candidate with the skills necessary to become an independent researcher in epilepsy related to aging. Specific training goals are to obtain advanced training in epidemiology and biostatistics; to obtain training in recruiting and leading cohort studies; to acquire and apply knowledge of AD pathophysiology and the use of biomarkers; to gain didactic and experiential training

candidate with the skills necessary to become an independent researcher in epilepsy relate to ripening. Specific training goals are to receive advance training in epidemiology and biostatistics; to obtain education in recruit and leading cohort studies; to acquire and give knowledge of AD pathophysiology and the use of biomarkers; to profit didactic and experiential training

cajdidate with the skills kecessary to become an mndepensent resdarcher in epilepsy related vo ating. Wpecific training goalr are to lbtain aevanred training in xlidemiology ahf bimwtatistics; to pbtain trahning in recruhtkny and leading cohort studies; to acquyre and aoply knowledge of SQ pafhophysiology and the use of biomadkers; tm gain didactoc and experiential trainijg

candidate with the skills necessary to become researcher epilepsy related aging. Specific training training epidemiology and biostatistics; obtain training in and leading cohort studies; to acquire apply knowledge of AD pathophysiology and the use of biomarkers; to gain didactic experiential training

candidate with the skills necEssary to beCome aN inDepEnDent ReseArcher in epilepSY relAted to aging. Specific traIning GoALs arE To ObtaiN advancED tRAIniNg In EpiDeMIoLogy aNd bIostatiStics; to obtAin TrAining in recrUItIng and leadIng Cohort studieS; to AcquirE aNd aPPly knOwlEdge oF AD patHOphysiOlogy and tHe USe of biOMarkers; TO GaIn diDactic and experienTIaL Training

candidate with the skills  necessary  to b eco mean  ind epen dent researche r  inepilepsy related to ag ing.Sp e cifi c  t raini ng goal s  a r e  to  o bt ain  a d va ncedtra ining i n epidemio log yand biostati s ti cs; to obt ain  training in  re cruiti ng  an d  lead ing  coho rt stu d ies; t o acquire  a n d appl y  knowle d g eof A D pathophysiology an d  the use of bi omarke rs ;  t o gai n d idactic an dexper i entialt ra i n i ng

candidate_with the_skills necessary to become_an independent_researcher_in epilepsy_related_to aging. Specific_training goals are_to obtain advanced training_in epidemiology and_biostatistics;_to obtain training in recruiting and leading cohort studies; to acquire and apply knowledge_of_AD pathophysiology_and_the_use of biomarkers; to gain_didactic and experiential training


, and 50 ppm for 7 weeks. At the end of 7 weeks they were mated with untreated males and continued on the same dosage throughout gestation and lactation. The offspring of these females were weaned at 21 days of age and continued on the same lead exposure regimen as their mothers. These offspring were used in immune

, and 50 ppm for 7 weeks. At the end of 7 weeks they were mated with untreated male and stay on the same dose throughout pregnancy and lactation. The offspring of these females were wean at 21 days of age and cover on the same lead photograph regimen as their mothers. These offspring were use in immune

, anf 50 ppm for 7 weeks. At the end of 7 weeks jhwy werx mated with ungreated males and continued ln the wame dosage throughout gestatioj and laxtatmon. The offsprinj of these femzpes cece weaned at 21 dsys of age and continued ov che same lead exposure regimen as thqir motnegs. These offspting eqre hsed in immune

, and 50 ppm for 7 weeks. end 7 weeks were mated with the dosage throughout gestation lactation. The offspring these females were weaned at 21 of age and continued on the same lead exposure regimen as their mothers. offspring were used in immune

, and 50 ppm for 7 weeks. At the end of 7 wEeks they weRe matEd wIth UnTreaTed mAles and continuED on tHe same dosage throughout GestaTiON and LAcTatioN. The offSPrING of ThEsE feMaLEs Were wEanEd at 21 dayS of age and cOntInUed on the same LEaD exposure rEgiMen as their moTheRs. ThesE oFfsPRing wEre Used iN immunE

, and 50 ppm for 7 weeks.At the end  of 7  we eks  t heywere  mated with un t reat ed males and continued  on t he same do sagethrough o ut g est at io n a nd la ctati on.  The of fspring of  th es e females we r eweaned at21days of ageand  conti nu edo n the  sa me le ad exp o sure r egimen as  t h eir mo t hers. T h e se  off spring were usedi ni mmune

, and_50 ppm_for 7 weeks. At_the end_of_7 weeks_they_were mated with_untreated males and_continued on the same_dosage throughout gestation_and_lactation. The offspring of these females were weaned at 21 days of age and_continued_on the_same_lead_exposure regimen as their mothers._These offspring were used in_immune


parameters are defined to analyze the factors affecting the viscosity of proteins; the interaction factor (delta) determines the maximum interaction radius, the constraint number (Nc) measures the lower limit of this interaction radius, and the compressibility factor (Fc) evaluates the capacity of proteins to compress their radius of interaction under increasing concentration.

parameters are defined to analyze the factors affecting the viscosity of protein; the interaction agent (delta) determines the maximum interaction spoke, the constraint issue (Nc) measures the lower terminus ad quem of this interaction spoke, and the compressibility factor (Fc) evaluates the capacity of proteins to compress their radius of interaction under increase concentration.

pagameters are defined to xnalyze the facjoes affxcting fhe viscusity of proteins; the interartiob facujr (delta) determiner the maxpmum inteeactmon radius, the constrainb numgcr (Nc) neasures the lpwer limit of this interdcgiln radius, and the compressibility fwctor (Fv) fvaluates the sapabiey or proteins to compress their radiua of inueraction under invreasing concentration.

parameters are defined to analyze the factors viscosity proteins; the factor (delta) determines constraint (Nc) measures the limit of this radius, and the compressibility factor (Fc) the capacity of proteins to compress their radius of interaction under increasing concentration.

parameters are defined to anaLyze the facTors aFfeCtiNg The vIscoSity of proteins; THe inTeraction factor (delta) deTermiNeS The mAXiMum inTeractiON rADIus, ThE cOnsTrAInT numbEr (NC) measurEs the lower LimIt Of this interaCTiOn radius, anD thE compressibiLitY factoR (FC) evALuateS thE capaCity of PRoteinS to compreSs THeir raDIus of inTERaCtioN under increasing cONcENtration.

parameters are defined to  analyze t he fa cto rsaf fect ingthe viscosityo f pr oteins; the interactio n fac to r  (de l ta ) det ermines th e max im um  in te r ac tionrad ius, th e constrai ntnu mber (Nc) me a su res the lo wer  limit of th isintera ct ion radiu s,and t he com p ressib ility fac to r  (Fc)e valuate s th e ca pacity of protein s  t o  compress thei r radi us of i nte rac tion under  i ncrea s ing con c en t r a tio n .

parameters_are defined_to analyze the factors_affecting the_viscosity_of proteins;_the_interaction factor (delta)_determines the maximum_interaction radius, the constraint_number (Nc) measures_the_lower limit of this interaction radius, and the compressibility factor (Fc) evaluates the capacity_of_proteins to_compress_their_radius of interaction under increasing_concentration.


. In AIM 1, the investigators will study the molecular mechanisms underlying perturbed protein homeostasis in a well-established mouse model for mitochondrial FAO disorders. For this they will determine the dynamics of metabolic signaling during fasting in liver, heart and skeletal muscle and will quantify metabolic fluxes in protein synthesis and degradation. They will use a

. In AIM 1, the investigators will study the molecular mechanisms underlying perturb protein homeostasis in a well - prove mouse model for mitochondrial FAO disorders. For this they will decide the dynamics of metabolic signaling during fast in liver, kernel and skeletal muscle and will quantify metabolic fluxes in protein synthesis and abasement. They will use a

. In AIM 1, the investigators dill study the moleculer mechznisms uvderlying perturbed protein iomeistasus in a well-establishea mouse mldel for mitixhondrial HZO disovbers. Rlr tkiw they will dejermine the gynamics of medacopic signaling during fasting in livqr, heary wnd skeletal moscle wnd splo quantify metabolic fluxes ih protepn synthesis and cegradation. They will use w

. In AIM 1, the investigators will molecular underlying perturbed homeostasis in a FAO For this they determine the dynamics metabolic signaling during fasting in liver, and skeletal muscle and will quantify metabolic fluxes in protein synthesis and degradation. will use a

. In AIM 1, the investigators will Study the moLeculAr mEchAnIsms UndeRlying perturbeD ProtEin homeostasis in a well-eStablIsHEd moUSe Model For mitoCHoNDRiaL FaO DisOrDErS. For tHis They wilL determine The DyNamics of metaBOlIc signalinG duRing fasting iN liVer, heaRt And SKeletAl mUscle And wilL QuantiFy metabolIc FLuxes iN Protein SYNtHesiS and degradation. ThEY wILl use a

. In AIM 1, the investigat ors will s tudythe  mo le cula r me chanisms under l ying  perturbed protein hom eosta si s  ina  w ell-e stablis h ed m ous emo del  f o rmitoc hon drial F AO disorde rs.  F or this they wi ll determi nethe dynamics  of  metab ol ics ignal ing  duri ng fas t ing in  liver, h ea r t ands keletal m us cleand will quantify me t abolic fluxesin pro te i ns y nth esi s and degr ad ation .  They w i ll u s e a

. In_AIM 1,_the investigators will study_the molecular_mechanisms_underlying perturbed_protein_homeostasis in a_well-established mouse model_for mitochondrial FAO disorders._For this they_will_determine the dynamics of metabolic signaling during fasting in liver, heart and skeletal muscle_and_will quantify_metabolic_fluxes_in protein synthesis and degradation._They will use a


been well documented. Our preliminary results demonstrate that all facets of Ag-specific CD8+ I cell homeostasis-expansion, death, memory and immunodominance are aberrant in perforin/IFN-y double deficient mice after LM infection. Examination of Ag-specific CD8+ T cell homeostasis in the parental perforin

been well documented. Our preliminary results demonstrate that all facets of Ag - specific CD8 + I cell homeostasis - expansion, end, memory and immunodominance are aberrant in perforin / IFN - y double over deficient mice after LM contagion. Examination of Ag - specific CD8 + T cellular telephone homeostasis in the parental perforin

befn well documented. Our pveliminary resuljs demonvtrate that alu facets of Ag-specific CD8+ I rell homeistasis-expansion, death, memory ajd immunidommnance are aberreht in pcxforih/LFN-y bonble deficient kice after LM infection. Axxmnnation of Ag-specific CD8+ T cell homejstasis ij the parental pergjrin

been well documented. Our preliminary results demonstrate facets Ag-specific CD8+ cell homeostasis-expansion, death, in double deficient mice LM infection. Examination Ag-specific CD8+ T cell homeostasis in parental perforin

been well documented. Our prelIminary resUlts dEmoNstRaTe thAt alL facets of Ag-speCIfic cD8+ I cell homeostasis-expaNsion, DeATh, meMOrY and iMmunodoMInANCe aRe AbErrAnT In PerfoRin/iFN-y douBle deficieNt mIcE after LM infeCTiOn. ExaminatIon Of Ag-specific cD8+ T Cell hoMeOstASis in The ParenTal perFOrin

been well documented. Our  prelimina ry re sul tsde mons trat e that all fac e ts o f Ag-specific CD8+ I c ell h om e osta s is -expa nsion,d ea t h , m em or y a nd im munod omi nance a re aberran t i nperforin/IFN - ydouble def ici ent mice aft erLM inf ec tio n . Exa min ation  of Ag - specif ic CD8+ T  c e ll hom e ostasis i ntheparental perforin

been_well documented._Our preliminary results demonstrate_that all_facets_of Ag-specific_CD8+_I cell homeostasis-expansion,_death, memory and_immunodominance are aberrant in_perforin/IFN-y double deficient_mice_after LM infection. Examination of Ag-specific CD8+ T cell homeostasis in the parental perforin


ating by pH and other factors. The CL-CT mediated regulation of Cx43 is crucial for its physiological function, and is a therapeutic target for cardiovascular pathologies. However, the role of CL-CT interactions in modulation of other connexin channels, just as likely to be biomedically important, and their mechanism of action

ating by pH and other factors. The CL - CT mediated regulation of Cx43 is all-important for its physiologic routine, and is a therapeutic prey for cardiovascular pathology. However, the role of CL - CT interactions in intonation of early connexin channels, just as likely to be biomedically important, and their mechanism of legal action

atijg by pH and other factovs. The CL-CT medicred rejulatioh of Cx43 ks crucial for its physiologmcal funcupon, and is a therapeugic targen for careiovescular pathologmss. Howeyzr, ths rolz if CL-CT interagtions in mmdulation of odhdr connexin channels, just as likely tj be bipmfdically imporjant, sgd tgviv mechanism of action

ating by pH and other factors. The regulation Cx43 is for its physiological target cardiovascular pathologies. However, role of CL-CT in modulation of other connexin channels, as likely to be biomedically important, and their mechanism of action

ating by pH and other factors. THe CL-CT mediAted rEguLatIoN of CX43 is cRucial for its phYSiolOgical function, and is a thErapeUtIC tarGEt For caRdiovasCUlAR PatHoLoGieS. HOWeVer, thE roLe of CL-Ct interactiOns In Modulation of OThEr connexin ChaNnels, just as lIkeLy to be BiOmeDIcallY imPortaNt, and tHEir mecHanism of aCtIOn

ating by pH and other fact ors. The C L-CTmed iat ed  reg ulat ion of Cx43 is cruc ial for its physiologi cal f un c tion ,  a nd is  a ther a pe u t icta rg etfo r  c ardio vas cular p athologies . H ow ever, the ro l eof CL-CT i nte ractions inmod ulatio nofo thercon nexin  chann e ls, ju st as lik el y  to be biomedi c a ll y im portant, and thei r  m e chanism of act ion

ating by_pH and_other factors. The CL-CT_mediated regulation_of_Cx43 is_crucial_for its physiological_function, and is_a therapeutic target for_cardiovascular pathologies. However,_the_role of CL-CT interactions in modulation of other connexin channels, just as likely to_be_biomedically important,_and_their_mechanism of action


and the kinetics of synthesis, processing and release. The experiments proposed here seek a precise definition of these complex properties in order to better understand the possible physiological role of the peptidergic neuron. Two simple nerve terminal preparations will be studied; the neural lobe of the rat pituitary and the sinus gland of the land crab. The

and the kinetics of synthesis, processing and release. The experiments aim here search a precise definition of these complex properties in order to well understand the possible physiologic role of the peptidergic neuron. Two simple heart terminal preparations will be learn; the neural lobe of the rat pituitary and the venous sinus gland of the farming crab. The

anf the kinetics of syntheris, processing cbd relxase. Ths experioents proposed here seek a pceciwe dedinition of these compuex propegties in irdec to better undecatand tmz posalble 'hbsiological rolg of the pepdidergic neurot. Gwl simple nerve terminal preparationf will ne studied; the ngural jobe of the rat pituitary and the sinua gland of the land vrab. The

and the kinetics of synthesis, processing and experiments here seek precise definition of to understand the possible role of the neuron. Two simple nerve terminal preparations be studied; the neural lobe of the rat pituitary and the sinus gland the land crab. The

and the kinetics of synthesis, Processing And reLeaSe. THe ExpeRimeNts proposed herE Seek A precise definition of thEse coMpLEx prOPeRties In order TO bETTer UnDeRstAnD ThE possIblE physioLogical rolE of ThE peptidergic NEuRon. Two simpLe nErve terminal PreParatiOnS wiLL be stUdiEd; the Neural LObe of tHe rat pituItARy and tHE sinus gLANd Of thE land crab. The

and the kinetics of synth esis, proc essin g a ndre leas e. T he experiments prop osed here seek a preci se de fi n itio n  o f the se comp l ex p rop er ti esin or der t o b etter u nderstandthe  p ossible phys i ol ogical rol e o f the peptid erg ic neu ro n.T wo si mpl e ner ve ter m inal p reparatio ns will b e  studie d ;  t he n eural lobe of the ra t  pituitary and  the s in u sg l and  of  the landcr ab. T h e

and_the kinetics_of synthesis, processing and_release. The_experiments_proposed here_seek_a precise definition_of these complex_properties in order to_better understand the_possible_physiological role of the peptidergic neuron. Two simple nerve terminal preparations will be studied;_the_neural lobe_of_the_rat pituitary and the sinus_gland of the land crab._The


personnel are scarce. The purpose of Project ECHO is to educate, train, and support rural general practitioners or other available healthcare representatives on the best practice treatment protocols for complex diseases they encounter in their communities. This model focuses on the principles of case-based learning and disease management using the telemedicine infrastructure and internet-

personnel are scarce. The purpose of Project ECHO is to educate, train, and confirm rural cosmopolitan practitioners or other available healthcare congressman on the good practice treatment protocol for complex diseases they encounter in their community. This model focuses on the principle of case - based eruditeness and disease management using the telemedicine infrastructure and internet-

pegsonnel are scarce. The pmrpose of Projecj WCHO iv to esucate, tfain, and support rural generel peactiuponers or other availxble healnhcare represtntatives on the usst pragcice fveatmznv protocols for complex dhseases they etcuuuter in their communities. This model focusex ln the principjes ps caav-bcsed learning and disease managsment uving the telekedicine infrastructure anf inhernet-

personnel are scarce. The purpose of Project to train, and rural general practitioners on best practice treatment for complex diseases encounter in their communities. This model on the principles of case-based learning and disease management using the telemedicine infrastructure internet-

personnel are scarce. The purpOse of ProjeCt ECHo is To eDuCate, TraiN, and support rurAL genEral practitioners or othEr avaIlABle hEAlThcarE represENtATIveS oN tHe bEsT PrActicE trEatment Protocols fOr cOmPlex diseases THeY encounter In tHeir communitIes. this moDeL foCUses oN thE prinCiples OF case-bAsed learnInG And disEAse manaGEMeNt usIng the telemedicinE InFRastructure and InternEt-

personnel are scarce. The  purpose o f Pro jec t E CH O is  toeducate, train ,  and  support rural general  prac ti t ione r sor ot her ava i la b l e h ea lt hca re re prese nta tives o n the best  pr ac tice treatme n tprotocolsfor  complex dis eas es the yenc o unter  in  thei r comm u nities . This mo de l  focus e s on th e pr inci ples of case-base d  l e arning and dis ease m an a ge m e ntusi ng the tel em edici n e infra s tr u c t ure and internet-

personnel_are scarce._The purpose of Project_ECHO is_to_educate, train,_and_support rural general_practitioners or other_available healthcare representatives on_the best practice_treatment_protocols for complex diseases they encounter in their communities. This model focuses on the_principles_of case-based_learning_and_disease management using the telemedicine_infrastructure and internet-


promote cancer progression. Based on previous studies and preliminary studies, we hypothesize that inflammatory chemokine expression in fibroblasts including CCL2 and CXCL1 mediate epithelial cell and immune cell motility and invasiveness to promote breast cancer progression. The objective of this proposal is determine the functions of chemokines, which are normally suppressed by TGF-B signaling

promote cancer progression. Based on previous report and preliminary cogitation, we hypothesize that incendiary chemokine expression in fibroblast including CCL2 and CXCL1 mediate epithelial cellular telephone and immune cell motility and invasiveness to promote breast cancer progress. The objective of this proposal is settle the functions of chemokines, which are normally suppressed by TGF - B signal

prlmote cancer progression. Based on previous stuvies ans prelimknary studies, we hypothesize tyat ibflammatory chemokine dxpressioj in fibeoblests including CRM2 and CWEL1 meslate zpmthelial cell akd immune call motility atd iuvasiveness to promote breast cancer progrexslon. The objectyve ps thjs proposal is determine the functjons of chemokines, wnich are normally suppressfd bj TGF-B signaling

promote cancer progression. Based on previous studies studies, hypothesize that chemokine expression in mediate cell and immune motility and invasiveness promote breast cancer progression. The objective this proposal is determine the functions of chemokines, which are normally suppressed by signaling

promote cancer progression. BAsed on prevIous sTudIes AnD preLimiNary studies, we hYPothEsize that inflammatory cHemokInE ExprESsIon in FibroblAStS INclUdInG CCl2 aND CxCL1 meDiaTe epithElial cell aNd iMmUne cell motilITy And invasivEneSs to promote bReaSt cancEr ProGRessiOn. THe objEctive OF this pRoposal is DeTErmine THe functIONs Of chEmokines, which are nORmALly suppressed bY TGF-B sIgNAlING

promote cancer progressio n. Based o n pre vio usst udie s an d preliminarys tudi es, we hypothesize tha t inf la m mato r ychemo kine ex p re s s ion  i nfib ro b la sts i ncl uding C CL2 and CX CL1  m ediate epith e li al cell an d i mmune cell m oti lity a nd  in v asive nes s topromot e  breas t cancerpr o gressi o n. Theo b je ctiv e of this proposa l  i s  determine the  funct io n so f  ch emo kines, whi ch  aren ormally su p p r ess e d by TGF-B si gnaling

promote_cancer progression._Based on previous studies_and preliminary_studies,_we hypothesize_that_inflammatory chemokine expression_in fibroblasts including_CCL2 and CXCL1 mediate_epithelial cell and_immune_cell motility and invasiveness to promote breast cancer progression. The objective of this proposal_is_determine the_functions_of_chemokines, which are normally suppressed_by TGF-B signaling


bp away from the recognition site. This implies the presence of two separate protein domains in this enzyme: one for sequence-specific recognition and the other for the endonuclease activity. Our studies o proteolytic fragments of FokI endonuclease have defined an N-terminal DNA- binding domain and C-terminal domain

bp away from the recognition site. This implies the bearing of two freestanding protein domains in this enzyme: one for sequence - specific realization and the other for the endonuclease activeness. Our studies o proteolytic fragments of FokI endonuclease have specify an N - terminal DNA- binding sphere and C - terminal knowledge domain

bp away from the recognitiun site. This imklues thx presehce of tdo separate protein domains mn tyis ebzyme: one for sequence-rpecific gecognitiin aid the other for the endonuclezde aetmvity. Our studigs o proteolftic fragments ow YokI endonuclease have defined an N-tqrminal DJA- binding domwin sgd C-fvrninal domain

bp away from the recognition site. This presence two separate domains in this and other for the activity. Our studies proteolytic fragments of FokI endonuclease have an N-terminal DNA- binding domain and C-terminal domain

bp away from the recognition sIte. This impLies tHe pResEnCe of Two sEparate protein DOmaiNs in this enzyme: one for seQuencE-sPEcifIC rEcognItion anD ThE OTheR fOr The EnDOnUcleaSe aCtivity. our studies O prOtEolytic fragmENtS of FokI endOnuClease have deFinEd an N-tErMinAL DNA- bIndIng doMain anD c-termiNal domain

bp away from the recognit ion site.Thisimp lie sthepres ence of two se p arat e protein domains in t his e nz y me:o ne  forsequenc e -s p e cif ic  r eco gn i ti on an d t he othe r for theend on uclease acti v it y. Our stu die s o proteoly tic  fragm en tso f Fok I e ndonu clease have d efined an  N - termin a l DNA-b i nd ingdomain and C-term i na l  domain

bp_away from_the recognition site. This_implies the_presence_of two_separate_protein domains in_this enzyme: one_for sequence-specific recognition and_the other for_the_endonuclease activity. Our studies o proteolytic fragments of FokI endonuclease have defined an N-terminal_DNA-_binding domain_and_C-terminal_domain


Pofutl gene as an essential component of the Notch signaling pathway. We now propose in Specific Aim 1 to investigate the molecular basis of the requirement for complex and hybrid A/-glycans in oogenesis, and to identify roles of mucin O-glycans and Ofucose glycans in early development after oocyte

Pofutl gene as an essential component of the Notch signaling pathway. We now nominate in Specific Aim 1 to investigate the molecular footing of the requirement for complex and hybrid A/-glycans in oogenesis, and to identify function of mucin oxygen - glycans and Ofucose glycans in early development after oocyte

Povutl gene as an essentiau component of jhw Notci signaming patfway. We now propose in Specihic Qim 1 uj investigate the oolecular basis od tht requirement for complex and hgnrid C/-goycans in oogekesis, and tm identify rolas oy mucin O-glycans and Ofucose glycans in earky development aster jocyfv

Pofutl gene as an essential component of signaling We now in Specific Aim basis the requirement for and hybrid A/-glycans oogenesis, and to identify roles of O-glycans and Ofucose glycans in early development after oocyte

Pofutl gene as an essential coMponent of tHe NotCh sIgnAlIng pAthwAy. We now propose IN SpeCific Aim 1 to investigate tHe molEcULar bASiS of thE requirEMeNT For CoMpLex AnD HyBrid A/-GlyCans in oOgenesis, anD to IdEntify roles oF MuCin O-glycanS anD Ofucose glycAns In earlY dEveLOpmenT afTer ooCyte

Pofutl gene as an essenti al compone nt of  th e N ot ch s igna ling pathway.W e no w propose in SpecificAim 1  t o  inv e st igate  the mo l ec u l arba si s o ft he  requ ire ment fo r complexand  h ybrid A/-gly c an s in oogen esi s, and to id ent ify ro le s o f  muci n O -glyc ans an d  Ofuco se glycan si n earl y  develo p m en t af ter oocyte

Pofutl_gene as_an essential component of_the Notch_signaling_pathway. We_now_propose in Specific_Aim 1 to_investigate the molecular basis_of the requirement_for_complex and hybrid A/-glycans in oogenesis, and to identify roles of mucin O-glycans and_Ofucose_glycans in_early_development_after oocyte


in others, the infections probably represent cross-contamination that occurred in other laboratories. We believe that the iGLuc strategy for detection of retroviral replication can have wide application. We have collaborated with Dr. Kenneth Cornetta (Indiana University) to demonstrate the utility of the iGLuc assay for testing gene-

in others, the infections probably represent cross - contaminant that occur in other laboratories. We think that the iGLuc strategy for signal detection of retroviral replication can have across-the-board application. We have collaborated with Dr. Kenneth Cornetta (Indiana University) to show the utility of the iGLuc assay for test gene-

in others, the infections pvobably represenj xross-cmntamihation tfat occurred in other laboravoriws. We believe that the iGLuz strategj for detwctiib of retrotjral reijicaflon ccn have wide appkication. Wa have collabosageb with Dr. Kenneth Cornetta (Indiana Ugiversiyy) to demonstratg the ttiljny of the iGLuc assay for testihg gene-

in others, the infections probably represent cross-contamination in laboratories. We that the iGLuc replication have wide application. have collaborated with Kenneth Cornetta (Indiana University) to demonstrate utility of the iGLuc assay for testing gene-

in others, the infections probAbly represEnt crOss-ConTaMinaTion That occurred in OTher Laboratories. We believe tHat thE igluc sTRaTegy fOr detecTIoN OF reTrOvIraL rEPlIcatiOn cAn have wIde applicaTioN. WE have collaboRAtEd with Dr. KeNneTh Cornetta (InDiaNa UnivErSitY) To demOnsTrate The utiLIty of tHe iGLuc asSaY For tesTIng gene-

in others, the infections  probablyrepre sen t c ro ss-c onta mination thato ccur red in other laborator ies.We beli e ve  that  the iG L uc s tra te gy  fo rd et ectio n o f retro viral repl ica ti on can havew id e applicat ion . We have co lla borate dwit h  Dr.Ken nethCornet t a (Ind iana Univ er s ity) t o  demons t r at e th e utility of thei GL u c assay for te stingge n e-

in_others, the_infections probably represent cross-contamination_that occurred_in_other laboratories._We_believe that the_iGLuc strategy for_detection of retroviral replication_can have wide_application._We have collaborated with Dr. Kenneth Cornetta (Indiana University) to demonstrate the utility of_the_iGLuc assay_for_testing_gene-


photoreceptor degeneration as well as regional brain iron accumulation. Once the HSS gene is cloned and characterized, the other pathologic changes may provide a context for understanding the mechanism of pigmentary retinopathy. Since defects in this non-retina-specific process may cause other forms of syndromic and isolated RP and may be

photoreceptor degeneration as well as regional brain iron accumulation. Once the HSS gene is clone and qualify, the other pathologic change may put up a context for understanding the mechanism of pigmentary retinopathy. Since defects in this non - retina - specific summons may induce other forms of syndromic and isolated RP and may be

phltoreceptor degeneration as well as regninal bcain irkn accumjlation. Once the HSS gene is cooned and characterized, the other panhologic xhanjes may provide e contexb for mndervvanding the mecmanism of phgmentary retitooachy. Since defects in this non-retina-s[ecific pgocess may caufe ouhew fodms of syndromic and isolated RP ahd may ue

photoreceptor degeneration as well as regional brain Once HSS gene cloned and characterized, provide context for understanding mechanism of pigmentary Since defects in this non-retina-specific process cause other forms of syndromic and isolated RP and may be

photoreceptor degeneration As well as reGionaL brAin IrOn acCumuLation. Once the Hss genE is cloned and characteriZed, thE oTHer pAThOlogiC changeS MaY PRovIdE a ConTeXT fOr undErsTanding The mechaniSm oF pIgmentary retINoPathy. Since DefEcts in this noN-reTina-spEcIfiC ProceSs mAy cauSe otheR Forms oF syndromiC aND isolaTEd RP and MAY bE

photoreceptor degeneratio n as wellas re gio nal  b rain  iro n accumulation .  Onc e the HSS gene is clon ed an dc hara c te rized , the o t he r pat ho lo gic  c h an ges m ayprovide  a context  fo runderstandin g  t he mechani smof pigmentar y r etinop at hy. Since  de fects  in th i s non- retina-sp ec i fic pr o cess ma y ca useother forms of sy n dr o mic and isolat ed RPan d  m a y  be

photoreceptor_degeneration as_well as regional brain_iron accumulation._Once_the HSS_gene_is cloned and_characterized, the other_pathologic changes may provide_a context for_understanding_the mechanism of pigmentary retinopathy. Since defects in this non-retina-specific process may cause other_forms_of syndromic_and_isolated_RP and may be


aim #2, we will determine if the sex chromosome effect in the CNS during EAE is due to the dose of X or Y genes. Finally in aim #3, we will use mice which differ in gonadal type, female vs. male, while having the same sex chromosome complement (XX vs. XX S

aim # 2, we will determine if the sex chromosome effect in the central nervous system during EAE is ascribable to the acid of X or Y genes. ultimately in bearing # 3, we will use mice which disagree in gonadal type, female vs. male, while having the same sexual activity chromosome complement (XX vs. XX S

ail #2, we will determine if uhe sex chromosomg wffect in ths CNS dufing EAE is due to the dose lf X or Y genes. Finally in aio #3, we wilp use mixe wiich differ in gonadal tn'e, fejwle rs. male, while haying the sake sex chromosmmd eomplement (XX vs. XX S

aim #2, we will determine if the effect the CNS EAE is due or genes. Finally in #3, we will mice which differ in gonadal type, vs. male, while having the same sex chromosome complement (XX vs. XX S

aim #2, we will determine if the seX chromosomE effeCt iN thE CnS duRing eAE is due to the dOSe of x or Y genes. Finally in aim #3, wE will UsE Mice WHiCh difFer in goNAdAL TypE, fEmAle Vs. MAlE, whilE haVing the Same sex chrOmoSoMe complement (xx vS. XX S

aim #2, we will determine  if the se x chr omo som eeffe ct i n the CNS duri n g EA E is due to the dose o f X o rY  gen e s.  Fina lly ina im # 3,we  w ill  u s emicewhi ch diff er in gona dal  t ype, femalev s.  male, whi lehaving the s ame  sex c hr omo s ome c omp lemen t (XXv s. XXS

aim_#2, we_will determine if the_sex chromosome_effect_in the_CNS_during EAE is_due to the_dose of X or_Y genes. Finally_in_aim #3, we will use mice which differ in gonadal type, female vs. male,_while_having the_same_sex_chromosome complement (XX vs. XX_S


modify these distinct substrates. Our long-term objectives are to determine the mechanism of protein specific polysialylation, what factors regulate the polymerization of polySia chains on specific substrates, and how polySia modulates the functions of the proteins it modifies. In this proposal we will test the hypothesis that the polySTs

modify these distinct substrates. Our long - condition aim are to determine the mechanism of protein specific polysialylation, what factors regulate the polymerization of polySia chain on specific substrates, and how polySia modulates the function of the protein it modifies. In this proposal we will test the hypothesis that the polySTs

mofify these distinct subsurates. Our long-tetm objecvives ade to degermine the mechanism of provein specufic polysialylation, wfat factogs regulare tie polymerizatioi of polnFia dmains in specific sunstrates, ang how polySia koaupates the functions of the proteins it modofles. In this prjpossj we will test the hypothesis that the polySTv

modify these distinct substrates. Our long-term objectives determine mechanism of specific polysialylation, what polySia on specific substrates, how polySia modulates functions of the proteins it modifies. this proposal we will test the hypothesis that the polySTs

modify these distinct substrAtes. Our lonG-term ObjEctIvEs arE to dEtermine the mecHAnisM of protein specific polySialyLaTIon, wHAt FactoRs regulATe THE poLyMeRizAtIOn Of polYSiA chains On specific SubStRates, and how pOLysia modulatEs tHe functions oF thE proteInS it MOdifiEs. IN this ProposAL we wilL test the hYpOThesis THat the pOLYSts

modify these distinct sub strates. O ur lo ng- ter mobje ctiv es are to dete r mine  the mechanism of prot ein s pe c ific po lysia lylatio n ,w h atfa ct ors  r e gu latethe  polyme rization o f p ol ySia chainso nspecific s ubs trates, andhow  polyS ia  mo d ulate s t he fu nction s  of th e protein si t modi f ies. In t hi s pr oposal we will te s tt he hypothesisthat t he po l y STs

modify_these distinct_substrates. Our long-term objectives_are to_determine_the mechanism_of_protein specific polysialylation,_what factors regulate_the polymerization of polySia_chains on specific_substrates,_and how polySia modulates the functions of the proteins it modifies. In this proposal_we_will test_the_hypothesis_that the polySTs


Potential clinical applications of inhibition of the JNK signaling may include: (1) the prevention of ischemic apoptosis; (2) attenuation of chronic glutamate excitotoxicity in amytrophic lateral sclerosis; (3) the prevention of neurodegneration (4) enhanced survival of grafted neurons in transplantation therapy. Preliminary evidence of feasibility

Potential clinical applications of inhibition of the JNK signaling may admit: (1) the prevention of ischemic apoptosis; (2) attenuation of chronic glutamate excitotoxicity in amytrophic lateral sclerosis; (3) the prevention of neurodegneration (4) enhance survival of grafted neurons in transplant therapy. Preliminary evidence of feasibility

Pohential clinical applicauions of inhibition of tie JNK aignaline may include: (1) the preventioi of ischtiic apoptosis; (2) attdnuation lf chronuc goytamate exrjtotoxignty ih amycriphic lateral xclerosis; (3) the preventiot uf neurodegneration (4) enhanced survivaj of grsfhed neurons in tramfplahnauion therapy. Preliminary evidence of feavibility

Potential clinical applications of inhibition of the may (1) the of ischemic apoptosis; excitotoxicity amytrophic lateral sclerosis; the prevention of (4) enhanced survival of grafted neurons transplantation therapy. Preliminary evidence of feasibility

Potential clinical applicatIons of inhiBitioN of The jNk sigNaliNg may include: (1) thE PrevEntion of ischemic apoptoSis; (2) atTeNUatiON oF chroNic glutAMaTE ExcItOtOxiCiTY iN amytRopHic lateRal sclerosIs; (3) tHe Prevention of NEuRodegneratIon (4) Enhanced survIvaL of graFtEd nEUrons In tRanspLantatIOn therApy. PrelimInARy evidENce of feASIbIlitY

Potential clinical applic ations ofinhib iti onof  the  JNK  signaling may incl ude: (1) the preventio n ofis c hemi c  a popto sis; (2 )  a t t enu at io n o fc hr onicglu tamateexcitotoxi cit yin amytrophi c  l ateral scl ero sis; (3) the  pr eventi on  of neuro deg nerat ion (4 )  enhan ced survi va l  of gr a fted ne u r on s in  transplantationt he r apy. Prelimina ry evi de n ce o f f eas ibility

Potential_clinical applications_of inhibition of the_JNK signaling_may_include: (1)_the_prevention of ischemic_apoptosis; (2) attenuation_of chronic glutamate excitotoxicity_in amytrophic lateral_sclerosis;_(3) the prevention of neurodegneration (4) enhanced survival of grafted neurons in transplantation therapy._Preliminary_evidence of_feasibility


provided expanded opportunities for training of the students in outstanding laboratories and has fostered collaboration between faculty and students at Columbia's Medical School and main campuses. The faculty members work in a broad range of fields including structural biology, molecular biology, genetics, bioinformatics and systems biology, developmental biology and neurobiology. Experimental systems are also

provided expanded opportunities for training of the student in great laboratories and has fostered collaboration between staff and students at Columbia's Medical School and independent campuses. The faculty penis work in a broad scope of fields including morphologic biology, molecular biology, genetics, bioinformatics and system biology, developmental biology and neurobiology. Experimental systems are also

prlvided expanded opportunlties for trainiut of tie studsnts in uutstanding laboratories and hqs fowtered collaboration bdtween fabulty and stuvents at Columbie'a Medical Schkll aud main campuses. The faculdy members worn kn a broad range of fields including ftructutap biology, molesulag fiolkgy, genetics, bioinformatics and syatems bpology, developmenyal biology and neurobiolohy. Edperimental systemd are also

provided expanded opportunities for training of the outstanding and has collaboration between faculty School main campuses. The members work in broad range of fields including structural molecular biology, genetics, bioinformatics and systems biology, developmental biology and neurobiology. Experimental systems also

provided expanded opportuniTies for traIning Of tHe sTuDentS in oUtstanding laboRAtorIes and has fostered collaBoratIoN BetwEEn FaculTy and stUDeNTS at coLuMbiA's mEdIcal SChoOl and maIn campuses. the FaCulty members WOrK in a broad rAngE of fields incLudIng strUcTurAL biolOgy, MolecUlar biOLogy, geNetics, bioInFOrmatiCS and sysTEMs BiolOgy, developmental bIOlOGy and neurobiolOgy. ExpErIMeNTAl sYstEms are also

provided expanded opportu nities for  trai nin g o fthestud ents in outsta n ding  laboratories and hasfoste re d  col l ab orati on betw e en f acu lt yand  s t ud entsatColumbi a's Medica l S ch ool and main ca mpuses. Th e f aculty membe rswork i na b r oad r ang e offields includ ing struc tu r al bio l ogy, mo l e cu larbiology, genetics ,  b i oinformatics a nd sys te m sb i olo gy,  developme nt al bi o logy an d  n e u r obi o logy. Experim ental syste m s a re als o

provided_expanded opportunities_for training of the_students in_outstanding_laboratories and_has_fostered collaboration between_faculty and students_at Columbia's Medical School_and main campuses._The_faculty members work in a broad range of fields including structural biology, molecular biology,_genetics,_bioinformatics and_systems_biology,_developmental biology and neurobiology. Experimental_systems are also


fashion. A portion of the pancreas cancer specific antibodies will be labeled with iodine-131 and assayed to determine their suitability for use in external computerized photoscanning for tumor localization. This project will significantly improve the micro-LAI assay and the serological and biochemical data obtained will complement the clinical results. The overall goal of

fashion. A portion of the pancreas cancer specific antibodies will be labeled with iodine-131 and assay to settle their suitability for use in external computerized photoscanning for tumor localization. This project will importantly improve the micro - LAI assay and the serological and biochemical datum receive will complement the clinical results. The overall goal of

fadhion. A portion of the pxncreas cancer specifir antibkdies wiul be labeled with iodine-131 anv aswayed to determine their suktability for use in txternal computermaed phobjscahking yoc tumor localizstion. This project will viennficantly improve the micro-LAI assay and thr derological anq bipshemjbao data obtained will complemeht the blinical results. Yhe overall goal of

fashion. A portion of the pancreas cancer will labeled with and assayed to in computerized photoscanning for localization. This project significantly improve the micro-LAI assay and serological and biochemical data obtained will complement the clinical results. The overall goal

fashion. A portion of the pancrEas cancer sPecifIc aNtiBoDies Will Be labeled with iODine-131 And assayed to determine tHeir sUiTAbilITy For usE in exteRNaL COmpUtErIzeD pHOtOscanNinG for tumOr localizaTioN. THis project wiLL sIgnificantLy iMprove the micRo-LaI assaY aNd tHE seroLogIcal aNd biocHEmical Data obtaiNeD Will coMPlement THE cLiniCal results. The overALl GOal of

fashion. A portion of the  pancreascance r s pec if ic a ntib odies will bel abel ed with iodine-131 and  assa ye d  tod et ermin e their su i t abi li ty  fo ru se  in e xte rnal co mputerized  ph ot oscanning fo r  t umor local iza tion. This p roj ect wi ll  si g nific ant ly im provet he mic ro-LAI as sa y  and t h e serol o g ic al a nd biochemical da t ao btained will c omplem en t  t h e  cl ini cal result s.  Theo verallg oa l o f

fashion._A portion_of the pancreas cancer_specific antibodies_will_be labeled_with_iodine-131 and assayed_to determine their_suitability for use in_external computerized photoscanning_for_tumor localization. This project will significantly improve the micro-LAI assay and the serological and_biochemical_data obtained_will_complement_the clinical results. The overall_goal of


availability of these services should facilitate research in rheumatic diseases for both clinical and basic scientists at the University of Tennessee, HSC. Maximum blood flow acceleration, beat-to-beat stroke volume and continuous external power of the left ventricle are derived from instantaneous (pulsatile) measurements of blood flow velocity and pressure in the

availability of these services should facilitate research in arthritic disease for both clinical and basic scientist at the University of Tennessee, HSC. Maximum blood flow acceleration, rhythm - to - beat stroke book and continuous external might of the left ventricle are deduce from instantaneous (pulsatile) measurements of blood menstruation velocity and pressure in the

avwilability of these servlces should facilitate cesearcg in rhejmatic diseases for both cliiicao and basic scientists at tfe Univerdity of Renntssee, HSC. Maximum blood flow acdcleraciin, beat-to-beat xtroke volgme and contingojs external power of the left ventricje are cegived from insjantamqous (iuosatile) measurements of blood flow vtlocity and pressute in the

availability of these services should facilitate research diseases both clinical basic scientists at Maximum flow acceleration, beat-to-beat volume and continuous power of the left ventricle are from instantaneous (pulsatile) measurements of blood flow velocity and pressure in the

availability of these servicEs should faCilitAte ResEaRch iN rheUmatic diseases FOr boTh clinical and basic scieNtistS aT The UNIvErsitY of TennESsEE, hSC. maXiMum BlOOd Flow aCceLeratioN, beat-to-beaT stRoKe volume and cONtInuous exteRnaL power of the lEft VentriClE arE DerivEd fRom inStantaNEous (puLsatile) meAsURementS Of blood FLOw VeloCity and pressure in THe

availability of these ser vices shou ld fa cil ita te  res earc h in rheumatic dise ases for both clinical  andba s ic s c ie ntist s at th e  U n i ver si ty  of  T e nn essee , H SC. Max imum blood  fl ow  acceleratio n ,beat-to-be atstroke volum e a nd con ti nuo u s ext ern al po wer of the le ft ventri cl e  are d e rived f r o minst antaneous (pulsat i le )  measurementsof blo od fl o w  ve loc ity and pr es surei n the

availability_of these_services should facilitate research_in rheumatic_diseases_for both_clinical_and basic scientists_at the University_of Tennessee, HSC. Maximum_blood flow acceleration,_beat-to-beat_stroke volume and continuous external power of the left ventricle are derived from instantaneous_(pulsatile)_measurements of_blood_flow_velocity and pressure in the


the following: (1) biochemical indices related to nutritional status, (2) trace element requirements, (3) immunological function related to trauma and nutrition, (4) metabolism of carbohydrate using 14C-glucose, (5) gluconeogenesis using 14C-L-alanine and 14C-glycerol, and

the following: (1) biochemical indices related to nutritional status, (2) hound chemical element requirements, (3) immunological function related to injury and nutrition, (4) metabolism of carbohydrate using 14C - glucose, (5) gluconeogenesis practice 14C - L - alanine and 14C - glycerol, and

thf following: (1) biochemical indices relateb to nuvritionzl statur, (2) trace element requirementd, (3) immubological function relxted to tgauma and nutcition, (4) metabolism of cavyohyddwte bsmng 14C-glucose, (5) gkuconeogenasis using 14C-L-anaviue and 14C-glycerol, and

the following: (1) biochemical indices related to (2) element requirements, immunological function related metabolism carbohydrate using 14C-glucose, gluconeogenesis using 14C-L-alanine 14C-glycerol, and

the following: (1) biochemical inDices relatEd to nUtrItiOnAl stAtus, (2) Trace element reQUireMents, (3) immunological funcTion rElATed tO TrAuma aNd nutriTIoN, (4) MEtaBoLiSm oF cARbOhydrAte Using 14C-gLucose, (5) glucOneOgEnesis using 14C-l-AlAnine and 14C-gLycErol, and

the following: (1) bioche mical indi ces r ela ted  t o nu trit ional status,( 2) t race element requireme nts,(3 )  imm u no logic al func t io n rel at ed  to  t r au ma an d n utritio n, (4) met abo li sm of carboh y dr ate using14C -glucose, (5 ) g lucone og ene s is us ing  14C- L-alan i ne and  14C-glyc er o l, and

the_following: (1)_biochemical indices related to_nutritional status,_(2)_trace element_requirements,_(3) immunological function_related to trauma_and nutrition, (4) metabolism_of carbohydrate using_14C-glucose,_(5) gluconeogenesis using 14C-L-alanine and 14C-glycerol, and


. Among these species are isolable compounds of pentacoordinate carbon, chiral sulfuranes and asasulfuranes. The generation of sulfuranes and persulfuranes by neighboring group participation in perester decompositions will be studied. The generation of radical pairs, and larger arrays of radicals, within the solvent cage

. Among these species are isolable compounds of pentacoordinate carbon, chiral sulfuranes and asasulfuranes. The generation of sulfuranes and persulfuranes by neighboring group engagement in perester decomposition will be studied. The generation of extremist couple, and larger arrays of radical, within the solution cage

. Amlng these species are isulable compounds of peitacoorsinate cxrbon, chiral sulfuranes and esasylfurqnes. The generation of sulfuranvs and peesulhuranes by neighukring gvjup lwrtiei'ation in peresjer decomposhtions will be sgubied. The generation of radical pairs, and latgfr arrays of rwdicsjs, wjnhln the solvent cage

. Among these species are isolable compounds carbon, sulfuranes and The generation of group in perester decompositions be studied. The of radical pairs, and larger arrays radicals, within the solvent cage

. Among these species are isolaBle compounDs of pEntAcoOrDinaTe caRbon, chiral sulfURaneS and asasulfuranes. The geNeratIoN Of suLFuRanes And persULfURAneS bY nEigHbORiNg groUp pArticipAtion in perEstEr DecompositioNS wIll be studiEd. THe generation Of rAdical PaIrs, ANd larGer ArrayS of radICals, wiThin the soLvENt cage

. Among these species areisolable c ompou nds  of  p enta coor dinate carbon, chir al sulfuranes and asas ulfur an e s. T h egener ation o f  s u l fur an es  an dp er sulfu ran es by n eighboring  gr ou p participat i on  in perest erdecompositio nswill b estu d ied.The  gene ration of rad ical pair s, and la r ger arr a y sof r adicals, within t h es olvent cage

. Among_these species_are isolable compounds of_pentacoordinate carbon,_chiral_sulfuranes and_asasulfuranes._The generation of_sulfuranes and persulfuranes_by neighboring group participation_in perester decompositions_will_be studied. The generation of radical pairs, and larger arrays of radicals, within the_solvent_cage


research in this critical area. The Collaborative HIV Prevention in Minority Communities (CRMC) program has been funded since 1997 to 1) increase the amount of innovative and scientifically excellent HIV prevention with minority communities and 2) to increase the number of funded investigators from underrepresented minority groups. To date we have trained 37

research in this critical area. The Collaborative HIV Prevention in Minority Communities (CRMC) program has been funded since 1997 to 1) increase the sum of advanced and scientifically excellent HIV prevention with minority communities and 2) to increase the number of fund investigator from underrepresented minority groups. To date we have trained 37

redearch in this critical xrea. The Collaborative HIV Pdeventiov in Minority Communities (CRLC) progeam has been funded sivce 1997 to 1) pncrease rhe emount of innovavjve and scienflficanoy excellent HLV preventimn with minoridy clmmunities and 2) to increase the numfer of gujded investigajors gwom hnderrepresented minority groups. Tk date xe have trained 37

research in this critical area. The Collaborative in Communities (CRMC) has been funded the of innovative and excellent HIV prevention minority communities and 2) to increase number of funded investigators from underrepresented minority groups. To date we have trained

research in this critical areA. The CollabOratiVe HiV PReVentIon iN Minority CommuNItieS (CRMC) program has been funDed siNcE 1997 To 1) inCReAse thE amount OF iNNOvaTiVe And ScIEnTificAllY excellEnt HIV prevEntIoN with minoritY CoMmunities aNd 2) tO increase the NumBer of fUnDed INvestIgaTors fRom undERrepreSented minOrITy grouPS. To date WE HaVe trAined 37

research in this critical  area. The  Coll abo rat iv e HI V Pr evention in Mi n orit y Communities (CRMC) p rogra mh as b e en  fund ed sinc e  1 9 9 7 t o1)  in cr e as e the  am ount of  innovativ e a nd  scientifica l ly  excellent  HI V prevention  wi th min or ity commu nit ies a nd 2)t o incr ease thenu m ber of fundedi n ve stig ators from underr e pr e sented minorit y grou ps .  T o dat e w e have tra in ed 37

research_in this_critical area. The Collaborative_HIV Prevention_in_Minority Communities_(CRMC)_program has been_funded since 1997_to 1) increase the_amount of innovative_and_scientifically excellent HIV prevention with minority communities and 2) to increase the number of_funded_investigators from_underrepresented_minority_groups. To date we have_trained 37


are to elucidate the molecular mechanisms of chromosome elimination and elucidate the selective advantages of asymmetric meiotic division. Errors in meiosis lead to the absence of one chromosome (monosomy) or the presence of an extra chromosome (trisomy) in 10-30% of human conceptions with the majority of these an

are to elucidate the molecular mechanisms of chromosome elimination and elucidate the selective advantages of asymmetrical meiotic part. Errors in meiosis spark advance to the absence of one chromosome (monosomy) or the bearing of an extra chromosome (trisomy) in 10 - 30% of human conceptions with the majority of these an

arf to elucidate the molecmlar mechanisms of chrokosome eliminagion and elucidate the selecvive advabtages of asymmetric mdiotic dinision. Ereors un meiosis lead to the agdencz if one chromospme (monosoky) or the presanze of an extra chromosome (trisomy) in 10-30% of humsn conceptions wyth uhe majkgiuy of these an

are to elucidate the molecular mechanisms of and the selective of asymmetric meiotic to absence of one (monosomy) or the of an extra chromosome (trisomy) in of human conceptions with the majority of these an

are to elucidate the moleculaR mechanismS of chRomOsoMe ElimInatIon and elucidatE The sElective advantages of asYmmetRiC MeioTIc DivisIon. ErroRS iN MEioSiS lEad To THe AbsenCe oF one chrOmosome (monOsoMy) Or the presencE Of An extra chrOmoSome (trisomy) iN 10-30% of Human cOnCepTIons wIth The maJority OF these An

are to elucidate the mole cular mech anism s o f c hr omos omeelimination an d  elu cidate the selective a dvant ag e s of as ymmet ric mei o ti c div is io n.Er r or s inmei osis le ad to theabs en ce of one ch r om osome (mon oso my) or the p res ence o fane xtrachr omoso me (tr i somy)in 10-30%  o f  human concept i o ns  wit h the majority of th e se an

are_to elucidate_the molecular mechanisms of_chromosome elimination_and_elucidate the_selective_advantages of asymmetric_meiotic division. Errors_in meiosis lead to_the absence of_one_chromosome (monosomy) or the presence of an extra chromosome (trisomy) in 10-30% of human_conceptions_with the_majority_of_these an


. Supriya Saha, a medical oncologist at the Massachusetts General Hospital (MGH) Cancer Center, toward his goal of becoming an independent physician-scientist with a focused clinical practice in hepatobiliary cancers and a research laboratory dedicated to the study of cholangiocarcinoma. Dr. Saha will be ment

. Supriya Saha, a medical oncologist at the Massachusetts General Hospital (MGH) Cancer Center, toward his goal of becoming an independent doctor - scientist with a focused clinical exercise in hepatobiliary cancer and a research laboratory dedicate to the study of cholangiocarcinoma. Dr. Saha will be ment

. Suoriya Saha, a medical onculogist at the Massachnsetts Feneral Fospital (MGH) Cancer Center, tlwqrd hus goal of becoming an independvnt physixian-wxientist wmfh a fogbsed dpinieao practice in mepatobiliasy cancers and a rzsearch laboratory dedicated to the ftudy og fholangiocarcigoma. Qr. Szha will be ment

. Supriya Saha, a medical oncologist at General (MGH) Cancer toward his goal with focused clinical practice hepatobiliary cancers and research laboratory dedicated to the study cholangiocarcinoma. Dr. Saha will be ment

. Supriya Saha, a medical oncoloGist at the MAssacHusEttS GEnerAl HoSpital (MGH) CanceR centEr, toward his goal of becomIng an InDEpenDEnT physIcian-scIEnTISt wItH a FocUsED cLinicAl pRactice In hepatobiLiaRy Cancers and a rESeArch laboraTorY dedicated to The Study oF cHolANgiocArcInoma. dr. Saha WIll be mEnt

. Supriya Saha, a medicaloncologist  at t heMas sa chus etts  General Hospi t al ( MGH) Cancer Center, to wardhi s  goa l  o f bec oming a n  i n d epe nd en t p hy s ic ian-s cie ntist w ith a focu sed  c linical prac t ic e in hepat obi liary cancer s a nd a r es ear c h lab ora torydedica t ed tothe study  o f  chola n giocarc i n om a. D r. Saha will be m e nt

. Supriya_Saha, a_medical oncologist at the_Massachusetts General_Hospital_(MGH) Cancer_Center,_toward his goal_of becoming an_independent physician-scientist with a_focused clinical practice_in_hepatobiliary cancers and a research laboratory dedicated to the study of cholangiocarcinoma. Dr. Saha_will_be ment


obscure diseases of man. These animal diseases are scrapie and progressive pneumonia of sheep and Aleutian disease and transmissible encephalopathy of mink. Their clinicopathologic, virologic, and immunologic features are studied to obtain an understanding of their natural history and pathogenesis. Such studies should provide not only information on

obscure diseases of man. These animal diseases are scrapie and progressive pneumonia of sheep and Aleutian disease and ancestral brain disorder of mink. Their clinicopathologic, virologic, and immunologic features are study to prevail an understanding of their natural history and pathogenesis. Such study should provide not only data on

obdcure diseases of man. Thtse animal diseasgs are srrapie znd progfessive pneumonia of sheep aid Aoeutiqn disease and transmirsible enbephaloparhy id mink. Themd clinigjpatgllognc, virologic, and immunologhc features ara rtbdied to obtain an understanding of eheir nstkral history agd psehogsnesis. Such studies should provide not onny informatiom on

obscure diseases of man. These animal diseases and pneumonia of and Aleutian disease Their virologic, and immunologic are studied to an understanding of their natural history pathogenesis. Such studies should provide not only information on

obscure diseases of man. These Animal diseAses aRe sCraPiE and ProgRessive pneumonIA of sHeep and Aleutian disease And trAnSMissIBlE encePhalopaTHy OF MinK. THeIr cLiNIcOpathOloGic, viroLogic, and imMunOlOgic features ARe Studied to oBtaIn an understaNdiNg of thEiR naTUral hIstOry anD pathoGEnesis. such studiEs SHould pROvide noT ONlY infOrmation on

obscure diseases of man.These anim al di sea ses  a re s crap ie and progres s ivepneumonia of sheep and  Aleu ti a n di s ea se an d trans m is s i ble  e nc eph al o pa thy o f m ink. Th eir clinic opa th ologic, viro l og ic, and im mun ologic featu res  are s tu die d  to o bta in an  under s tandin g of thei rn atural history a nd  pat hogenesis. Such s t ud i es should prov ide no to nl y inf orm ation on

obscure_diseases of_man. These animal diseases_are scrapie_and_progressive pneumonia_of_sheep and Aleutian_disease and transmissible_encephalopathy of mink. Their_clinicopathologic, virologic, and_immunologic_features are studied to obtain an understanding of their natural history and pathogenesis. Such_studies_should provide_not_only_information on


entry into island countries and the combination of NPIs that are likely to be most effective at achieving this. [unreadable] - Data on the prevalence of influenza in passengers from various origins and flying times would provide an important input for decisions about the efficacy of traveler exclusion, quarantine and screening. Results could also be contrasted

entry into island countries and the combination of NPIs that are likely to be most effective at achieve this. [ indecipherable ] - Data on the preponderance of influenza in passengers from various origins and flight times would provide an important input signal for decisions about the efficacy of traveler exclusion, quarantine and cover. result could also be contrast

enhry into island countrier and the combiuqtion mf NPIa that afe likely to be most effectite ar achueving this. [unreadable] - Data on the precaleice of influenza in passcugers nrom racious origins akd flying thmes would proeiae an important input for decisions afout thr ffficacy of trwveltr qxclhsion, quarantine and screening. Reshlts colld also be contrssted

entry into island countries and the combination that likely to most effective at on prevalence of influenza passengers from various and flying times would provide an input for decisions about the efficacy of traveler exclusion, quarantine and screening. Results also be contrasted

entry into island countries aNd the combiNatioN of nPIS tHat aRe liKely to be most efFEctiVe at achieving this. [unreaDable] - daTA on tHE pRevalEnce of iNFlUENza In PaSseNgERs From vAriOus origIns and flyiNg tImEs would proviDE aN important InpUt for decisioNs aBout thE eFfiCAcy of TraVeler ExclusIOn, quarAntine and ScREening. rEsults cOULd Also Be contrasted

entry into island countri es and the  comb ina tio nof N PIsthat are likel y  tobe most effective at a chiev in g  thi s .[unre adable] -D a taon  t hepr e va lence  of  influe nza in pas sen ge rs from vari o us  origins a ndflying times  wo uld pr ov ide an im por tantinputf or dec isions ab ou t  the e f ficacyo f  t rave ler exclusion, qu a ra n tine and scree ning.Re s ul t s  co uld  also be c on trast e d

entry_into island_countries and the combination_of NPIs_that_are likely_to_be most effective_at achieving this._[unreadable] - Data on_the prevalence of_influenza_in passengers from various origins and flying times would provide an important input for_decisions_about the_efficacy_of_traveler exclusion, quarantine and screening._Results could also be contrasted


may be applicable for the assessment of other medical technologies and to aid in the comparison of investments in such technologies. Intercellular RNA transport is a potentially important means of cell-cell communication. In the nematode C. elegans the RNA channel SID-1 is essential for the cell-to-cell transport of silencing RNAs

may be applicable for the assessment of other medical technologies and to help in the comparison of investment in such technologies. Intercellular RNA transport is a potentially important mean of cell - cell communication. In the nematode C. elegans the RNA channel SID-1 is all-important for the cell - to - cell conveyance of silencing RNAs

maj be applicable for the xssessment of ojhwr medmcal tedhnologids and to aid in the comparidob of unvestments in such tezhnologied. Intercwlluoqr RNA traiaport is a pofcntianoy important mgans of cell-well communicadiun. In the nematode C. elegans the RNA shannel SLD-1 is essentiaj fog ehe dvlo-to-cell transport of silencinf RNAs

may be applicable for the assessment of technologies to aid the comparison of RNA is a potentially means of cell-cell In the nematode C. elegans the channel SID-1 is essential for the cell-to-cell transport of silencing RNAs

may be applicable for the asseSsment of otHer meDicAl tEcHnolOgieS and to aid in the COmpaRison of investments in suCh tecHnOLogiES. INtercEllular rnA TRAnsPoRt Is a PoTEnTiallY imPortant Means of celL-ceLl CommunicatioN. in The nematodE C. eLegans the RNA ChaNnel SId-1 iS esSEntiaL foR the cEll-to-cELl tranSport of siLeNCing RNaS

may be applicable for the  assessmen t ofoth erme dica l te chnologies and to a id in the comparison o f inv es t ment s  i n suc h techn o lo g i es.  I nt erc el l ul ar RN A t ranspor t is a pot ent ia lly importan t  m eans of ce ll- cell communi cat ion. I nthe nemat ode  C. e legans the RN A channel  S I D-1 is essenti a l  f or t he cell-to-cell t r an s port of silenc ing RN As

may_be applicable_for the assessment of_other medical_technologies_and to_aid_in the comparison_of investments in_such technologies. Intercellular RNA_transport is a_potentially_important means of cell-cell communication. In the nematode C. elegans the RNA channel SID-1_is_essential for_the_cell-to-cell_transport of silencing RNAs


[unreadable] 2. After adjustment for pertinent cancer risk factors, to determine the potential direct effects of the neighborhood environmental factors on incident cancer outcomes (breast, colorectal, total). [unreadable] [unreadable] 3. Using multivariable models, to ascertain the direct, mediated or moderated effects of both the neighborhood environment

[ unreadable ] 2. After adjustment for pertinent cancer risk divisor, to settle the potential direct effects of the region environmental factors on incident cancer outcomes (breast, colorectal, full). [ indecipherable ] [ unreadable ] 3. Using multivariable models, to ascertain the direct, mediated or moderated effect of both the neighborhood environment

[ungeadable] 2. After adjustmekt for pertinent cancer risk ractors, go determine the potential dmrecr efftbts of the neighborhoud envirojmental dacties on incivsnt cangzr oufgomes (ureast, colorectsl, total). [utreadable] [unreddxbpe] 3. Using multivariable models, to afcertaim hhe direct, medyatec or joderated effects of both the neiggborhoov environment

[unreadable] 2. After adjustment for pertinent cancer to the potential effects of the cancer (breast, colorectal, total). [unreadable] 3. Using models, to ascertain the direct, mediated moderated effects of both the neighborhood environment

[unreadable] 2. After adjustment For pertineNt canCer RisK fActoRs, to Determine the poTEntiAl direct effects of the neIghboRhOOd enVIrOnmenTal factORs ON IncIdEnT caNcER oUtcomEs (bReast, coLorectal, toTal). [UnReadable] [unreADaBle] 3. Using muLtiVariable modeLs, tO ascerTaIn tHE direCt, mEdiatEd or moDErated Effects of BoTH the neIGhborhoOD EnViroNment

[unreadable] 2. After adj ustment fo r per tin ent  c ance r ri sk factors, to dete rmine the potential di rectef f ects of  theneighbo r ho o d  en vi ro nme nt a lfacto rson inci dent cance r o ut comes (breas t ,colorectal , t otal). [unre ada ble] [ un rea d able]  3.  Usin g mult i variab le models ,t o asce r tain th e di rect , mediated or mod e ra t ed effects ofboth t he ne i g hbo rho od environ me nt

[unreadable]_2. After_adjustment for pertinent cancer_risk factors,_to_determine the_potential_direct effects of_the neighborhood environmental_factors on incident cancer_outcomes (breast, colorectal,_total)._[unreadable] [unreadable] 3. Using multivariable models, to ascertain the direct, mediated or moderated effects_of_both the_neighborhood_environment


shown to be rich in cytokines such as IL10, IL13, and TGF2, which promote Treg induction or amplification of their suppressive function. Some of the cytokines elaborated by Tregs may serve as survival factors for transformed B cells. Finally, as lymphoma cells constitutively express MHC class II antigens, they are capable

shown to be rich in cytokines such as IL10, IL13, and TGF2, which promote Treg evocation or amplification of their suppressive affair. Some of the cytokines elaborated by Tregs may serve as survival component for transformed B cell. last, as lymphoma cells constitutively carry MHC class II antigens, they are able

shlwn to be rich in cytokikes such as IL10, IL13, and TJF2, whicg promotd Treg induction or amplificetiob of ukeir suppressive funztion. Somv of the xytojunes elaboczted by Tregs lay vxrve as survivak factors xor transformeg C eells. Finally, as lymphoma cells conseitutivrlj express MHC slasx II zntigens, they are capable

shown to be rich in cytokines such IL13, TGF2, which Treg induction or Some the cytokines elaborated Tregs may serve survival factors for transformed B cells. as lymphoma cells constitutively express MHC class II antigens, they are capable

shown to be rich in cytokines sUch as IL10, IL13, aNd TGF2, WhiCh pRoMote treg Induction or ampLIficAtion of their suppressivE funcTiON. SomE Of The cyTokines ELaBORatEd By treGs MAy Serve As sUrvival Factors for TraNsFormed B cells. fInAlly, as lympHomA cells constiTutIvely eXpResS mHC clAss iI antIgens, tHEy are cApable

shown to be rich in cytok ines suchas IL 10,  IL 13 , an d TG F2, which prom o te T reg induction or ampli ficat io n  oft he ir su ppressi v ef u nct io n.  So me of  thecyt okineselaborated  by  T regs may ser v eas surviva l f actors for t ran sforme dB c e lls.Fin ally,  as ly m phomacells con st i tutive l y expre s s  M HC c lass II antigens, th e y are capable

shown_to be_rich in cytokines such_as IL10,_IL13,_and TGF2,_which_promote Treg induction_or amplification of_their suppressive function. Some_of the cytokines_elaborated_by Tregs may serve as survival factors for transformed B cells. Finally, as lymphoma_cells_constitutively express_MHC_class_II antigens, they are capable


and presenilin comprise one of just three superfamilies of intramembrane proteases. The details of regulated intramembrane proteolysis, from cell biological signaling to active site chemistry, are of both fundamental biochemical importance and potential therapeutic application. How substrates are presented and hydrolyzed within the confines of the hydrophobic space of the

and presenilin comprise one of just three superfamilies of intramembrane proteases. The detail of determine intramembrane proteolysis, from cell biological signaling to active site chemistry, are of both cardinal biochemical importance and potential therapeutic application. How substrate are presented and hydrolyzed within the confines of the hydrophobic outer space of the

anf presenilin comprise ont of just three sopwrfaminies or intramdmbrane proteases. The detaild if retulated intramembrane oroteolysps, from cwll uiological signaling to active dite rhemistry, are on both funddmental biochekizap importance and potential therapeueic appkifation. How subftraues are irtsented and hydrolyzed within the confints of the hydrophonic space of the

and presenilin comprise one of just three intramembrane The details regulated intramembrane proteolysis, active chemistry, are of fundamental biochemical importance potential therapeutic application. How substrates are and hydrolyzed within the confines of the hydrophobic space of the

and presenilin comprise one oF just three SuperFamIliEs Of inTramEmbrane proteasES. The Details of regulated intrAmembRaNE proTEoLysis, From celL BiOLOgiCaL sIgnAlINg To actIve Site cheMistry, are oF boTh Fundamental bIOcHemical impOrtAnce and potenTiaL theraPeUtiC AppliCatIon. HoW substRAtes arE presenteD aND hydroLYzed witHIN tHe coNfines of the hydropHObIC space of the

and presenilin comprise o ne of just  thre e s upe rf amil iesof intramembra n e pr oteases. The details o f reg ul a tedi nt ramem brane p r ot e o lys is ,fro mc el l bio log ical si gnaling to  ac ti ve site chem i st ry, are of  bo th fundament albioche mi cal impor tan ce an d pote n tial t herapeuti ca pplica t ion. Ho w su bstr ates are presente d  a n d hydrolyzed w ithinth e  c o n fin esof the hyd ro phobi c  spaceo ft h e

and_presenilin comprise_one of just three_superfamilies of_intramembrane_proteases. The_details_of regulated intramembrane_proteolysis, from cell_biological signaling to active_site chemistry, are_of_both fundamental biochemical importance and potential therapeutic application. How substrates are presented and hydrolyzed_within_the confines_of_the_hydrophobic space of the


of vertebrate embryos and give rise to a diverse range of cell types, including most of the peripheral nervous system, melanocytes and the craniofacial skeleton. It has been classically assumed that the neutral crest is a segregated population in the early ectoderm, lying between the neutral plate and presumptive epidermis. However, our

of vertebrate embryos and give rise to a diverse compass of cellular telephone types, including most of the peripheral skittish organization, melanocytes and the craniofacial skeleton. It has been classically assumed that the impersonal crest is a segregated population in the early ectoderm, lying between the impersonal plate and presumptive epidermis. However, our

of vertebrate embryos and nive rise to a dncerse cange or cell thpes, including most of the pxripyeral nervous system, melanozytes and the crabiofecial skeleton. Iv has becu claadicanoy assumed thaj the neutran crest is a sagfeyated population in the early ectodewm, lyinb hetween the neotral [lats and presumptive epidermis. Howeved, our

of vertebrate embryos and give rise to range cell types, most of the the skeleton. It has classically assumed that neutral crest is a segregated population the early ectoderm, lying between the neutral plate and presumptive epidermis. However, our

of vertebrate embryos and givE rise to a diVerse RanGe oF cEll tYpes, Including most oF The pEripheral nervous system, MelanOcYTes aND tHe craNiofaciAL sKELetOn. it Has BeEN cLassiCalLy assumEd that the nEutRaL crest is a segREgAted populaTioN in the early eCtoDerm, lyInG beTWeen tHe nEutraL plate ANd presUmptive epIdERmis. HoWEver, our

of vertebrate embryos and  give rise  to a  di ver se  ran ge o f cell types,i nclu ding most of the perip heral  n e rvou s  s ystem , melan o cy t e s a nd  t hecr a ni ofaci alskeleto n. It hasbee nclassicallya ss umed thatthe  neutral cre stis a s eg reg a ted p opu latio n in t h e earl y ectoder m, lyingb etweent h eneut ral plate and pre s um p tive epidermis . Howe ve r ,o u r

of_vertebrate embryos_and give rise to_a diverse_range_of cell_types,_including most of_the peripheral nervous_system, melanocytes and the_craniofacial skeleton. It_has_been classically assumed that the neutral crest is a segregated population in the early_ectoderm,_lying between_the_neutral_plate and presumptive epidermis. However,_our


and bone marrow of subjects with sickle cell anemia. We hypothesize that therapeutic interventions that interrupt adhesive interactions between sickle erythrocytes, leukocytes, platelets and vascular endothelium will lessen the vaso occlusion, hemoglobin desaturations, and release of mediators of vascular damage induced by intermittent hypoxia. While sickle cell anemia (SCA

and bone marrow of subjects with sickle cell anemia. We hypothesize that curative interposition that interrupt adhesive interactions between sickle erythrocytes, leukocyte, platelets and vascular endothelium will decrease the vaso occlusion, hemoglobin desaturations, and acquittance of mediators of vascular damage induce by intermittent hypoxia. While sickle cell anemia (SCA

anf bone marrow of subjectr with sickle cglo anemma. We hgpothesixe that therapeutic intervenvionw thau interrupt adhesivd interacnions betqeen wickle eryvgrocytes, leukkgytes, 'latelets and vsscular engothelium will ldsden the vaso occlusion, hemoglobin dqsaturayilns, and releasg of kqdiafors of vascular damage induced by intermpttent hypoxia. Whole sickle cell anemia (SCA

and bone marrow of subjects with sickle We that therapeutic that interrupt adhesive platelets vascular endothelium will the vaso occlusion, desaturations, and release of mediators of damage induced by intermittent hypoxia. While sickle cell anemia (SCA

and bone marrow of subjects wiTh sickle ceLl aneMia. we hYpOtheSize That therapeutiC InteRventions that interrupt AdhesIvE InteRAcTions Between SIcKLE erYtHrOcyTeS, LeUkocyTes, PlateleTs and vascuLar EnDothelium wilL LeSsen the vasO ocClusion, hemogLobIn desaTuRatIOns, anD reLease Of mediATors of Vascular dAmAGe induCEd by intERMiTtenT hypoxia. While sickLE cELl anemia (SCA

and bone marrow of subjec ts with si cklecel l a ne mia.  Wehypothesize th a t th erapeutic intervention s tha ti nter r up t adh esive i n te r a cti on sbet we e nsickl e e rythroc ytes, leuk ocy te s, platelets an d vascular  en dothelium wi lllessen  t hev aso o ccl usion , hemo g lobindesaturat io n s, and release o fmedi ators of vascular da m age induced by  inter mi t te n t  hy pox ia. Whilesi cklec ell ane m ia ( S CA

and_bone marrow_of subjects with sickle_cell anemia._We_hypothesize that_therapeutic_interventions that interrupt_adhesive interactions between_sickle erythrocytes, leukocytes, platelets_and vascular endothelium_will_lessen the vaso occlusion, hemoglobin desaturations, and release of mediators of vascular damage induced_by_intermittent hypoxia._While_sickle_cell anemia (SCA


the female menstrual cycle. Based on this hypohesis, two predictions regarding IC will be investigated: first, that IC is associated with a generalized increase in pain sensitivity, which includes enhanced response to somatic as well as visceral stimuli; and second, that both clinical symptoms and responses to experimentally-evoked pain will be influenced

the female menstrual cycle. Based on this hypohesis, two predictions regarding intelligence community will be investigate: first, that IC is associated with a generalized addition in pain sensitivity, which admit enhanced response to somatic equally well as intuitive stimuli; and second, that both clinical symptoms and responses to experimentally - evoked pain will be charm

thf female menstrual cycle. Based on this ktpohesms, two lredictiuns regarding IC will be invxstitated: first, that IC is assoziated winh a geneealieed increase in pejn senslcivitg, whieh includes enhakced responve to somatic ds wzll as visceral stimuli; and second, trat botn flinical symptjms sgd rssponses to experimentally-evoked pzin wiln be influencrd

the female menstrual cycle. Based on this predictions IC will investigated: first, that generalized in pain sensitivity, includes enhanced response somatic as well as visceral stimuli; second, that both clinical symptoms and responses to experimentally-evoked pain will be influenced

the female menstrual cycle. BaSed on this hYpoheSis, Two PrEdicTionS regarding IC wiLL be iNvestigated: first, that IC Is assOcIAted WItH a genEralizeD InCREasE iN pAin SeNSiTivitY, whIch inclUdes enhancEd rEsPonse to somatIC aS well as visCerAl stimuli; and SecOnd, thaT bOth CLinicAl sYmptoMs and rESponseS to experiMeNTally-eVOked paiN WIlL be iNfluenced

the female menstrual cycl e. Based o n thi s h ypo he sis,  two  predictions r e gard ing IC will be investi gated :f irst ,  t hat I C is as s oc i a ted  w it h a  g e ne raliz edincreas e in painsen si tivity, whic h  i ncludes en han ced response  to  somat ic  as wellasvisce ral st i muli;and secon d, that b o th clin i c al  sym ptoms and respons e st o experimental ly-evo ke d  p a i n w ill  be influe nc ed

the_female menstrual_cycle. Based on this_hypohesis, two_predictions_regarding IC_will_be investigated: first,_that IC is_associated with a generalized_increase in pain_sensitivity,_which includes enhanced response to somatic as well as visceral stimuli; and second, that_both_clinical symptoms_and_responses_to experimentally-evoked pain will be_influenced


and prognosis as well as providing novel targets for therapeutic discovery and treatment of esophageal adenocarcinoma. The p53 tumor suppressor is central to human DNA repair, damage checkpoints and many aspects of human biology. Importantly, most cancers are altered for p53 function. Although the guardian of the genome p53, much about its function and

and prognosis as well as providing novel targets for curative discovery and discussion of esophageal adenocarcinoma. The p53 tumor suppressor is cardinal to human DNA repair, damage checkpoints and many aspect of human biology. Importantly, most cancers are interpolate for p53 routine. Although the guardian of the genome p53, a lot about its affair and

anf prognosis as well as pvoviding novel tcegets hor thedapeutic discovery and treatment of xsopyageao adenocarcinoma. The p53 tumor suipressor us ctntral to human DIZ repaiv, damzne chzcjpoints and maky aspects mf human biolocy. Ilportantly, most cancers are altered for p53 gujction. Althougr tht gtardjan of the genome p53, much about its functimn and

and prognosis as well as providing novel therapeutic and treatment esophageal adenocarcinoma. The to DNA repair, damage and many aspects human biology. Importantly, most cancers are for p53 function. Although the guardian of the genome p53, much about its and

and prognosis as well as proviDing novel tArgetS foR thErApeuTic dIscovery and treATmenT of esophageal adenocarcInoma. thE P53 tumOR sUppreSsor is cENtRAL to HuMaN DNa rEPaIr, damAge CheckpoInts and manY asPeCts of human biOLoGy. ImportanTly, Most cancers aRe aLtered FoR p53 fUNctioN. AlThougH the guARdian oF the genomE p53, MUch aboUT its funCTIoN and

and prognosis as well asprovidingnovel  ta rge ts  for  the rapeutic disco v eryand treatment of esoph ageal  a d enoc a rc inoma . The p 5 3t u mor  s up pre ss o ris ce ntr al to h uman DNA r epa ir , damage che c kp oints andman y aspects of  hu man bi ol ogy .  Impo rta ntly,  mostc ancers  are alte re d  for p 5 3 funct i o n.  Alt hough the guardia n  o f  the genome p5 3, muc ha bo u t  it s f unction an d

and_prognosis as_well as providing novel_targets for_therapeutic_discovery and_treatment_of esophageal adenocarcinoma._The p53 tumor_suppressor is central to_human DNA repair,_damage_checkpoints and many aspects of human biology. Importantly, most cancers are altered for p53_function._Although the_guardian_of_the genome p53, much about_its function and


interconversion enzymes will be purified to see whether they occur in an enzyme aggregate. The intracellular localization of these enzymes will be determined. Mutants with alterations in the function or regulation of proteases will be isolated and characterized both with respect to genetics and biochemistry. The consequences to the cell of such alterations in protease function will be

interconversion enzymes will be purified to see whether they occur in an enzyme sum. The intracellular localization of function of these enzyme will be determined. Mutants with alterations in the routine or regulation of proteases will be isolate and characterize both with respect to genetics and biochemistry. The consequence to the cell of such alterations in protease routine will be

inherconversion enzymes wiul be purified jo see wiether fhey occjr in an enzyme aggregate. Thx inrraceolular localization of these endymes wilo be eetermined. Mutants with zpterctmons in the fungtion or reculation of prmtdades will be isolated and characterised botn aith respect tj gemqtica and biochemistry. The consequencea to tht cell of such altrrations in protease functlon aill be

interconversion enzymes will be purified to see occur an enzyme The intracellular localization determined. with alterations in function or regulation proteases will be isolated and characterized with respect to genetics and biochemistry. The consequences to the cell of such in protease function will be

interconversion enzymes wilL be purifieD to seE whEthEr They OccuR in an enzyme aggREgatE. The intracellular localIzatiOn OF theSE eNzymeS will be DEtERMinEd. muTanTs WItH alteRatIons in tHe function Or rEgUlation of proTEaSes will be iSolAted and charaCteRized bOtH wiTH respEct To genEtics aND biochEmistry. ThE cONsequeNCes to thE CElL of sUch alterations in pROtEAse function wilL be

interconversion enzymes w ill be pur ified  to  se ewhet herthey occur ina n en zyme aggregate. The in trace ll u larl oc aliza tion of th e s e e nz ym eswi l lbe de ter mined.Mutants wi thal terations in th e function  or  regulationofprotea se s w i ll be  is olate d andc haract erized bo th with r e spect t o ge neti cs and biochemist r y. The consequenc es toth e  c e l l o f s uch altera ti ons i n  protea s ef u n cti o n will be

interconversion_enzymes will_be purified to see_whether they_occur_in an_enzyme_aggregate. The intracellular_localization of these_enzymes will be determined._Mutants with alterations_in_the function or regulation of proteases will be isolated and characterized both with respect_to_genetics and_biochemistry._The_consequences to the cell of_such alterations in protease function_will be


of proteins, polypeptides and lipoproteins across cells and basement membranes. The studies will be done on isolated segments of renal tubules employing in vitro and in situ microperfusion methods and electron microscopy. Functional, quantitative data on the absorption and transport of various macromolecular substances will be directly correlated with fine structural changes at the

of proteins, polypeptides and lipoproteins across cells and basement membrane. The cogitation will be done on sequester segment of renal tubules hire in vitro and in situ microperfusion method acting and electron microscopy. Functional, quantitative datum on the concentration and transport of versatile macromolecular substances will be directly correlate with all right structural changes at the

of proteins, polypeptides akd lipoproteins cxross rells ahd basemdnt membranes. The studies wipl be dine on isolated segmengs of renwl tubulws enploying in vitro akb in altu mnccoperfusion metmods and elactron microscmph. Yunctional, quantitative data on the wbsorptooj and transporj of nawioua macromolecular substances will bs direculy correlated witn fine structural changes wt tje

of proteins, polypeptides and lipoproteins across cells membranes. studies will done on isolated in and in situ methods and electron Functional, quantitative data on the absorption transport of various macromolecular substances will be directly correlated with fine structural changes the

of proteins, polypeptides and LipoproteiNs acrOss CelLs And bAsemEnt membranes. ThE StudIes will be done on isolateD segmEnTS of rENaL tubuLes emplOYiNG In vItRo And In SItU micrOpeRfusion Methods and EleCtRon microscopY. fuNctional, quAntItative data oN thE absorPtIon ANd traNspOrt of VariouS MacromOlecular sUbSTances WIll be diRECtLy coRrelated with fine sTRuCTural changes at The

of proteins, polypeptides  and lipop rotei nsacr os s ce llsand basement m e mbra nes. The studies willbe do ne on i s ol atedsegment s  o f ren al  t ubu le s  e mploy ing  in vit ro and insit umicroperfusi o nmethods an d e lectron micr osc opy. F un cti o nal,qua ntita tive d a ta onthe absor pt i on and transpo r t  o f va rious macromolecu l ar substances wil l be d ir e ct l y  co rre lated with  f ine s t ructura l  c h a n ges at the

of_proteins, polypeptides_and lipoproteins across cells_and basement_membranes._The studies_will_be done on_isolated segments of_renal tubules employing in_vitro and in_situ_microperfusion methods and electron microscopy. Functional, quantitative data on the absorption and transport of_various_macromolecular substances_will_be_directly correlated with fine structural_changes at the


heart morphometry, microscopic analysis of capillary density, fibrosis and apoptosis and determination of tissue ATP levels. Transgenic overexpression is a valuable tool to analyze the tissue function of PR-M. We believe that enhanced ATP production secondary to PR-M expression will diminish cardiac hypertrophy secondary to volume and pressure overload in the study models.

heart morphometry, microscopic analysis of capillary density, fibrosis and apoptosis and determination of tissue ATP degree. Transgenic overexpression is a valuable cock to analyze the tissue function of PR - M. We believe that enhanced ATP output secondary to PR - M expression will decrease cardiac hypertrophy secondary to volume and pressure overload in the survey models.

hewrt morphometry, microscokic analysis of ccpillarb densify, fibroris and apoptosis and determmnatuon od tissue ATP levels. Trxnsgenic lverexprwssiib is a valnzble tool to zkalyzz vhe tissue funcjion of PR-M. Fe believe thad dnkanced ATP production secondary to PW-M exprrsdion will dimigish sardjac hypertrophy secondary to volums and pgessure overload on the study models.

heart morphometry, microscopic analysis of capillary density, apoptosis determination of ATP levels. Transgenic to the tissue function PR-M. We believe enhanced ATP production secondary to PR-M will diminish cardiac hypertrophy secondary to volume and pressure overload in the study

heart morphometry, microscopIc analysis Of capIllAry DeNsitY, fibRosis and apoptoSIs anD determination of tissue aTP leVeLS. TraNSgEnic oVerexprESsION is A vAlUabLe TOoL to anAlyZe the tiSsue functiOn oF Pr-M. We believe tHAt Enhanced ATp prOduction secoNdaRy to PR-m eXprESsion WilL dimiNish caRDiac hyPertrophy SeCOndary TO volume AND pRessUre overload in the sTUdY Models.

heart morphometry, micros copic anal ysisofcap il lary  den sity, fibrosis andapoptosis and determin ation  o f  tis s ue  ATPlevels. Tr a n sge ni cove re x pr essio n i s a val uable tool  to  a nalyze the t i ss ue functio n o f PR-M. We b eli eve th at  en h anced  AT P pro ductio n  secon dary to P R- M  expre s sion wi l l  d imin ish cardiac hyper t ro p hy secondary t o volu me an d pre ssu re overloa din th e  studym od e l s .

heart_morphometry, microscopic_analysis of capillary density,_fibrosis and_apoptosis_and determination_of_tissue ATP levels._Transgenic overexpression is_a valuable tool to_analyze the tissue_function_of PR-M. We believe that enhanced ATP production secondary to PR-M expression will diminish_cardiac_hypertrophy secondary_to_volume_and pressure overload in the_study models.


superimposed acute injury. This Project is critically linked to Project 1, as studies in chronic AB-enrichment in the CMSstrongly support deleterious and maladaptive roles for RAGE in neuronal stress. As antagonism of RAGE nears clinical trials in Alzheimer's Disease and diabetes, it is imperative to dissect

superimposed acute injury. This Project is critically linked to Project 1, as report in chronic AB - enrichment in the CMSstrongly documentation deleterious and maladaptive roles for RAGE in neuronal tension. As antagonism of RAGE nears clinical trials in Alzheimer's Disease and diabetes, it is imperative to analyze

suoerimposed acute injury. Uhis Project is ctiricallb linkes to Progect 1, as studies in chronic EB-eneichmtut in the CMSstronglh support deleteruous qnd malada'five roles fod RAGZ mn neuronal strgss. As antagmnism of RAGE texrd clinical trials in Alzheimer's Disqase anc fiabetes, it is imptraeive no dissect

superimposed acute injury. This Project is critically Project as studies chronic AB-enrichment in maladaptive for RAGE in stress. As antagonism RAGE nears clinical trials in Alzheimer's and diabetes, it is imperative to dissect

superimposed acute injury. ThIs Project iS critIcaLly LiNked To PrOject 1, as studies IN chrOnic AB-enrichment in the CmSstrOnGLy suPPoRt delEteriouS AnD MAlaDaPtIve RoLEs For RAgE iN neuronAl stress. As AntAgOnism of RAGE nEArS clinical tRiaLs in AlzheimeR's DIsease AnD diABetes, It iS impeRative TO disseCt

superimposed acute injury . This Pro jectiscri ti call y li nked to Projec t  1,as studies in chronicAB-en ri c hmen t  i n the  CMSstr o ng l y  su pp or t d el e te rious  an d malad aptive rol esfo r RAGE in ne u ro nal stress . A s antagonism  of  RAGEne ars clini cal  tria ls inA lzheim er's Dise as e  and d i abetes, i tis i mperative to diss e ct

superimposed_acute injury._This Project is critically_linked to_Project_1, as_studies_in chronic AB-enrichment_in the CMSstrongly_support deleterious and maladaptive_roles for RAGE_in_neuronal stress. As antagonism of RAGE nears clinical trials in Alzheimer's Disease and diabetes,_it_is imperative_to_dissect


regulate the membrane potential of glia and 4) the characteristics of ion transport systems in glia. We plan to develop a cell culture facility in support of these specific projects. The purpose of this facility will be two-fold; first, to provide each investigator with preparations of cultured cells that are standardized within the current limits

regulate the membrane potential of glia and 4) the characteristics of ion ecstasy system in glia. We design to develop a cellular telephone culture facility in accompaniment of these specific project. The purpose of this adeptness will be two - fold; foremost, to provide each investigator with readiness of cultured cells that are standardized within the current limit

rehulate the membrane potektial of glia anb 4) the rharactsristics of ion transport systems in goia. Wt plan to develop a cell culnure facioity un support of thesc spedlfic 'rijects. The purkose of this facility will bd cwo-fold; first, to provide each investygator eihh preparationf of sulthgeb cells that are standardized wjthin tie current limiys

regulate the membrane potential of glia and characteristics ion transport in glia. We culture in support of specific projects. The of this facility will be two-fold; to provide each investigator with preparations of cultured cells that are standardized within current limits

regulate the membrane potentIal of glia aNd 4) the ChaRacTeRistIcs oF ion transport sYStemS in glia. We plan to develop A cell CuLTure FAcIlity In suppoRT oF THesE sPeCifIc PRoJects. the Purpose Of this faciLitY wIll be two-fold; FIrSt, to providE eaCh investigatOr wIth prePaRatIOns of CulTured Cells tHAt are sTandardizEd WIthin tHE currenT LImIts

regulate the membrane pot ential ofgliaand  4)  t he c hara cteristics ofi on t ransport systems in gl ia. W ep lant odevel op a ce l lc u ltu re  f aci li t yin su ppo rt of t hese speci fic  p rojects. The pu rpose of t his  facility wi llbe two -f old ;  firs t,to pr ovidee ach in vestigato rw ith pr e paratio n s  o f cu ltured cells that ar e  standardizedwithin  t h ec u rre ntlimits

regulate_the membrane_potential of glia and_4) the_characteristics_of ion_transport_systems in glia._We plan to_develop a cell culture_facility in support_of_these specific projects. The purpose of this facility will be two-fold; first, to provide_each_investigator with_preparations_of_cultured cells that are standardized_within the current limits


ates for certain glycosyltransferases have already been accomplished in our laboratory. A number of these synthetic substrates have proven to be very useful and valuable acceptors for glycosyltransferases from sources other than human. Our main strategy for the characterization of the product resulting from the reaction of a glycosyltransferase and its acceptor involves

ates for certain glycosyltransferases have already been accomplished in our laboratory. A numeral of these man-made substrates have proven to be very useful and valuable acceptor for glycosyltransferases from sources other than human. Our independent scheme for the characterization of the product resulting from the reaction of a glycosyltransferase and its acceptor involves

ated for certain glycosyltrxnsferases have alreadb been zccomplirhed in our laboratory. A numuer if thtfe synthetic substfates havv proven ro bt very useful and valuablc accsitors hor glycosyltraksferases fsom sources otvef chan human. Our main strategy for the characyegization of thg proctct dvsmlting from the reaction of a glgcosyltgansferase and itx acceptor involves

ates for certain glycosyltransferases have already been our A number these synthetic substrates useful valuable acceptors for from sources other human. Our main strategy for the of the product resulting from the reaction of a glycosyltransferase and its acceptor

ates for certain glycosyltraNsferases hAve alReaDy bEeN accOmplIshed in our laboRAtorY. A number of these synthetIc subStRAtes HAvE provEn to be vERy USEfuL aNd ValUaBLe AccepTorS for glyCosyltransFerAsEs from sourceS OtHer than humAn. OUr main strateGy fOr the cHaRacTErizaTioN of thE produCT resulTing from tHe REactioN Of a glycOSYlTranSferase and its accePToR Involves

ates for certain glycosylt ransferase s hav e a lre ad y be en a ccomplished in ourlaboratory. A number o f the se synt h et ic su bstrate s  h a v e p ro ve n t ob everyuse ful and  valuableacc ep tors for gly c os yltransfer ase s from sourc esotherth anh uman.  Ou r mai n stra t egy fo r the cha ra c teriza t ion oft h eprod uct resulting fro m  t h e reaction ofa glyc os y lt r a nsf era se and its  a ccept o r invol v es

ates for_certain glycosyltransferases_have already been accomplished_in our_laboratory._A number_of_these synthetic substrates_have proven to_be very useful and_valuable acceptors for_glycosyltransferases_from sources other than human. Our main strategy for the characterization of the product_resulting_from the_reaction_of_a glycosyltransferase and its acceptor_involves


-invasive disease monitoring, stem cell therapies, cell transplantation, tumor growth, in vivo gene expression analysis, immune cell tracking, and neurogenesis, and remains a critical element of our research program. The Perkin/Elmer IVIS Spectrum In Vivo Imaging System is a top-level research instrument that combines cutting edge

-invasive disease monitoring, stem cell therapies, cell transplant, tumor increase, in vivo gene expression analysis, immune cell trailing, and neurogenesis, and remains a critical element of our research plan. The Perkin / Elmer IVIS Spectrum In Vivo Imaging System is a top - level research legal document that combines cutting boundary

-invwsive disease monitoring, stem cell thercpies, cxll trahsplantagion, tumor growth, in vivo geie ezpreswion analysis, immune cdll trackpng, and nwurojenesis, and remamhs a crlcical clemeut of our researgh program. Dhe Perkin/Elmes KVNS Spectrum In Vivo Imaging System if a top-kegel research igstrlmqnt fhat combines cutting edge

-invasive disease monitoring, stem cell therapies, cell growth, vivo gene analysis, immune cell a element of our program. The Perkin/Elmer Spectrum In Vivo Imaging System is top-level research instrument that combines cutting edge

-invasive disease monitoring, Stem cell thErapiEs, cEll TrAnspLantAtion, tumor growTH, in vIvo gene expression analySis, imMuNE celL TrAckinG, and neuROgENEsiS, aNd RemAiNS a CritiCal Element Of our reseaRch PrOgram. The PerkIN/ELmer IVIS SpEctRum In Vivo ImaGinG SysteM iS a tOP-leveL reSearcH instrUMent thAt combineS cUTting eDGe

-invasive disease monitori ng, stem c ell t her api es , ce ll t ransplantation ,  tum or growth, in vivo gen e exp re s sion an alysi s, immu n ec e lltr ac kin g, an d neu rog enesis,  and remai nsacritical ele m en t of our r ese arch program . T he Per ki n/E l mer I VIS  Spec trum I n  VivoImaging S ys t em isa  top-le v e lrese arch instrument t h at combines cutti ng edg e

-invasive disease_monitoring, stem_cell therapies, cell transplantation,_tumor growth,_in_vivo gene_expression_analysis, immune cell_tracking, and neurogenesis,_and remains a critical_element of our_research_program. The Perkin/Elmer IVIS Spectrum In Vivo Imaging System is a top-level research instrument_that_combines cutting_edge