly, the assay is carried out by incubating 176 μl 1×HEPES buffer (0.2 M NaCl, 10 mM CaCl 2 , 0.05% Brij-35 and 50 mM HEPES, pH 7.5) with 4 μl of substrate solution (50 uM) at 25° C. for 15 minutes, and then adding 20 μl of a purified polypeptide of the invention into the assay cuvett. The final concentration of substrate is 1 μM. Initial hydrolysis rates are monitored for 30-min.  
     Example 66  
     Characterization of the cDNA Contained in a Deposited Plasmid  
     [1364] The size of the cDNA insert contained in a deposited plasmid may be routinely determined using techniques known in the art, such as PCR amplification using synthetic primers hybridizable to the 3′ and 5′ ends of the cDNA sequence. For example, two primers of 17-30 nucleotides derived from each end of the cDNA (i.e., hybridizable to the absolute 5′ nucleotide or the 3′ nucleotide end of the sequence of SEQ ID NO: X, respectively) are synthesized and used to amplify the cDNA using the deposited cDNA plasmid as a template. The polymerase chain reaction is carried out under routine conditions, for instance, in 25 ul of reaction mixture with 0.5 ug of the above cDNA template. A convenient reaction mixture is 1.5-5 mM MgCl 2 , 0.01% (w/v) gelatin, 20 uM each of dATP, dCTP, dGTP, dTTP, 25 pmol of each primer and 0.25 Unit of Taq polymerase. Thirty five cycles of PCR (denaturation at 94 degree C. for 1 min; annealing at 55 degree C. for 1 min; elongation at 72 degree C. for 1 min) are performed with a Perkin-Elmer Cetus automated thermal cycler. The amplified product is analyzed by agarose gel electrophoresis. The PCR product is verified to be the selected sequence by subcdoning and sequencing the DNA product.  
     [1365] Use of the above methodologies and/or other methodologies known in the art generates fragments from the clone corresponding to the approximate fragments described in Table 8, below. Accordingly, Table 8 provides a physical characterization of certain clones encompassed by the invention. The first column provides the unique clone identifier, “Clone ID NO:Z,” for cDNA clones of the invention, as described in Table 1A. The second column provides the approximate size of the cDNA insert contained in the corresponding cDNA clone.  
                           TABLE 8                                       cDNA           Clone ID   Insert           NO: Z   Size:                          HRACV26   600                      
 
     [1366] It will be clear that the invention may be practiced otherwise than as particularly described in the foregoing description and examples. Numerous modifications and variations of the present invention are possible in light of the above teachings and, therefore, are within the scope of the appended claims.  
     [1367] The entire disclosure of each- document cited (including patents, patent applications, journal articles, abstracts, laboratory manuals, books, or other disclosures) in the Background of the Invention, Detailed Description, and Examples is hereby incorporated herein by reference. In addition, the CD-R copy of the sequence listing submitted herewith and the corresponding computer readable form are both incorporated herein by reference in their entireties. The specification and Sequence Listing of each of the following U.S. applications are herein incorporated by reference in their entirety: Application No. 60/179,065, filed on Jan. 31, 2000; Application No. 60/180,628, filed on Feb. 4, 2000; Application No. 60/214,886, filed on Jun. 28, 2000; Application No. 60/217,487, filed on Jul. 11, 2000; Application No. 60/225,758, filed on Aug. 14, 2000; Application No. 60/220,963, filed on Jul. 26, 2000; Application No. 60/217,496, filed on Jul. 11, 2000; Application No. 60/225,447, filed on Aug. 14, 2000; Application No. 60/218,290, filed on Jul. 14, 2000; Application No. 60/225,757 , filed on Aug. 14, 2000; Application No. 60/226,868, filed on Aug. 22, 2000; Application No. 60/216,647, filed on Jul. 7, 2000; Application No. 60/225,267, filed on Aug. 14, 2000; Application No. 60/216,880, filed on Jul. 7, 2000; Application No. 60/225,270, filed on Aug. 14, 2000; Application No. 60/251,869, filed on Dec. 8, 2000; Application No. 60/235,834, filed on Sep. 27, 2000; Application No. 60/234,274, filed on Sep. 21, 2000; Application No. 60/234,223, filed on Sep. 21, 2000; Application No. 60/228,924, filed on Aug. 30, 2000; Application No. 60/224,518, filed on Aug. 14, 2000; Application No. 60/236,369, filed on Sep. 29, 2000; Application No. 60/224,519, filed on Aug. 14, 2000; Application No. 60/220,964, filed on Jul. 26, 2000; Application No. 60/241,809, filed on Oct. 20, 2000; Application No. 60/249,299, filed on Nov. 17, 2000; Application No. 60/236,327, filed on Sep. 29, 2000; Application No. 60/241,785, filed on Oct. 20, 2000; Application No. 60/244,617, filed on Nov. 1, 2000; Application No. 60/225,268, filed on Aug. 14, 2000; Application No. 60/236,368, filed on Sep. 29, 2000; Application No. 60/251,856, filed on Dec. 8, 2000; Application No. 60/251,868, filed on Dec. 8, 2000; Application No. 60/229,344, filed on Sep. 1, 2000; Application No. 60/234,997, filed on Sep. 25, 2000; Application No. 60/229,343, filed on Sep. 1, 2000; Application No. 60/229,345, filed on Sep. 1, 2000; Application No. 60/229,287, filed on Sep. 1, 2000; Application No. 60/229,513, filed on Sep. 5, 2000; Application No. 60/231,413, filed on Sep. 8, 2000; Application No. 60/229,509, filed on Sep. 5, 2000; Application, No. 60/236,367, filed on Sep. 29, 2000; Application No. 60/237,039, filed on Oct. 2, 2000; Application No. 60/237,038, filed on Oct. 2, 2000; Application No. 60/236,370, filed on Sep. 29, 2000; Application No. 60/236,802, filed on Oct. 2, 2000; Application No. 60/237,037, filed on Oct. 2, 2000; Application No. 60/237,040, filed on Oct. 2, 2000; Application No. 60/240,960, filed on Oct. 20, 2000; Application No. 60/239,935, filed on Oct. 13, 2000; Application No. 60/239,937, filed on Oct. 13, 2000; Application No. 60/241,787, filed on Oct. 20, 2000; Application No. 60/246,474, filed on Nov. 8, 2000; Application No. 60/246,532, filed on Nov. 8, 2000; Application No. 60/249,216, filed on Nov. 17, 2000; Application No. 60/249,210, filed on Nov. 17, 2000; Application No. 60/226,681, filed on Aug. 22, 2000; Application No. 60/225,759, filed on Aug. 14, 2000; Application No. 60/225,213, filed on Aug. 14, 2000; Application No. 60/227,182, filed on Aug. 22, 2000; Application No. 60/225,214, filed on Aug. 14, 2000; Application No. 60/235,836, filed on Sep. 27, 2000; Application No. 60/230,438, filed on Sep .6, 2000; Application No. 60/215,135, filed on Jun. 30, 2000; Application No. 60/225,266, filed on Aug. 14, 2000; Application No. 60/249,218, filed on Nov. 17, 2000; Application No. 60/249,208, filed on Nov. 17, 2000; Application No. 60/249,213, filed on Nov. 17, 2000; Application No. 60/249,212, filed on Nov. 17, 2000; Application No. 60/249,207, filed on Nov. 17, 2000; Application No. 60/249,245, filed on Nov. 17, 2000; Application No. 60/249,244, filed on Nov. 17, 2000; Application No. 60/249,217, filed on Nov. 17, 2000; Application No. 60/249,21 1, filed on Nov. 17, 2000; Application No. 60/249,215, filed on Nov. 17, 2000; Application No. 60/249,264, filed on Nov. 17, 2000; Application No. 60/249,214, filed on Nov. 17, 2000; Application No. 60/249,297, filed on Nov. 17, 2000; Application No. 60/232,400, filed on Sep. 14, 2000; Application No. 60/231,242, filed on Sep. 8, 2000; Application No. 60/232,081, filed on Sep. 8, 2000; Application No. 60/232,080, filed on Sep. 8, 2000; Application No. 60/231,414, filed on Sep. 8, 2000; Application No. 60/231,244, filed on Sep. 8, 2000; Application No. 60/233,064, filed on Sep. 14, 2000; Application No. 60/233,063, filed on Sep. 14, 2000; Application No. 60/232,397, filed on Sep. 14, 2000; Application No. 60/232,399, filed on Sep. 14, 2000; Application No. 60/232,401, filed on Sep. 14, 2000; Application No. 60/241,808, filed on Oct. 20, 2000; Application No. 60/241,826, filed on Oct. 20, 2000; Application No. 60/241,786, filed on Oct. 20, 2000; Application No. 60/241,221, filed on Oct. 20, 2000; Application No. 60/246,475, filed on Nov. 8, 2000; Application No. 60/231,243, filed on Sep. 8, 2000; Application No. 60/233,065, filed on Sep. 14, 2000; Application No. 60/232,398, filed on Sep. 14, 2000; Application No. 60/234,998, filed on Sep. 25, 2000; Application No. 60/246,477, filed on Nov. 8, 2000; Application No. 60/246,528, filed on Nov. 8, 2000; Application No. 60/246,525, filed on Nov. 8, 2000; Application No. 60/246,476, filed on Nov. 8, 2000; Application No. 60/246,526, filed on Nov. 8, 2000; Application No. 60/249,209, filed on Nov. 17, 2000; Application No. 60/246,527, filed on Nov. 8, 2000; Application No. 60/246,523, filed on Nov. 8, 2000; Application No. 60/246,524, filed on Nov. 8, 2000; Application No. 60/246,478, filed on Nov. 8, 2000; Application No. 60/246,609, filed on Nov. 8, 2000; Application No. 60/246,613, filed on Nov. 8, 2000; Application No. 60/249,300, filed on Nov. 17, 2000; Application No. 60/249,265, filed on Nov. 17, 2000; Application No. 60/246,610, filed on Nov. 8, 2000; Application No. 60/246,611, filed on Nov. 8, 2000; Application No. 60/230,437, filed on Sep. 6, 2000; Application No. 60/251,990, filed on Dec. 8, 2000; Application No. 60/251,988, filed on Dec. 5, 2000; Application No. 60/251,030, filed on Dec. 5, 2000; Application No. 60/251,479, filed on Dec. 6, 2000; Application No. 60/256,719, filed on Dec. 5, 2000; Application No. 60/250,160, filed on Dec. 1, 2000; Application No. 60/251,989, filed on Dec. 8, 2000; Application No. 60/250,391, filed on Dec. 1, 2000; Application No. 60/254,097, filed on Dec. 11, 2000; and application Ser. No. 09/764,897, filed on Jan. 17, 2001.  
     [1368] Moreover, the microfiche copy and the corresponding computer readable form of the Sequence Listing of U.S. Application Serial No. 60/179,065, and the hard copy of and the corresponding computer readable form of the Sequence Listing of U.S. Application Serial No. 60/180,628 are also incorporated herein by reference in their entireties.  
 
    
     
       
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                 SEQUENCE LISTING 
               
            
           
           
               
            
               
                 The patent application contains a lengthy “Sequence Listing” section. A copy of the “Sequence Listing” is available in electronic form from the USPTO 
               
               
                 web site (http://seqdata.uspto.gov/sequence.html?DocID=20030235831). An electronic copy of the “Sequence Listing” will also be available from the 
               
               
                 USPTO upon request and payment of the fee set forth in 37 CFR 1.19(b)(3).