**ABSTRACTS OF K99/R00 PATHWAY TO INDEPENDENCE AWARDS**

Date Run: 11/30/06 **PUBLIC ABSTRACTS**

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  **Grant:**         1K99AA016731-01                 

  **Program          GRANDISON, LINDSEY              
  Director:**                                        

  **Principal        SABINO, VALENTINA               PHD
  Investigator:**                                    

  **Title:**         Role of sigma receptors in      
                     ethanol reinforcement           

  **Institution:**   SCRIPPS RESEARCH INSTITUTE      LA JOLLA, CA

  **Project          2006/12/01-2008/11/30           
  Period:**                                          
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  DESCRIPTION (provided by applicant): Summary: The application proposes
  a career development plan for Dr. Valentina Sabino, a
  pharmacologically-trained post-doctoral fellow committed to a research
  career in ethanol addiction aimed towards understand its molecular
  basis. The applicant will be mentored by Dr. George Koob in behavioral
  neuroscience methods and animal models of alcoholism and co-mentored by
  Dr. Pietro Sanna in immunohistochemical and molecular techniques. The
  project, to be conducted at The Scripps Research Institute in the rich
  neuroscience community of San Diego, concerns sigma receptors, unique
  mammalian binding sites that modulate other neurotransmitter systems
  and which are richly expressed in limbic brain structures.
  Pharmacological studies indicate that sigma receptors modulate actions
  of cocaine and methamphetamine. Recently, sigma receptors also have
  been proposed to modulate motivating properties of ethanol, consistent
  with findings of sigma receptor polymorphisms in human alcoholism.
  Until very recently, however, the understanding of sigma receptor
  systems had been hampered by the unavailability of specific,
  subtype-selective ligands or of mutant mouse models that lack sigma
  receptor subtypes. Furthermore, the role of sigma receptors in
  voluntary intake or self-administration of ethanol are unknown. The
  present multipdisciplinary application uses behavioral, pharmacologic,
  and molecular techniques to determine the modulatory role of sigma
  receptors with subtype specificity on ethanol reward and reinforcement
  in distinct models of excessive ethanol consumption. Two models of
  excess ethanol intake will be studied in Specific Aims 1 and 3 \--
  genetically selected alcohol-preferring rats and withdrawn outbred rats
  made dependent during chronic, intermittent exposure to ethanol vapor,
  emphasizing positive and negative reinforcing properties of ethanol,
  respectively. Ethanol self-administration will be pharmacologically
  modulated (in Specific Aim 1), through the administration of novel a
  receptor ligands, and molecularly (in Specific Aim 2), through the use
  of o-1 receptor KO mice. The impact of chronic exposure to ethanol and
  of innate preference for ethanol on o receptor protein expression in
  discrete limbic brain regions will be investigated in Specific Aim 3.
  Relevance: The project will define the physiologic and potential
  therapeutic relevance of an under characterized modulatory receptor
  system for alcohol abuse and dependence.

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Date Run: 11/30/06 **PUBLIC ABSTRACTS**

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  **Grant:**         1K99AG029726-01                 

  **Program          BUCKHOLTZ, NEIL                 
  Director:**                                        

  **Principal        TOWN, TERRENCE C                PHD
  Investigator:**                                    

  **Title:**         Blocking TGF-Beta immune        
                     signaling as a therapeutic      
                     target for Alzheimer\'s diseas  

  **Institution:**   YALE UNIVERSITY                 NEW HAVEN, CT

  **Project          2006/12/01-2007/11/30           
  Period:**                                          
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  DESCRIPTION (provided by applicant): The overriding aim of this
  proposal is to investigate the therapeutic potential of blocking
  transforming growth factor-beta (TGF-beta) signaling for Alzheimer\'s
  disease. Terrence Town, Ph.D. is currently an NRSA/NIA post-doctoral
  fellow with the immediate goal of completing an additional year of
  mentored research. Dr. Town has been working at the interface of the
  immunology and neuroscience fields, and his current environment in Dr.
  Flavell\'s laboratory with co-sponsorship from Dr. Rakic positions him
  in the ideal environment within which to complete the mentored phase of
  the proposed project. Dr. Town\'s long-term goals inclulde establishing
  himself as an independent scientist in a tenure-track academic
  position, and contributing to understanding neuroimmune aspects of
  Alzheimer\'s disease, with the hope of finding novel therapeutic
  targets for this devastating illness. Dr. Town\'s career development
  plan includes receiving training and mentorship in neuroimmunology.
  Following the proposed one year period of mentored research, Dr. Town
  plans to make the transition to independence with the assistance of the
  proposed award. For the mentored period, Dr. Town proposes to evaluate
  Alzheimer-like pathology in a transgenic mouse model of the disease
  crossed with a transgenic mouse that has blocked TGF-beta signaling in
  innate immune cells. The proposed work during the mentored phase builds
  heavily on preliminary data that show that one such crossed mouse has
  mitigation of Alzheimer-like pathology. For the independent phase, Dr.
  Town will 1) investigate the potential cellular mechanism underlying
  reduced Alzheimer pathology in crossed mice, 2) adopt a
  pharmacotherapeutic approach by treating Alzheimer transgenic mice with
  TGF-beta receptor blocking antibody, and 3) conduct another mouse
  crossing experiment to determine if blocking TGF-beta signaling on
  innate immune cells mitigates Alzheimer-like pathology during its
  initial establishment or after active lesions are formed. RELEVANCE:
  Alzheimer\'s disease is the most common dementing illness in the United
  States, and it is estimated that over 3 million Americans over the age
  of 65 have the disease. This project aims to uncover a new avenue for
  the treatment of Alzheimer\'s disease by blocking a protein that has
  been shown to be involved in the pathological changes of the disease,
  specifically the brain\'s inflammatory response.

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Date Run: 11/30/06 **PUBLIC ABSTRACTS**

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  **Grant:**         1K99AG029760-01                 

  **Program          KOHANSKI, RONALD                
  Director:**                                        

  **Principal        ROSSI, DERRICK J.               PHD
  Investigator:**                                    

  **Title:**         Stem Cell Aging: Functional     
                     Decline, DNA damage and         
                     Therapeutic Targets             

  **Institution:**   STANFORD UNIVERSITY             STANFORD, CA

  **Project          2006/12/01-2008/11/01           
  Period:**                                          
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  DESCRIPTION (provided by applicant): The etiology of the age-associated
  pathophysiological changes of the hematopoietic system including the
  onset of anemia, diminished immune competence, and myelogenous disease
  development suggests profound losses of homeostatic control. Because
  homeostatic control is mediated by the activity of stem and progenitor
  cells, we propose that the homeostatic imbalances associated with the
  aged hematopoietic system result from alterations in the prevalence
  and/or functional capacity of hematopoietic stem and progenitor cells.
  The mechanisms driving loss of homeostatic control are poorly
  understood. The accumulation of somatic damage to cellular
  macromolecules is considered to be a major cause of cellular attrition
  and aging. In particular, the accumulation of DMA damage has been
  implicated as a central mechanism contributing to age-associated
  decline. In such a model of aging, DMA damage accrues in cells as they
  age and when accumulated damage becomes sufficiently disruptive can
  drive cells to 1) malignant transformation 2) cellular senescence, 3)
  programmed cell death, or 4) dysfunction. When this aging paradigm is
  considered within the context of stem cell biology, malignant
  transformation of stem cells would be predicted to result in increased
  cancer stem cell development, while stem cell senescence, cell death,
  and dysfunction would be predicted to lead to the diminished functional
  stem cell reserves. If stem cell depletion surpasses levels of stem
  cell self-renewal, then homeostatic failure - the physiological
  hallmark of aging - ensues. The objective of our research is to
  functionally characterize hematopoietic stem and progenitor cell aging
  to determine the extent to which dysfunction of these cells contributes
  to age- associated pathophysiological decline, and to uncover the
  extent to which this dysfunction is driven by accumulated DMA damage.

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Date Run: 11/30/06 **PUBLIC ABSTRACTS**

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  **Grant:**         1K99AI072834-01                 

  **Program          PETERS, N. KENT                 
  Director:**                                        

  **Principal        GALONIC, DANICA P               PHD
  Investigator:**                                    

  **Title:**         Methylation in Antibiotic       
                     Biosynthesis:                   
                     Methylcobalamin-Radical SAM     
                     Enzymes                         

  **Institution:**   HARVARD UNIVERSITY (MEDICAL     BOSTON, MA
                     SCHOOL)                         

  **Project          2006/12/01-2007/11/30           
  Period:**                                          
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  DESCRIPTION (provided by applicant): I have obtained B.Sc. in chemistry
  from University of Belgrade, Serbia and Montenegro, in 2000, and Ph.D.
  in organic chemistry from University of Illinois at Urbana-Champaign in
  May 2005. During graduate studies, I have developed new methods for the
  chemoselective carbohydrate-peptide ligations under the joint guidance
  of Professors David Y. Gin and Wilfred A. van der Donk. Currently, I am
  a Damon Runyon Cancer Research Foundation postdoctoral fellow in the
  laboratory of Professor Christopher T. Walsh at Harvard Medical School.
  HMS and Professor Walsh is providing an outstanding research
  environment and is committed to the success of the postdoctoral
  fellows. My postdoctoral research is focused on the characterization of
  a recently discovered class of nonheme Fe (II) halogenases, capable of
  carrying out halogenation of unactivated carbon centers. Thus far, we
  have reconstituted halogenation activity in the barbamide system. In
  this study, we demonstrated that the triple chlorination of the
  unactivated methyl group of the carrier-protein tethered L-leucine
  substrate is mediated by the tandem action of two nonheme Fell
  halogenases, BarB1 and BarB2. I am currently investigating mechanistic
  aspects of halogenation of unactivated carbon centers through the
  investigation of pre-steady state kinetic parameters and EPR and
  Mossbauer investigation of metal center during the catalysis. The
  objective of the proposed project is mechanistic description of
  methylcobalamin-radical SAM enzymes that carry out methylations of sp2
  carbon centers in antibiotic biosynthesis. Our goal is to understand
  the logic that nature uses to channel methylcobalamin, iron-sulfur
  clusters and deoxyadenosyl radicals to perform this novel carbon-carbon
  bond formation in enzymology. The methylation event will be studied in
  the context of generation of the 5-methylpyrrole-2-carboxylate
  pharmacophore in aminocoumarin antibiotic biosynthesis, and
  hydroxyethyl side chain in the biosynthesis of beta lactam antibiotic
  thienamycin. Better understanding of enzymes involved in the antibiotic
  biosynthesis can lead to the development of new antibiotic variants
  through combinatorial biosynthesis. This is especially important
  because of the development of bacterial resistance to commonly used
  antibiotics.

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Date Run: 11/30/06 **PUBLIC ABSTRACTS**

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  **Grant:**         1K99AI072955-01                 

  **Program          PROGRAIS, LAWRENCE J.           
  Director:**                                        

  **Principal        KAGAN, JONATHAN C               PHD
  Investigator:**                                    

  **Title:**         Cellular and molecular aspects  
                     of Toll-like receptor signal    
                     transduction.                   

  **Institution:**   YALE UNIVERSITY                 NEW HAVEN, CT

  **Project          2006/12/01-2007/11/30           
  Period:**                                          
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  DESCRIPTION (provided by applicant): The ability to mount an effective
  immune response is critical for human health. Toll-like receptors
  (TLRs) are transmembrane proteins expressed on phagocytes and other
  cells that act as sensors of microbial infection. Recent studies have
  underscored the importance of TLRs in innate and adaptive immunity as
  mice deficient in TLR signaling have defects in controlling bacterial
  and viral infections. Despite the identification of several genes
  required for TLR signaling, a clear picture of how TLR signaling
  complexes are assembled and how assembly is regulated is lacking. This
  proposal will investigate cellular and molecular aspects of TLR signal
  transduction. We will focus on the characterization of the four
  essential TLR adaptor proteins in terms of their localization and
  recruitment to membranes bearing activated TLRs. Cis-acting domains
  that mediate adaptor localization and recruitment to TLRs will be
  identified and mutated as a means of addressing the functional
  significance of adaptor localization in TLR signaling. Trans-acting
  factors that regulate adaptor localization will be identified with a
  particular focus on the transport regulation by phosphoinositides. The
  successful completion of this project will yield important insight into
  cellular control of TLR signal transduction and thus, mechanisms of
  immunity.

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Date Run: 11/30/06 **PUBLIC ABSTRACTS**

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  **Grant:**         1K99AI072973-01                 

  **Program          WASSEF, NABILA M.               
  Director:**                                        

  **Principal        ALTER, GALIT                    PHD
  Investigator:**                                    

  **Title:**         Anergizing effect of NK cell    
                     receptor expression on          
                     HIV-specific CD8+ T cells       

  **Institution:**   MASSACHUSETTS GENERAL HOSPITAL  BOSTON, MA

  **Project          2006/12/01-2007/11/30           
  Period:**                                          
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  DESCRIPTION (provided by applicant): Virus-specific-CD8+ T cells play a
  central role in the control of viral infections by direct elimination
  of infected cells and secretion of a number of soluble factors.
  However, despite the induction of strong and broad HIV specific CD8+ T
  cell responses in chronic HIV-1 infection, these cells progressively
  lose critical effector functions. A number of recent studies have shown
  that a significant subset of CD8+ T cells appear to upregulate
  inhibitory \"NK cell receptor\" expression following encounter with
  antigen, and that CD8+ T cells expressing NK cell receptors persist in
  chronically infected mice but not in mice that clear the infection.
  These receptors included members of the KIR family, as well as of the
  C-type lectin family (NKG2) in humans and the Ly49 family in mice. The
  expression of these receptors on CD8+ T cells can have a profound
  effect on the functional capacity of both tumor-specific and
  virus-specific T cells. Recently, increased levels of KIR and NKG2A
  expression have also been described on discrete populations of CD8+ T
  cells in chronic HIV-1 infection. Given the profound inhibitory effect
  of these receptors, this application aims to gain a better
  understanding of the role of KIR and NKG2A receptor expression on
  HIV-1-specific CD8+ T cell function. In this application, the
  expression profile of both KIR and NKG2 receptors will be characterized
  on CD8+ T cells in subjects at different stages of HIV-1 infection to
  determine the kinetics of NK cell receptor upregulation in HIV-1
  infection, to elucidate the impact of NK cell receptor expression on
  CD8+ T cell function, whether these receptors are preferentially
  enriched on the surface of HIV-specific CD8+ T cells, and whether this
  inhibitory effect can be reversed. Furthermore, the precise mechanisms
  accounting for NK cell receptor-mediated inhibition of CD8+ T cell
  activation will be characterized on the immunological synaptic level as
  well as the TCR signaling-cascade level. Thus this application aims to
  determine whether one of the mechanisms contributing to impaired CD8+ T
  cell activity during persistent viral infections may be due to an
  up-regulation of inhibitory NK cell receptors. These in depth studies
  geared towards understanding the underlying mechanism of KIR/NKG2A
  inhibitory activity on CD8+ T cells will certainly contribute to the
  field of basic CD8+ T cell biology and potentially allow for the
  identification of novel targets to reconstitute effective of CD8+ T
  cell immunity in the setting of chronic infections, such as HIV.

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Date Run: 11/30/06 **PUBLIC ABSTRACTS**

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  **Grant:**         1K99CA125937-01                 

  **Program          ECKSTEIN, DAVID J               
  Director:**                                        

  **Principal        XIN, LI                         PHD
  Investigator:**                                    

  **Title:**         Characterization of prostatic   
                     stem cells and prostate         
                     cancer-initiating cells         

  **Institution:**   UNIVERSITY OF CALIFORNIA LOS    LOS ANGELES, CA
                     ANGELES                         

  **Project          2006/12/01-2008/11/30           
  Period:**                                          
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  DESCRIPTION (provided by applicant): Prostate cancer is the
  second-leading cause of the cancer-related death in men in the United
  States. We have enriched prostate stem cell activity using the Sca-1
  surface antigen and demonstrated that cells with enriched stem cell
  activity serve as a target for tumor initiation. Our long-term goals
  are to fully characterize the identity of stem cells and
  cancer-initiating cells in prostate. This study will provide general
  insights for the studies on stem cell biology and cancer biology. Our
  specific aims are: (1) Fully characterize the prostatic stem cells. (A)
  We will investigate whether stem cells reside in a specific prostatic
  epithelial cell lineage using the dissociated prostate cell
  regeneration system. We will (i) isolate individual lineages and test
  their regenerative capacity, and (ii) permanently mark individual
  lineages and determine the lineage status of their progeny. These can
  be achieved by creating a prostate basal cell-specific green
  fluorescence protein-marked transgenic mouse model or through the
  Cre-loxp marking system regulated by prostate lineage-specific
  promoters. (B) We will continue to screen the expression of surface
  antigens in prostate, fractionate prostate cells using surface antigens
  and identify the fraction(s) with enriched stem cell activity using the
  regeneration system. (2) Identify the prostate cancer-initiating cells.
  (A) We will evaluate the susceptibility of basal cells and luminal
  cells to oncogenic transformation. We will induce Pten deletion in
  individual lineages by infecting prostate epithelial cells from the
  PTENIoxp/loxp transgenic mouse model with lentivirus that express the
  Cre recombinase regulated by lineage-specific promoters. Infected cells
  will be tested in the regeneration system to determine which cell
  lineage(s) have been transformed. (B) We will determine the
  susceptibility of each cell population fractionated in Aim1 B to
  malignant transformation induced by single or a combination of
  oncogenic stimuli. Cell fractions from the wild type and P53-/- mice
  that represent stem cells, short-term progenitor cells and terminally
  differentiated cells will be infected with lentivirus that mediate
  distinct oncogenic signals, such as myc, inactivation of the pRB family
  proteins, perturbations in the PTEN-AKT signaling pathway and others.
  The infected cells will be microinjected into immunodeficient host
  mouse prostate or tested in the regeneration system to determine their
  capacity to initiate cancer.

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Date Run: 11/30/06 **PUBLIC ABSTRACTS**

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  **Grant:**         1K99CA125991-01                 

  **Program          ECKSTEIN, DAVID J               
  Director:**                                        

  **Principal        LI, ZIQIANG                     PHD
  Investigator:**                                    

  **Title:**         Dissect roles of mismatch       
                     repair proteins in              
                     Lymphomagenesis and Ig          
                     diversity                       

  **Institution:**   YESHIVA UNIVERSITY              BRONX, NY

  **Project          2007/03/01-2009/02/28           
  Period:**                                          
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  DESCRIPTION (provided by applicant): Mismatch repair (MMR) proteins are
  responsible for removing DNA mismatches, inhibiting recombination
  between divergent DNA sequences, and signaling for apoptosis to
  maintain the integrity of the genome and to prevent malignant
  transformation. The generation of antibody diversity by B cells
  involves somatic hypermutation (SHM) and class switch recombination
  (CSR), two processes which are initiated by G-U mismatches generated by
  activation-induced cytidine deaminase (AID). Mistargeting of SHM and/or
  CSR leads to the B-cell malignancies. MMR proteins are involved in SHM
  and CSR presumably through the error-prone repair of G-U mismatches to
  increase the genomic instability of immunoglobulin (Ig) genes. However,
  how the error-prone MMR repair is achieved in activated B cells remains
  elusive. In addition, MMR proteins Msh2 and Msh6 form a heterodimer
  that recognizes mismatched bases and initiates the MMR process, but
  Msh2-/- mice die early predominantly from T-cell lymphomas and
  intestine tumors whereas Msh6-/- mice die later predominantly from
  B-cell lymphomas. To understand the difference between the function of
  Msh2 and that of Msh6 in mismatch repair, SHM and CSR, and B-cell
  lymphomagenesis, I propose to generate Msh2-/- Msh6-/- doubly deficient
  mice, to extensively characterize the lymphomas derived from various
  MMR deficient mice and mutant mice, and to determine the role of AID in
  B-cell malignancies by generating AID-/- MMR-/- mice.

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Date Run: 11/30/06 **PUBLIC ABSTRACTS**

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  **Grant:**         1K99CA126173-01                 

  **Program          ECKSTEIN, DAVID J               
  Director:**                                        

  **Principal        ZHANG, YOU-WEI                  PHD
  Investigator:**                                    

  **Title:**         Roles of the Checkpoint Kinase  
                     Chk1 in Cancer Biology and      
                     Therapy                         

  **Institution:**   SALK INSTITUTE FOR BIOLOGICAL   LA JOLLA, CA
                     STUDIES                         

  **Project          2006/12/01-2008/11/30           
  Period:**                                          
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  DESCRIPTION (provided by applicant): Summary Eukaryotic cells have
  evolved an elaborate network of genome surveillance and repair proteins
  to insure that DNA replication will occur in an accurate and timely
  fashion. This surveillance pathway is termed the S phase replication
  checkpoint. Defects in this \'caretaker'machinery lead to genetic
  instability, a hallmark feature of human cancers. The replication
  checkpoint monitors the progress of replication forks, and when fork
  stalls, transmits signals that delay S-phase progression, and maintains
  the stability of stalled forks so that DNA replication can resume after
  the initial error is corrected. Two key components of the replication
  checkpoint are the apical protein kinase, ATR, and its downstream
  target kinase, Chk1. Loss of ATR or Chk1 function is lethal, even in
  the absence of extrinsic genotoxic stress, underscoring the importance
  of the replication checkpoint in the maintenance of cell viability. In
  preliminary work, we tested the hypothesis that certain anti-tumor
  agents, such as the topoisomerase 1 (Top I) poisons (e.g., camptothecin
  (CPT)) selectively kill cancer cells through the induction of
  protracted, high-intensity replication stress. Our studies unexpectedly
  revealed that treatment with CPT or other replication stress inducers
  (e.g., deep hypoxia or methylmethane sulfonate) triggers the
  ubiquitin-dependent degradation of Chk1 in both normal and transformed
  human cells. The degradation of Chk1 was dependent on the
  Skp1-Cullin-F-box (SCF) E3 ubiquitin ligase complex, and the
  consequences of severe Chk1 destruction were replication fork collapse
  and ultimate cell death. Remarkably, defects in the Chk1 degradation
  pathway confer resistance to the cytotoxic effect of CPT - a major
  problem with this class of drugs in the clinical arena. Thus, this
  novel layer of Chk1 regulation has important implications for our
  understanding of replication checkpoint signaling, as well as
  mechanisms of anticancer resistance in cancer patients. I now propose
  to elucidate the underlying mechanisms and biological significance of
  the stress-induced Chk1 destruction through pursuit of the following
  specific aims: In the mentored-phase, (1) To identify the F-box
  proteins of the E3 ligase complexes responsible for Chk1 destruction;
  In the independent phase, (2) To identify the putative \'Degron'region
  and the lysine residues targeted for ubiquitin modification in Chk1;
  (3) To investigate the roles of de-phosphorylation in Chk1 degradation;
  (4) To characterize the molecular mechanisms underlying the defect in
  Chk1 degradation in CPT-resistant cancer cells. Relevance: The results
  of these studies will not only advance our understanding of the
  genotoxic stress response machinery in human cells, but also provide
  novel insights into the causes of genetic instability and anticancer
  drug resistance in cancer cells, and these lines of research have
  direct implications for the development of novel therapeutic agents
  targeted against tumors.

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Date Run: 11/30/06 **PUBLIC ABSTRACTS**

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  **Grant:**         1K99CA126186-01                 

  **Program          ECKSTEIN, DAVID J               
  Director:**                                        

  **Principal        HE, LIN                         PHD
  Investigator:**                                    

  **Title:**         Functions of microRNAs in       
                     lymphomagenesis                 

  **Institution:**   COLD SPRING HARBOR LABORATORY   COLD SPRING HARBOR,
                                                     NY

  **Project          2006/12/01-2008/11/30           
  Period:**                                          
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  DESCRIPTION (provided by applicant): Malignant transformation
  represents the phenotypic endpoint of successive genetic lesions that
  confer uncontrolled proliferation and survival, unlimited replicative
  potential, and invasive growth. Recent evidence has suggested that
  non-coding RNAs, in particular, microRNAs (miRNAs), are subjected to
  changes in gene structure and expression regulation in tumors. I
  identified a polycistronic miRNA cluster, mir17-92, as a target of
  chromosome 13q31 amplicon found in human B-cell lymphomas. In a mouse
  model for B-cell lymphoma, enforced mir17-92 expression cooperates with
  c-myc and accelerates tumor growth by repressing cell death. These
  findings provided some of the first functional evidence that changes in
  miRNAs could contribute to oncogenesis. The work described in this
  application continues my studies on the oncogenic effects of mir17-92
  using both cell culture systems and animal tumor models. First, I
  propose to identify the oncogenic miRNA components within the mir17-92
  cluster, and to dissect the molecular basis for the tumorigenic effects
  of mir17-92. Second, the effects of mir17-92 in tumor maintenance and
  therapy response will be investigated. Finally, combined expression
  studies, copy number studies and functional characterization will be
  applied to examine more broadly the miRNA pathways in the oncogenic and
  tumor suppressor network. These studies, if successful, will produce
  fundamental insights into the functions of miRNAs during tumor
  development and tumor maintenance, which can be applied for discovery
  of both diagnostic markers and therapeutic targets.

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Date Run: 11/30/06 **PUBLIC ABSTRACTS**

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  **Grant:**         1K99DA023700-01                 

  **Program          WU, DA-YU                       
  Director:**                                        

  **Principal        XU, XIANGMIN                    PHD
  Investigator:**                                    

  **Title:**         Local Connections and In Vivo   
                     Physiology of Inhibitory        
                     Cortical Neurons                

  **Institution:**   SALK INSTITUTE FOR BIOLOGICAL   LA JOLLA, CA
                     STUDIES                         

  **Project          2006/12/01-2008/11/30           
  Period:**                                          
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  DESCRIPTION (provided by applicant): Project Summary: Despite extensive
  knowledge of the basic blueprint of cortical circuits, detailed
  knowledge about the connectivity of specific cell types and how they
  function is still limited. The studies proposed here will investigate
  the laminar and fine-scale specificities of excitatory and inhibitory
  synaptic input to identified inhibitory neurons in the cerebral cortex,
  and will examine in vivo physiology of specific inhibitory cell types
  and their participation in regulating synchronous and oscillatory
  cortical activities. Recordings of specific inhibitory cell types can
  be facilitated by visualization of green fluorescent protein (GFP)
  expression restricted to known inhibitory neuron types in transgenic
  mice. Laminar specificity of functional input to specific cell types
  will be understood by using the technique combining whole cell
  recordings with scanning laser photostimulation. Furthermore, the
  fine-scale specificity of connections between pairs of neighboring
  inhibitory cells or excitatory and inhibitory cells will be revealed by
  cross-correlation analyses of synaptic responses evoked by
  photostimulation and recorded simultaneously from the neighboring
  pairs. In addition, to understand in vivo physiology and function of
  specific inhibitory cell types, targeted recordings under the guidance
  of 2- photon imaging will be made from these same cell types in
  GFP-expressing transgenic mice. We will record spikes from the target
  cells and measure local field potentials (LFPs) through
  electrocorticogram (ECoG) recordings. For each inhibitory neuron type,
  the overall spiking pattern in relation to LFPs and spike- triggered
  average of LFPs will be assessed to determine whether a correlative
  relationship exists between spike times and cortical oscillations.
  Other physiological properties of the recorded cells will also be
  assessed to further understand the properties of inhibitory neurons and
  their circuits. Relevance: Studies of the detailed organization of
  cortical circuits involving specific inhibitory cell types are
  necessary toward understanding cortical function. Understanding the
  specific roles of inhibitory cortical neurons has important
  implications for human health, as these cell types and their activities
  are involved in the cortical mechanisms that regulate attention and
  their disruption is implicated in schizophrenia.

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Date Run: 11/30/06 **PUBLIC ABSTRACTS**

  ------------------ ------------------------------- ---------------------
  **Grant:**         1K99DE018088-01                 

  **Program          AVILA, ALBERT                   
  Director:**                                        

  **Principal        EBERHART, JOHANN                PHD
  Investigator:**                                    

  **Title:**         Genetic Hierarchies and         
                     Cellular Behaviors during       
                     Zebrafish Palatogenesis         

  **Institution:**   UNIVERSITY OF OREGON            EUGENE, OR

  **Project          2006/12/01-2008/11/30           
  Period:**                                          
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  DESCRIPTION (provided by applicant): There are hundreds of craniofacial
  diseases in humans and cleft palate is common among these. The goal of
  this proposal is to elucidate the signaling interactions and cellular
  behaviors underlying palatogenesis. The zebrafish provides a useful
  model system in which to study palatal development. Powerful genetic
  and cellular techniques are available in the zebrafish for studying
  gene function as well as cell and tissue signaling interactions.
  Additionally, the simplified palatal skeleton, consisting of far fewer
  neural crest palate progenitors than in mammals, and the optic clarity
  of the zebrafish embryo makes it ideal for analyzing cell behaviors
  occurring in palatogenesis. I propose to examine predictions of a
  reciprocal signaling hypothesis, in which signals from neural crest to
  the oral ectoderm and then back from the oral ectoderm to neural crest
  induce palatogenesis, and cause elongation of the palate through cell
  intercalations. In Specific Aim 1,1 examine the role of candidate genes
  for neural crest-derived signals and oral ectoderm response genes,
  turned on in the oral ectoderm. I use loss-of-function, gene
  expression, imaging, and genetic mosaic analyses to test the model that
  FgflO and Bmp4 signaling from the neural crest turns on pitx2 in the
  oral ectoderm, which, in turn, promotes palatogenesis. In Specific Aim
  2,1 analyze the reciprocal signal, from oral ectoderm to neural crest.
  I use loss-of-function, imaging, and genetic mosaic analyses as well as
  construction of inducible transgenic zebrafish lines to test the
  prediction that Pdgf and ph/ephrin signaling from the oral ectoderm
  promotes palatogenesis. In Specific Aim 3,1 determine the cell
  behaviors that drive elongation of the palate. I use confocal time
  lapse analysis as well as cloning and characterization of novel
  zebrafish palate mutants to test the prediction that cell
  intercalations drive the extension of the zebrafish palate. The results
  I obtain during the course of these studies will shed light on the
  genetic and cellular causes of cleft palate. Additionally, two genes I
  propose to analyze, pitx2 and ephrin-B1, are known to be human
  craniofacial disease genes. Therefore, my analyses of these genes will
  provide direct insight into the cause of human disease.

  -----------------------------------------------------------------------

Date Run: 11/30/06 **PUBLIC ABSTRACTS**

  ------------------ ------------------------------- ---------------------
  **Grant:**         1K99DK077427-01                 

  **Program          HYDE, JAMES F.                  
  Director:**                                        

  **Principal        SRINIVASAN, SUPRIYA             PHD
  Investigator:**                                    

  **Title:**         The Role of Serotonin in Energy 
                     Homeostasis in C. elegans       

  **Institution:**   UNIVERSITY OF CALIFORNIA SAN    SAN FRANCISCO, CA
                     FRANCISCO                       

  **Project          2007/07/01-2009/06/30           
  Period:**                                          
  ------------------ ------------------------------- ---------------------

  -----------------------------------------------------------------------
  DESCRIPTION (provided by applicant): To ensure survival, animals must
  constantly assess food status in the environment, and respond
  appropriately by matching food intake to energy expenditure. The net
  balance between the two is reflected in the fat stores of the animal.
  The neurotransmitter serotonin plays a central role in maintaining this
  dynamic balance, by relaying food signals from the environment to
  elicit changes in behavior and physiology of the animal so that fat
  homeostasis is maintained. The goal of the research proposed here is to
  address the question: \"How does serotonin signaling modulate energy
  balance in C. elegans?\" I have identified a few key genes that are
  important for serotonin fat regulation in C. elegans. Using a
  combination of behavioral and physiological assays, I will examine the
  roles of these newly-identified genes in food intake and energy
  expenditure. Together with molecular and genetic analyses, I aim to
  specify the serotonergic network that couples food sensation to changes
  in feeding regulation and energy expenditure in C. elegans. My current
  research objectives are well-aligned with my long-term interest in
  understanding how the environment influences complex behavior and
  physiology at the organismal level. Understanding the complex
  intersection of genetics and environment is a frontier in the
  biological sciences with major, direct impacts on human health. The
  work proposed here lays the foundation upon which I will embark as an
  independent investigator at an academic research institution in the
  next two years. My current environment at the University of
  California-San Francisco under the mentorship of Dr. Kaveh Ashrafi and
  Dr. Keith Yamamoto, is ideally suited for my scientific and
  professional interests. The de-regulation of energy balance leads to
  obesity, a rising health concern world-wide. Indeed, current estimates
  suggest that more than 30% of Americans are obese, a condition that is
  a prime risk factor for cardiovascular disease, diabetes and reduced
  life expectancy. The ancient conservation of serotonin function in many
  species including mice and humans suggests that work proposed here will
  provide novel genetic targets for the study of body fat regulation.

  -----------------------------------------------------------------------

Date Run: 11/30/06 **PUBLIC ABSTRACTS**

  ------------------ ------------------------------- ---------------------
  **Grant:**         1K99DK077445-01                 

  **Program          HYDE, JAMES F.                  
  Director:**                                        

  **Principal        ZHOU, QAIO                      PHD
  Investigator:**                                    

  **Title:**         Diversity and Specification of  
                     Pancreatic Progenitor Cells     

  **Institution:**   HARVARD UNIVERSITY              CAMBRIDGE, MA

  **Project          2006/12/01-2008/11/30           
  Period:**                                          
  ------------------ ------------------------------- ---------------------

  -----------------------------------------------------------------------
  DESCRIPTION (provided by applicant): Progenitor cells are immature cell
  types that are responsible for constructing the entire organism during
  embryonic development as well as for replenishing and repairing tissues
  in adult life. Understanding progenitor cells is therefore a central
  question in biology. This problem applies to the pancreas, an organ of
  vital importance to human physiology because of the production of
  digestive enzymes and hormones such as insulin. The long term goal of
  this project is to understand the diversity and development of
  pancreatic progenitor cells in order to devise better strategies to
  treat pancreatic diseases such as diabetes. In Specific Aim I of this
  proposal, we will determine the diversity of progenitor cells in the
  developing pancreas by a genome scale expression analysis to identify
  unique molecular markers that will mark each progenitor population. In
  Specific Aim II, we will determine the lineage of two specific
  pancreatic progenitor populations by genetic lineage tracing
  experiments with mutant mouse lines. In Specific Aim III, we will
  functionally test hypotheses of how transcription factors regulate the
  development of different progenitor cell types. The proposed studies
  are expected to shed important light on the diversity and specification
  of pancreatic progenitor cells. A better understanding of the biology
  of pancreatic progenitor cells should aid efforts to derive functional
  endocrine cells for cell replacement therapies to treat diabetes. In
  addition, these studies may lead to greater insights into adult
  pancreatic progenitors that may be exploited for regeneration based
  therapy.

  -----------------------------------------------------------------------

Date Run: 11/30/06 **PUBLIC ABSTRACTS**

  ------------------ ------------------------------- ---------------------
  **Grant:**         1K99DK077573-01                 

  **Program          HYDE, JAMES F.                  
  Director:**                                        

  **Principal        HOSTETLER, HEATHER A            PHD
  Investigator:**                                    

  **Title:**         The role of long chain          
                     acyl-CoAs in nuclear receptor   
                     regulation                      

  **Institution:**   TEXAS A&M UNIVERSITY SYSTEM     COLLEGE STATION, TX

  **Project          2007/04/01-2009/03/31           
  Period:**                                          
  ------------------ ------------------------------- ---------------------

  -----------------------------------------------------------------------
  DESCRIPTION (provided by applicant): The peroxisome proliferator
  activated-receptor ( (PPAR() plays a central role in energy homeostasis
  by initiating transcription of multiple genes in fatty acid and glucose
  metabolism, while concomitantly downregulating genes in insulin
  signaling. In liver, PPAR( induces transcription of many genes involved
  in fatty acid degradation by (-oxidation, fatty acid uptake and
  transport, and lipoprotein metabolism. Thus, PPAR( is responsible for
  control of a number of lipid metabolic proteins that may contribute to
  obesity, diabetes, lipotoxicity, and subsequent cardiovascular
  disorders. However, relatively little is known regarding either the
  mechanisms that regulate the availability of endogenous fatty acyl-CoA
  ligands to the nucleus for interaction with PPAR( or the effect of
  these ligands on PPAR( interaction with heterodimer partners. Although
  it is known that PPAR( must heterodimerize with either the retinoid X
  receptor (RXR) or the liver X receptor (LXR) prior to binding DNA
  response elements, for transcriptional regulation, surprisingly little
  is known about the effect of endogenous ligands on the choice of
  heterodimer partners. Furthermore, the effect of PPAR( ligands on
  heterodimer partners is incompletely resolved. In order to address
  these issues, this proposal is focused in two phases: First, the
  \'mentored phase'will: 1. Resolve whether PPAR(-mediated transcription
  of genes is regulated by long-chain fatty acyl-CoAs (LCFA-CoA). 2.
  Determine the effect of LCFA-CoA on the molecular interaction of PPAR(
  with L-FABP. Second, the \'independent phase'will: 3. Determine if LXR(
  binds LCFA-CoA with high affinity, in the physiological range of
  nuclear LCFA-CoA levels. 4. Elucidate the effect of LCFA-CoA on the
  molecular interaction of PPAR( with LXR(. It is hoped that the results
  of this work will provide a mechanistic role of LCFA-CoAs in nuclear
  receptor regulation. Relevance to Public Health: This work aims at
  studying a protein whose abnormal expression/regulation is associated
  with obesity, diabetes, and cardiovascular disease. This research is a
  step towards the development of new methods and more efficient drugs
  for the treatment of such disorders.

  -----------------------------------------------------------------------

Date Run: 11/30/06 **PUBLIC ABSTRACTS**

  ------------------ ------------------------------- ---------------------
  **Grant:**         1K99EB007129-01                 

  **Program          BAIRD, RICHARD                  
  Director:**                                        

  **Principal        ALLEN, MATTHEW J                MB, PHD
  Investigator:**                                    

  **Title:**         Increasing the Utility of       
                     Contrast Agents for MRI         

  **Institution:**   UNIVERSITY OF WISCONSIN MADISON Madison, WI

  **Project          2006/12/01-2007/11/30           
  Period:**                                          
  ------------------ ------------------------------- ---------------------

  -----------------------------------------------------------------------
  DESCRIPTION (provided by applicant): The long-term goals of this
  proposal are to address critical barriers to progress in the field of
  contrast agent-enhanced magnetic resonance imaging (MRI). My plan to
  overcome these barriers is to increase the utility of lanthanide-based
  contrast agents. Efforts will be focused on the development of contrast
  agents for high field MRI and activatable agents that are
  physiologically viable. Mentored K99 Phase: The postdoctoral phase
  (aim 1) of the proposal will be carried out under the mentorship of
  Professors L. L. Kiessling and R. T. Raines at the University of
  Wisconsin-Madison. The K99 phase goal is to develop exquisitely
  sensitive MRI agents using polymeric hydroxypyridonate (HOPO)-based
  chelates. This training at the interface of chemistry and biology will
  provide expertise in conjugation chemistries, manipulation and
  characterization of macromolecules, and the synthesis of novel
  lanthanide chelators. The acquired knowledge will prove invaluable for
  completion of aims 2-4 and transition into a successful career as an
  independent scientist. Independent ROO Phase: In the independent phase
  (aims 2-4), aims 2 and 3 focus on the development of biologically
  responsive contrast agents for MRI. Aim 2 involves the development of a
  novel class of activatable agents using dendrimer chemistry that have a
  true zero-background state. Zero background enhancement would enable
  concentration-independent imaging, overcoming a major barrier to the
  clinical use of activatable agents for diagnostic purposes. The
  experiments described in aim 3 focus on modulation of the innersphere
  water coordination number of HOPO-based agents. The new agents will
  have advantages over similar poly(aminocarboxylate)-based agents due to
  differences in water exchange rate and number of innersphere water
  molecules. In aim 4, methods to stabilize Eu(ll) complexes from
  oxidation are proposed. Stable Eu(ll) complexes will enhance contrast
  at high field strengths filling the void where Gd(lll) complexes cease
  to be viable contrast agents because of long electronic correlation
  times. Relevance: This proposal has the potential to greatly improve
  public health through advancement of the diagnostic capabilities of MRI
  by overcoming current technological limitations. The proposed research
  may lead to the ability to diagnose diseases at the earliest stages
  where treatments are often more effective.

  -----------------------------------------------------------------------

Date Run: 11/30/06 **PUBLIC ABSTRACTS**

  ------------------ ------------------------------- ---------------------
  **Grant:**         1K99EB007151-01                 

  **Program          BAIRD, RICHARD                  
  Director:**                                        

  **Principal        KARTALOV, EMIL P                PHD
  Investigator:**                                    

  **Title:**         Integrated Nanofluidic BioMEMS  
                     for Biomedical Diagnostics and  
                     Analysis                        

  **Institution:**   UNIVERSITY OF SOUTHERN          LOS ANGELES, CA
                     CALIFORNIA                      

  **Project          2006/12/01-2008/11/30           
  Period:**                                          
  ------------------ ------------------------------- ---------------------

  -----------------------------------------------------------------------
  DESCRIPTION (provided by applicant): Mentored section: As part of the
  mentored project, the candidate would extend his published results of
  high-throughput multiantigen fluorescence microfluidic immunoassays
  (BioTechniques 40: 85-90) to more complex samples, such as human blood
  serum and plasma, thereby paving the way to portable microfluidic blood
  test systems. Relevance: Portable microfluidic blood tests would
  produce major savings in cost and time in modern biomedical diagnostics
  with concomitant savings in healthcare in general. Such systems would
  also use finger-prick amounts of sample, eliminating the need for
  phlebotomy and the danger of hematomas, as well as making blood tests
  more accessible to pediatric patients, particularly infants. Low costs
  and small amounts of sample would also mean more frequent and
  ubiquitous testing, resulting in earlier diagnosis and thus saving
  lives. Independent research section: The applicant has a detailed plan
  outlined further below and including microfluidic immunoassays for
  viral detection, nanodetector and microfluidics integration for
  portable diagnostic devices, devices for large-scale cellular
  screening, on-chip PCR machine for on-the-spot forensic analysis,
  nested bioarrays for nanomedicine chips, DNA intercalator-separator of
  unknown samples, and a microfluidic cellular transfector.

  -----------------------------------------------------------------------

Date Run: 11/30/06 **PUBLIC ABSTRACTS**

  ------------------ ------------------------------- ---------------------
  **Grant:**         1K99EB007182-01                 

  **Program          BAIRD, RICHARD                  
  Director:**                                        

  **Principal        LIU, CHUNLEI                    PHD
  Investigator:**                                    

  **Title:**         High Resolution                 
                     Diffusion-Weighted Magnetic     
                     Resonance Imaging at 300-Micron 
                     Level                           

  **Institution:**   STANFORD UNIVERSITY             STANFORD, CA

  **Project          2006/12/01-2008/11/30           
  Period:**                                          
  ------------------ ------------------------------- ---------------------

  -----------------------------------------------------------------------
  DESCRIPTION (provided by applicant): Diffusion-weighted imaging (DWI)
  and diffusion-tensor imaging (DTI) are important magnetic resonance
  imaging (MRI) tools with significant clinical utility. However, current
  available spatial resolution for DWI is typically around 2mm per pixel,
  which is substantially lower than the submilimeter resolution of
  anatomical MRI. Such low spatial resolution severely limits the ability
  of diffusion MRI in investigating white matter structure and integrity,
  for example. Ultra high field strengths and emerging applications of
  DWI and DTI in pediatric neuroimaging, small animal neuroimaging,
  surgical planning and neural fiber tractography have created a strong
  demand for 1) higher image spatial resolution and 2) larger number of
  diffusion gradient directions. The overall goal of this proposal is to
  develop and refine advanced image formation techniques and novel
  diffusion analysis models. Towards this end, we propose to employ an
  array of novel techniques including motion navigated multi-shot
  sequences, parallel imaging with multiple coils, at high (3T) and ultra
  high magnetic field strengths (7T). Inherent advantages are that
  multi-shot sequences allow for improved data acquistion schemes with
  better SNR and reduced artifacts, which also alleviates the problem of
  rapid signal decay; parallel imaging provides a method for shortening
  the total scan time and further reducing image artifacts, while ultra
  high field offers stronger SNR and T2\* sensitivity at the expense of
  potential artifacts. Although the synergy of these techniques holds
  great potential for high resolution DWI and DTI, many technical
  challenges remain. The specific aims of this research are to meet these
  challenges by: 1) developing multi-shot DW sequences with efficient
  volumetric imaging with 3D motion navigation and ; 2) developing
  multi-shot parallel imaging acquistion techniques and fast image
  reconstruction algorithms that can efficiently and rapidly post-process
  thousands of images in a clinical setting, and finally; 3) measuring
  higher order diffusion tensor parameters to resolve multi-modal white
  matter structures. These advanced techniques will not only allow better
  visualization and quantitation of in vivo water proton diffusion
  processes on the scale of a few hundred microns, but will also
  significantly improve the quality and speed of the image acquistions.
  These techniques will eventually result better diagnostic potential for
  diffusion-weighted images, and, ultimately, more accurate
  quantification of complex tissue diffusion properties.

  -----------------------------------------------------------------------

Date Run: 11/30/06 **PUBLIC ABSTRACTS**

  ------------------ ------------------------------- ---------------------
  **Grant:**         1K99ES015426-01                 

  **Program          SHREFFLER, CAROL K              
  Director:**                                        

  **Principal        NYLAND, JENNIFER F              PHD
  Investigator:**                                    

  **Title:**         Mercury exposure and the innate 
                     immune response in autoimmune   
                     heart disease                   

  **Institution:**   JOHNS HOPKINS UNIVERSITY        BALTIMORE, MD

  **Project          2006/12/01-2008/11/30           
  Period:**                                          
  ------------------ ------------------------------- ---------------------

  -----------------------------------------------------------------------
  DESCRIPTION (provided by applicant) The overall goal is to demonstrate
  a link between mercury (Hg) exposure and elevated risks of autoimmune
  disease. In this project, the investigators will test two hypotheses in
  translational research linking basic research in an animal model of
  autoimmune disease and a pilot epidemiological study in a Hg-exposed
  human population in Amazonian Brazil. The hypotheses are that: 1)
  exposure of mice (adults and fetuses) to Hg, at low dose, can result in
  changes in the innate immune response to infection such that ultimately
  post-infection autoimmune disease is exacerbated in terms of severity
  and prevalence and 2) exposure of humans to Hg, at low dose, can result
  in changes in the immune system that are measurable and indicative of
  elevated risk of autoimmune dysfunction. Autoimmune diseases are among
  the most devastating chronic diseases in the US, affecting nearly 50
  million people. While autoimmune diseases are generally recognized to
  involve both heritable and acquired risk factors, relatively little is
  known about the latter risks for human disease aside from exposure to
  infectious agents, such as viruses and bacteria. These infectious
  agents are believed to trigger the development of autoimmune diseases,
  but the expression and severity of disease may be a reflection of
  pre-existing genetic susceptibility. This project will assess
  programming changes that occur during the innate immune response to
  infection following exposure (either at adulthood or during fetal
  development) to Hg, with an overall effect on the progression of
  Coxsackie virus-induced autoimmune heart disease in mice and apply the
  biomarkers mined from the studies in animals to a Hg-exposed human
  population in Amazonian Brazil. Specific Aim 1: To test the hypothesis
  that adult (murine) exposure to Hg induces changes in the innate immune
  response to Coxsackie virus infection, which result in exacerbation of
  subsequent autoimmune heart disease. Specific Aim 2: To test the
  hypothesis that fetal (murine) exposure to Hg induces changes in the
  immune system that are long lasting and that these early events affect
  the innate immune response to Coxsackie virus infection and the
  subsequent development of autoimmune heart disease in adulthood.
  Specific Aim 3: To test the hypothesis that human exposure to Hg
  induces changes in the immune system that are measurable and indicative
  of elevated risk of autoimmune dysfunction.

  -----------------------------------------------------------------------

Date Run: 11/30/06 **PUBLIC ABSTRACTS**

  ------------------ ------------------------------- ---------------------
  **Grant:**         1K99ES015428-01                 

  **Program          SHREFFLER, CAROL K              
  Director:**                                        

  **Principal        SABLE, HELEN J                  PHD
  Investigator:**                                    

  **Title:**         Assessment of Psychostimulant   
                     Addiction Risk Following        
                     Developmental PCB Exposure      

  **Institution:**   UNIVERSITY OF ILLINOIS          CHAMPAIGN, IL
                     URBANA-CHAMPAIGN                

  **Project          2006/12/01-2008/11/30           
  Period:**                                          
  ------------------ ------------------------------- ---------------------

  -----------------------------------------------------------------------
  DESCRIPTION (provided by applicant) Relatively little is known about
  the effects of exposure to environmental contaminants on substance
  abuse risk. The goal of this project is to determine if developmental
  exposure to polychlorinated biphenyls (PCBs) enhances the
  predisposition to develop drug addiction using a rodent model. Recent
  theories propose that drug addiction occurs due to increasing incentive
  salience for the drug and drug-associated cues as well as impaired
  inhibitory control at the cognitive level. Research in animal models
  suggests that reduced dopamine (DA) activity in the medial prefrontal
  cortex (mPFC) may mediate this process. PCB exposure reduces brain DA
  and impairs mPFC-mediated cognitive functions. Based on these findings
  it is hypothesized that PCB exposure during early development will
  result in reduced DA function in mPFC, produce inhibitory control
  deficits and enhance the incentive salience of psychostimulants. The
  objectives of the current proposal are to: (1) characterize inhibitory
  control deficits and determine psychostimulant sensitivity in rats
  developmentally exposed to an environmentally relevant PCB mixutre and
  (2) determine whether PCB induced changes in DA receptor expression in
  the mPFC mediate both the enhanced psychostimulant sensitivity and the
  inhibitory control deficits. The specific aims of the mentored phase
  are to: (1) quantify differences in inhibitory control on a multiple
  fixed interval/extinction task, (2) measure changes in the expression
  of the dopamine transporter (DAT), vesicular monoamine transporter
  (VMAT2), D1, D2, and D4 receptor subtypes in the mPFC of rats
  developmentally exposed to PCBs relative to controls, and (3) determine
  if perinatal PCB exposure is associated with enhanced sensitivity to
  the discriminative stimulus or motor-activating properties of
  psychostimulants. The specific aims of the independent phase are to:
  (1) determine which DA receptor subtypes in the mPFC mediate the
  enhanced psychostimulant sensitivity and inhibitory control deficits in
  PCB-exposed animals, and (2) Determine whether developmental exposure
  to the polybrominated diphenyl ethers (PBDEs), ubiquitous environmental
  chemicals which are chemically similar to the PCBs, results in changes
  in DA receptor expression and enhanced psychostimulant sensitivity that
  parallel the effects produced by PCBs. The results will provide
  valuable information about substance abuse risk following developmental
  exposure to environmental contaminants that target the DA system.

  -----------------------------------------------------------------------

Date Run: 11/30/06 **PUBLIC ABSTRACTS**

  ------------------ ------------------------------- ---------------------
  **Grant:**         1K99EY018042-01                 

  **Program          OBERDORFER, MICHAEL             
  Director:**                                        

  **Principal        DING, LONG                      PHD
  Investigator:**                                    

  **Title:**         Neuronal basis of reward-biased 
                     visual perception               

  **Institution:**   UNIVERSITY OF PENNSYLVANIA      PHILADELPHIA, PA

  **Project          2007/01/01-2008/12/31           
  Period:**                                          
  ------------------ ------------------------------- ---------------------

  -----------------------------------------------------------------------
  DESCRIPTION (provided by applicant): The objectives of this Pathway to
  Independence Award for Long Ding, Ph.D., are to expand the candidate\'s
  expertise in the field of visual perceptual decision-making and to
  establish a novel experimental model to fill the knowledge gap on how
  visual perception is affected by reward-induced internal preferences.
  Achieving the first objective will complement the candidate\'s previous
  training in basal ganglia physiology related to learning and neural
  representation of reward. Achieving the second objective will provide a
  launching point for the candidate to develop an independent research
  career, toward a long-term goal of gaining a better understanding of
  the basal ganglia functions in reward modulation of perception. These
  objectives will be accomplished in two phases. In the 2-year mentored
  phase, the candidate will conduct supervised research in Dr. Joshua
  Gold\'s lab at the University of Pennsylvania to identify neural
  correlates of external evidence-based perceptual decisions in the basal
  ganglia and frontal cortex, using single-unit recordings in monkeys
  performing a visual motion discrimination task (Aim 1). This training
  environment is uniquely suitable because of Dr. Gold\'s expertise in
  visual perceptual decision-making, the immediate availability of
  well-trained monkeys and the intellectual resources available at Penn,
  which is renowned for its research on vision and perception. In the
  next 3-year phase, the candidate\'s independent research will identify
  neural correlates of decision-making that integrates reward-induced
  internal preference and external evidence in the basal ganglia and
  frontal cortex (Aim 2). This research will be based on single unit
  recordings in monkeys performing a novel visual motion discrimination
  task that also incorporates reward bias. The proposed research is
  designed to test the central hypothesis that the neural representations
  of external evidence and reward-induced internal preference are
  co-localized and incorporated in individual neurons in the basal
  ganglia and frontal cortex. It represents an innovative merging of
  established lines of research and will advance our understanding of the
  neural mechanisms underlying normal visual perception. Relevance to
  public health: The proposed research represents an important research
  area of visual perception and will facilitate future identification of
  neural targets for better treatment of patients with perceptual
  impairment.

  -----------------------------------------------------------------------

Date Run: 11/30/06 **PUBLIC ABSTRACTS**

  ------------------ ------------------------------- ---------------------
  **Grant:**         1K99GM079921-01                 

  **Program          OKITA, RICHARD T                
  Director:**                                        

  **Principal        JONES, TONI I                   PHD PHARMACOLGY
  Investigator:**                                    

  **Title:**         Spinal Cord Signal Transduction 
                     in a Rat Model of Post-Surgical 
                     Pain                            

  **Institution:**   UNIVERSITY OF CALIFORNIA SAN    LA JOLLA, CA
                     DIEGO                           

  **Project          2006/12/01-2008/11/30           
  Period:**                                          
  ------------------ ------------------------------- ---------------------

  -----------------------------------------------------------------------
  DESCRIPTION (provided by applicant): Post-operative pain is a major
  clinical concern, as it can delay patient recovery and increase
  probability of chronic pain syndromes. More than half of patients
  report moderate to severe pain after surgery, thus, it is important to
  investigate the mechanisms that generate and maintain this condition.
  Plantar incision in the rat hind paw is a model of post-operative pain
  resulting in spontaneous pain and hyperalgesia, or increased pain in
  response to stimulation, symptoms that are observed in patients. Spinal
  glutamate receptor pharmacology of this model is distinct. Spinally
  administered conventional antagonists to NMDA receptors have no effect
  on any aspect of incision-evoked pain in the rat. However, NR2B-NMDA
  and calcium-permeable AMPA/KA glutamate receptor subtypes appear to
  mediate separate aspects of post-operative pain behavior, although this
  is not certain. No studies have addressed the role of spinal signal
  transduction cascades occurring downstream from calcium-permeable
  AMPA/KA and NR2B-NMDA receptor activation after incision. This
  application examines post-operative pain behaviors by targeting the
  facilitation of various elements of these cascades. Aim 1 will measure
  increases in incision-evoked activation of protein kinase A (PKA),
  conventional protein kinase C (PKC), and calcium/ calmodulin-dependent
  protein kinase II alpha (CaMKII alpha) over a 5-day period.
  Administration of selective kinase antagonists will demonstrate if
  these changes are necessary for the manifestation of pain behavior. Aim
  2 will determine if pain behavior and/or CaMKII alpha activation are
  downstream of N-type calcium channel activation. Aim 3 will focus on
  events downstream of calcium-permeable AMPA/KA and NR2B-NMDA receptors.
  Receptor-specific antagonists will be administered to determine, if
  indeed, separate aspects of post-operative pain are diminished and, if
  so, whether each antagonist produces a distinct pattern of kinase
  inhibition. Aim 4 will measure phosphorylation of AMPA GLUR1 and NMDA
  NR1 and NR2B receptor subunits and AMPA GLUR1 receptor subunit
  insertion into the synaptic membrane after incision. These events are
  associated with synaptic strengthening and increased spinal
  sensitization. Treatment with calcium-permeable AMPA/KA and NR2B-NMDA
  receptor antagonists will be used to ascertain if these events occur
  downstream of receptor activation. Western blots and protein kinase
  activity assays will be used to measure activation and/or
  phosphorylation of specific agents. Subcellular fractionation combined
  with Western blots will be used to demonstrate receptor movement from
  cytosol to membrane, while immunohistochemistry in tandem with confocal
  microscopy will be used to determine cellular or regional localization
  of phosphorylated proteins. Delineation of these important spinal
  signaling mechanisms and identification of relevant receptor subtypes
  involved in post-operative pain will increase our ability to develop
  effective treatments for pain after surgery.

  -----------------------------------------------------------------------

Date Run: 11/30/06 **PUBLIC ABSTRACTS**

  ------------------ ------------------------------- ---------------------
  **Grant:**         1K99GM079922-01                 

  **Program          OKITA, RICHARD T                
  Director:**                                        

  **Principal        GARG, NEIL K                    PHD
  Investigator:**                                    

  **Title:**         New Asymmetric Transformations  
                     and Chemical Synthesis of       
                     Natural Products                

  **Institution:**   UNIVERSITY OF CALIFORNIA IRVINE IRVINE, CA

  **Project          2006/12/01-2008/11/30           
  Period:**                                          
  ------------------ ------------------------------- ---------------------

  -----------------------------------------------------------------------
  DESCRIPTION (provided by applicant): This research program aims to
  develop new and efficient methods for the preparation of complex
  bioactive organic molecules. Research proposed in the K99 Mentored
  phase will be carried out over one to two years with Professor Larry
  Overman and involve the discovery of new asymmetric Pd(ll)-catalyzed
  reactions of allylic trichloroacetimidates. Pending the development of
  this methodology, it will be evaluated in the context of an efficient
  synthesis of microphyllaquinone, a small molecule that exhibits
  cytotoxicity against several cell lines. The R00 Independent phase
  (years 3 to 5) will focus on the discovery of an asymmetric
  metal-mediated coupling reaction to promote the formation of all-carbon
  quaternary stereocenters, a challenge often encountered in complex
  molecule synthesis. This powerful methodology will be expanded to
  include cascade reactions for the rapid construction of
  enantio-enriched fused and bicyclic ring systems beginning from simple,
  prochiral starting materials. Finally, the asymmetric total syntheses
  of two potent anti-inflammatory compounds, mangicols A and C, will be
  pursued. If the goals of this proposal are achieved, new chemical
  methods for preparing biologically active molecules will be developed.
  Ultimately, this contribution will facilitate the discovery of new
  medicinal agents for treating human illnesses.

  -----------------------------------------------------------------------

Date Run: 11/30/06 **PUBLIC ABSTRACTS**

  ------------------ ------------------------------- ---------------------
  **Grant:**         1K99GM079955-01                 

  **Program          RODEWALD, RICHARD D.            
  Director:**                                        

  **Principal        SCHULDINER, MAYA B              PHD
  Investigator:**                                    

  **Title:**         Exploring Regulation of ER      
                     Homeostasis Using Quantitative  
                     Genetic Interaction Map         

  **Institution:**   UNIVERSITY OF CALIFORNIA SAN    SAN FRANCISCO, CA
                     FRANCISCO                       

  **Project          2006/12/01-2008/11/30           
  Period:**                                          
  ------------------ ------------------------------- ---------------------

  -----------------------------------------------------------------------
  DESCRIPTION (provided by applicant): My research interests focus on
  bridging the gap between systems biology and cell biology. My long-term
  goal is to couple my expertise in cell biology of the endoplasmic
  reticulum (ER) with high throughput tools and novel analytical methods
  to create a model for a self-contained unit within the cell. In the
  short term I plan to focus on the genes essential for maintaining
  homeostasis in the ER. The importance of a robustly functioning ER is
  underscored by its requirement for the normal development of
  multicellular organisms, especially differentiation of dedicated
  secretors such as plasma cells and insulin-secreting pancreas cells. To
  gain novel insights on maintenance of homeostasis in the ER, I propose
  to screen for all genes in whose absence the ER accumulates unfolded
  proteins. This can be measured accurately by utilizing a reporter for
  induction of the ER stress-induced unfolded protein response (UPR).
  Once all genes are identified, I plan to make a quantitative and
  accurate genetic interaction map, showing the extent by which a
  mutation in one of these genes changes the phenotype of all the others.
  Based on previous work, I believe that analysis of this map will allow
  me to predict functions for unknown proteins as well as organize all
  proteins into complexes and pathways. It will also allow me to study
  the hierarchy of the different processes involved in maintaining a
  fully functional ER. I propose to do this both in yeast (by using the
  yeast deletion strain library and a novel library of hypomorphic
  alleles of essential genes) and human cells (using RNAi technology).
  This comparison should allow me to define the evolutionary constraints
  leading to conservation of the organelle functions, thus developing a
  new understanding of the secretion process and its players in
  eukaryotes. Summary: All secreted and membrane-bound proteins essential
  for cellular communication and reaction to the environment are first
  translocated into the endoplasmic reticulum (ER) where they fold and
  mature into their native conformations aided by a variety of folding
  enzymes. A change in conditions in the ER causes activation of a stress
  response that mediates return to homeostasis. Mutations causing this
  response to be overactive or underactive have been reported to play a
  role in diseases as varied as cancer, cystic fibrosis (CF), diabetes,
  neurodegeneration and heart disease. Thus, gaining a deeper
  understanding of the genes regulating homeostasis in the ER and the
  stress response will allow us to treat such human pathologies.

  -----------------------------------------------------------------------

Date Run: 11/30/06 **PUBLIC ABSTRACTS**

  ------------------ ------------------------------- ---------------------
  **Grant:**         1K99GM079960-01                 

  **Program          CARTER, ANTHONY D.              
  Director:**                                        

  **Principal        LEE, TAE-HEE                    
  Investigator:**                                    

  **Title:**         Dynamics in Translation: the    
                     Role of Fluctuation in Protein  
                     Synthesis                       

  **Institution:**   STANFORD UNIVERSITY             STANFORD, CA

  **Project          2006/12/01-2007/11/30           
  Period:**                                          
  ------------------ ------------------------------- ---------------------

  -----------------------------------------------------------------------
  DESCRIPTION (provided by applicant): Translation, in vivo protein
  synthesis, is a vital process in maintaining cell life by producing
  enzymes performing almost every critical function in the cell including
  gene transcription, gene repair, protein synthesis, and protein
  folding/degradation. Understanding translation is essential in
  controlling cell function/life by offering ways to control enzyme
  production in the cell. The ribosome selects the correct transfer RNA
  (tRNA) based on mRNA(codon)-tRNA(anticodon) interaction to synthesize
  protein with the correct sequence. The selection is composed of two
  sub-steps\--initial selection and proofreading. Candidate is currently
  trying to elucidate the mechanism of proofreading. During the initial
  selection, ternary complex of elongation factor Tu (EF-Tu), tRNA, and
  GTP delivers tRNA to the mRNA/ribosome complex. Only when codon matches
  with anticodon, EF-Tu hydrolyzes GTP and changes conformation to
  dissociate from the ribosome. Candidate hypothesizes that this
  recognition process (codon-dependent GTP hydrolysis on EF-Tu) is
  enabled by tRNA fluctuations, dynamics of which is determined by
  codon-anticodon interaction. Therefore, tRNA acts as a communication
  channel between the ribosome decoding site and EF-Tu. To examine the
  hypothesis, candidate proposes to monitor individual working ribosome
  in real-time through single molecule fluorescence measurement. Single
  molecule measurement enables high time-resolution real-time monitoring
  of individual steps in non-synchronizable multi-step enzymatic
  processes. Candidate proposes following specific aims to test the
  hypothesis: (1) Construct an experimental system to monitor tRNA
  movement, elongation factor Tu (EF-Tu) movement, and GTP hydrolysis
  through single molecule fluorescence resonance energy transfer (SM
  FRET): (a) achieve 3 ms time resolution to monitor the dynamics, (b)
  label EF-Tu and test fluorescent GTP analogues to monitor EF-Tu
  movement and GTP hydrolysis; (2) Achieve the highest possible
  signal-to-noise ratio (S/N) for SM FRET measurements: (a) optimize
  instrumentation for highest possible S/N, (b) optimize oxygen scavenger
  system, (c) Implement noise removal algorithm based on stochastic
  prediction; (3) Relate tRNA motion to GTP hydrolysis and EF-Tu
  dissociation: (a) monitor GTP hydrolysis and tRNA motion
  simultaneously, (b) monitor EF-Tu movement and tRNA motion
  simultaneously. Successful completion of proposed research will greatly
  enhance our understanding of in translation. Understanding how the
  translation machinery synthesizes proteins with such an unusually high
  accuracy will open ways to control cell function/life.

  -----------------------------------------------------------------------

Date Run: 11/30/06 **PUBLIC ABSTRACTS**

  ------------------ ------------------------------- ---------------------
  **Grant:**         1K99GM080099-01                 

  **Program          CARTER, ANTHONY D.              
  Director:**                                        

  **Principal        SONG, YUN S                     PHD
  Investigator:**                                    

  **Title:**         Novel Methods for               
                     Characterizing Recombination    
                     and Selection                   

  **Institution:**   UNIVERSITY OF CALIFORNIA DAVIS  DAVIS, CA

  **Project          2006/12/01-2007/11/30           
  Period:**                                          
  ------------------ ------------------------------- ---------------------

  -----------------------------------------------------------------------
  DESCRIPTION (provided by applicant): Two known types of meiotic
  recombination are crossovers and gene conversions, which have different
  effects on the pattern of linkage disequilibrium (LD). Efforts to
  deduce patterns of historical recombination are central to the design
  and analysis of disease association studies, which depend on
  understanding the structure of LD in population data. The focus of the
  PI\'s current research is on developing efficient algorithms for
  reconstructing parsimonious evolutionary histories with recombination.
  The PI\'s long-term objective is to characterize quantitatively the
  effect of various evolutionary forces on shaping the structure of LD in
  the human genome. Some motivations for the proposed research are as
  follows: (1) Gene conversion has been hard to study in populations
  because of the lack of analytical tools and the lack of fine-scale
  data. However, genomic data produced over the next several years should
  allow quantification of the fundamental parameters of gene conversion,
  and the contribution of gene conversion to the overall patterns of
  sequence variations in a population. (2) Natural selection is an
  important evolutionary force that shapes genomic variation within
  species and the divergence between species. It has been shown recently
  that the patterns of LD generated by strong positive selection can
  resemble that generated by crossover hotspots. The specific aims of the
  independent phase of the award are: (1) Develop novel statistical
  methods for estimating crossover and gene conversion rates. A
  mathematical framework based on diffusion approximation will be used to
  obtain novel multi-locus sampling distributions. Gene conversion will
  be included in that framework. A likelihood method that utilizes the
  new sampling distributions will be developed to enable joint estimation
  of crossover and gene conversion rates. (2) Study the effects of
  natural selection on the pattern of LD. The interaction of selection at
  multiple loci will be studied analytically and the structure of LD
  shaped by interacting selection will be characterized. Relevance:
  Understanding the structure of variation in the human genome is central
  to the study of the genetic basis of disease risk and variation in drug
  response. The aim of this research, which is relevant to disease
  association studies, is to characterize various evolutionary mechanisms
  that shape the pattern of non-independence of genetic forms at
  different positions in the genome.

  -----------------------------------------------------------------------

Date Run: 11/30/06 **PUBLIC ABSTRACTS**

  ------------------ ------------------------------- ---------------------
  **Grant:**         1K99HD055030-01                 

  **Program          HUANG, TERRY T-K                
  Director:**                                        

  **Principal        TAMASHIRO, KELLIE L             PHD
  Investigator:**                                    

  **Title:**         Influences of the prenatal      
                     environment on metabolic        
                     programming                     

  **Institution:**   JOHNS HOPKINS UNIVERSITY        BALTIMORE, MD

  **Project          2006/12/01-2008/11/30           
  Period:**                                          
  ------------------ ------------------------------- ---------------------

  -----------------------------------------------------------------------
  DESCRIPTION (provided by applicant): Obesity is a major public health
  problem worldwide and recent work has suggested that exposure to a
  suboptimal early environment may increase the risk of becoming obese.
  Epidemiological data show that an unfavorable intrauterine environment
  has long-term consequences in offspring including hypertension,
  cardiovascular disease, type 2 diabetes, obesity and neuropsychiatric
  disease. Specifically, prenatal stress and/or consumption of a high fat
  diet, characteristics of modern day human lifestyle, have been shown to
  lead to metabolic disorders such as obesity and insulin resistance in
  offspring. However, the mechanisms involved are not well understood.
  The overall goal of this proposal is to characterize the short- and
  long-term effects of changes in the prenatal environment - stress and
  nutrition - on the behavioral and physiological development of
  offspring and to explore the possible neuropeptide and epigenetic
  mechanisms involved using a rat animal model. Specific aims are: 1) To
  determine the developmental time course of behavioral and endocrine
  alterations resulting from prenatal stress. We will also test the
  hypothesis that prenatal stress will accentuate diet-induced obesity.
  Time points during lactation, adolescence, and adulthood will be
  examined to characterize the phenotype and to direct examination of
  possible mechanisms; 2) To test the hypothesis that prenatal stress,
  high fat diet, or both result in alterations in neuropeptide systems
  regulating energy homeostasis that are consistent with other rodent
  models of obesity; and 3) To test the hypothesis that prenatal stress
  and nutrition results in obesity in offspring through epigenetic
  modifications via differential DNA methylation of genes that are
  critical to energy homeostasis. These experiments will enhance our
  understanding of the etiology of obesity and metabolic disease
  ultimately allowing the development of rational clinical interventions
  for such conditions. This proposal has also been structured to provide
  a rich and diverse training opportunity. The trainee has assembled a
  mentoring committee that will provide expertise in the development and
  regulation of ingestive behavior (Dr. Timothy Moran), neurobiology of
  stress and the hypothalamic-pituitary-adrenal axis (Dr. James Koenig)
  and the role of epigenetics in the etiology of disease (Dr. Andrew
  Feinberg and Dr. James Potash). The guidance of this committee in
  conjunction with the trainee\'s previous work in behavioral and
  molecular neuroendocrinology, will provide a solid foundation for the
  trainee to develop a multi-disciplinary program of research including
  behavioral, physiological, cellular/molecular, and genetic/epigenetic
  studies that will facilitate her transition to an independent
  investigator.

  -----------------------------------------------------------------------

Date Run: 11/30/06 **PUBLIC ABSTRACTS**

  ------------------ ------------------------------- ---------------------
  **Grant:**         1K99HD055033-01                 

  **Program          HAVERKOS, LYNNE                 
  Director:**                                        

  **Principal        SLATER, SANDY J                 PHD
  Investigator:**                                    

  **Title:**         Is the Built Environment        
                     Associated with Youth Physical  
                     Activity and Weight?            

  **Institution:**   UNIVERSITY OF ILLINOIS AT       CHICAGO, IL
                     CHICAGO                         

  **Project          2006/12/01-2008/11/30           
  Period:**                                          
  ------------------ ------------------------------- ---------------------

  -----------------------------------------------------------------------
  DESCRIPTION (provided by applicant): Sandy Slater, Ph.D., Research
  Specialist at the University of Illinois at Chicago (UIC) is a health
  policy analyst whose research focuses on the impact of state and local
  policies, and other environmental factors on health behavior. Specific
  to this application, Dr. Slater plans to study how the built
  environment and related policies influence adolescent physical activity
  and ultimately overweight and obesity. She will do this by drawing upon
  multiple theories and analytic techniques rather than limiting her
  research to only one discipline, while also seeking a permanent
  academic position in either the field of urban planning or public
  health. She plans to conduct this research at the UIC Institute for
  Health Research and Policy (IHRP). The work at IHRP spans social and
  behavioral health research, from basic science (including methods and
  theory development) and intervention development, to clinical and
  efficacy trials, research-to-practice and practice-to-policy
  translation, and dissemination. Under the mentored phase, she will
  complete two analyses using existing data that study the association
  between youth active travel, physical activity, overweight and obesity
  and a variety of built environmental measures. The results of these
  analyses will then be used to inform and guide the development of a
  pilot project for the independent scientist phase of this award. In
  addition, both the mentored and independent research plans will allow
  for the utilization of multi-disciplinary analytic skills and
  techniques to be acquired in the mentored phase of this award. For the
  independent phase, Dr. Slater proposes to develop and initiate a pilot
  project to examine the importance of school and community physical
  activity settings and opportunities on youth physical activity levels,
  overweight and obesity. The proposed study will combine detailed
  individual and parental survey data of Kindergarten, 3rd grade, and 5th
  grade students with community-level built environmental and related
  policy data, and school-level measures. The intent of the study is to
  examine the direct impact of individual and contextual factors on
  measures of BMI and overweight status, as well as their indirect
  influence on these outcomes via their effect on intermediary behaviors
  related to physical activity behaviors. The results of the pilot will
  then inform a larger R01 application. The results from a large-scale
  empirical study could then inform community-based interventions to
  reduce adolescent obesity.

  -----------------------------------------------------------------------

Date Run: 11/30/06 **PUBLIC ABSTRACTS**

  ------------------ ------------------------------- ---------------------
  **Grant:**         1K99HD055034-01                 

  **Program          HENKEN, DEBORAH                 
  Director:**                                        

  **Principal        TANEYHILL, LISA A               PHD
  Investigator:**                                    

  **Title:**         Functional Roles of Wnt and     
                     Snail2 Target Genes in Neural   
                     Crest Development               

  **Institution:**   CALIFORNIA INSTITUTE OF         PASADENA, CA
                     TECHNOLOGY                      

  **Project          2006/12/01-2008/11/30           
  Period:**                                          
  ------------------ ------------------------------- ---------------------

  -----------------------------------------------------------------------
  DESCRIPTION (provided by applicant): The general theme of the
  candidate\'s research career has been to determine the molecular basis
  by which the Wnt signaling pathway activates expression of target genes
  and subsequently affects the generation of a particular cell type, in a
  context-dependent and temporal manner. The Wnt signaling pathway and
  its components are used reiteratively throughout embryonic development
  and in mature tissues during the transformation of normal cells to
  cancerous ones, demonstrating the importance of this pathway. Wnt
  signaling plays a significant role in the development of the neural
  crest, a population of migratory cells that helps pattern the embryo.
  Because of its contribution to embryonic structures, defects in neural
  crest development give rise to multiple syndromes, diseases, and
  cancers, including Axenfeld-Rieger, DiGeorge, and Treacher-Collins
  syndromes, and neurofibromatosis. To further understand how Wnt
  signaling regulates neural crest development, the candidate has
  performed a screen to identify novel targets of Wnt signaling involved
  in this process. Furthermore, investigation into the role of known Wnt
  target genes, such as Snail2 (Slug) allows her to elucidate how Snail2
  regulates expression of its molecular targets in the context of neural
  crest development. Embryological and biochemical methods will be
  employed to determine the functional significance of these targets and
  their mode of regulation by Wnt. Overall, these approaches will provide
  her with a group of candidate molecules that will likely function in
  the generation of structures derived from the neural crest, such as the
  craniofacial skeleton and peripheral nervous system, as well as provide
  insight into the development of neural crest-derived cancers. In
  summary, the candidate\'s long-term research and career objectives
  include conducting mentored research (in the final years of her
  postdoctoral training) and independent research (as a principal
  investigator) to elucidate the molecular mechanism underlying Wnt
  signaling during the development of the neural crest, and applying this
  knowledge to human development as a whole. This research is relevant to
  public health because of the biological significance of the neural
  crest to the proper formation of human bodies, such as the bones of the
  face, nerves, and skin pigment cells. How neural crest cells properly
  become such diverse structures can help us comprehend what happens when
  neural crest development is impaired, and human syndromes and cancers
  arise.

  -----------------------------------------------------------------------

Date Run: 11/30/06 **PUBLIC ABSTRACTS**

  ------------------ ------------------------------- ---------------------
  **Grant:**         1K99HD055052-01                 

  **Program          TASCA, RICHARD J                
  Director:**                                        

  **Principal        CHEN, XIN                       PHD
  Investigator:**                                    

  **Title:**         Epigenetic Regulation of Germ   
                     Cell Differentiation from a     
                     Stem Cell Lineage               

  **Institution:**   STANFORD UNIVERSITY             STANFORD, CA

  **Project          2006/12/01-2008/11/30           
  Period:**                                          
  ------------------ ------------------------------- ---------------------

  -----------------------------------------------------------------------
  DESCRIPTION (provided by applicant): The mechanisms that regulate
  differentiation of cells from undifferentiated precursors play key
  roles in development, adult tissue maintenance, and gametogenesis.
  Precursor germ cells must commit to differentiate at the right place
  and with the right timing to generate or maintain the pools of
  functional gametes. The maintenance of the precursor germ cells in an
  undifferentiated and proliferative state and the subsequent reversal of
  these controls to allow terminal differentiation are both critical to
  continuous production of gametes throughout lifetime. The candidate is
  using the differentiation of Drosophila male germline cells from an
  adult stem cell lineage as a model system to investigate the roles of
  epigenetic control of cell-type specific transcription programs. She
  discovered that developmentally programmed expression and action of
  testis specific TAP (TBP-associated factors) homologs are responsible
  for expression of spermatid differentiation genes by counteracting the
  Polycomb transcription repressor. She now proposes to investigate the
  roles and regulation of Polycomb group (PcG) machinery and epigenetic
  chromatin modifications in precursor germ cell proliferation versus
  terminal differentiation. These studies have significant implications
  for reproductive biology, since the increasing evidence demonstrates
  conserved mechanisms that regulate spermatogenesis between flies and
  mammals. In addition, uncontrolled proliferation at the expense of
  differentiation leads to cancer, and PcG proteins have been implicated
  in both precursor cell fate and tumorigenesis, for example, in
  mammalian hematopoietic cells. Thus the studies will also shed light on
  the molecular mechanisms of cancer progression and treatment. The
  candidate\'s future work will use a combination of molecular, genetic,
  and biochemical strategies to explore the molecular mechanisms
  underlying a dramatic epigenetic switch, visualized by changes in level
  and/or localization of a set of covalently modified histones and
  chromatin modifiers at the precursor-to-differentiation transition
  during spermatogenesis. The candidate\'s immediate career goal is to
  obtain a tenure-track faculty position in an academic environment after
  her postdoctoral training. Her ultimate research plan is to understand
  fundamental biological questions about the mechanisms that regulate
  proliferation versus cellular differentiation during male germ cell
  development. The candidate is committed to the research in biomedical
  science, and to the education of future scientists.

  -----------------------------------------------------------------------

Date Run: 11/30/06 **PUBLIC ABSTRACTS**

  ------------------ ------------------------------- ---------------------
  **Grant:**         1K99HG004183-01                 

  **Program          SCHLOSS, JEFFERY                
  Director:**                                        

  **Principal        SCHROEDER, CHARLES M            PHD
  Investigator:**                                    

  **Title:**         Single Molecule Technology for  
                     Genome-Wide Association Studies 

  **Institution:**   HARVARD UNIVERSITY              CAMBRIDGE, MA

  **Project          2006/12/01-2008/11/30           
  Period:**                                          
  ------------------ ------------------------------- ---------------------

  -----------------------------------------------------------------------
  DESCRIPTION (provided by applicant): The candidate is a postdoctoral
  fellow in the laboratory of X. Sunney Xie at Harvard University and has
  been trained in single molecule polymer physics. The candidate\'s
  long-term scientific research goal is to study fundamental processes in
  biological systems and to develop new technologies based on single
  molecule tools for genomics, disease diagnosis, and biotechnology. The
  NIH PI Award will facilitate the candidate\'s career development by
  providing training in protein expression and purification, benchtop
  biochemistry, enzymology, and single molecule fluorescence imaging.
  Harvard University has a vibrant single molecule research community and
  will provide an excellent training environment for the candidate. The
  overarching goal of this research program is to develop novel single
  molecule technologies for advancement of human health. The specific
  goal of the current research proposal is to develop a single molecule
  technology for conducting genome-wide association studies for complex
  diseases in a low-cost, high-throughput format. Identification of genes
  associated with common diseases will lead to a major breakthrough in
  our understanding of the causes of human disease and will catalyze a
  new paradigm for diagnosis of diseases, prediction of drug response,
  and development of new disease therapies. The goal of this research
  proposal will be achieved by addressing the following specific aims:
  1.) Demonstration of a high-throughput method for analyzing stretched
  and trapped genomic DNA molecules using a microfluidic device; 2.)
  Development of molecular tags for sequence-specific marker recognition
  in genomic DNA; 3.) Linking of fluorescent probes to these molecular
  tags; 4.) Development of methods for extraction and manipulation of
  intact genomic DNA from cells in a \"lab-on-a-chip\" format. The
  proposed single molecule-based technology will deeply impact human
  health by providing a cost efficient method for genotyping appropriate
  for routine clinical diagnoses. Specifically, the new technology will
  facilitate identification of genes that contribute to complex diseases,
  guide the fast and early diagnosis of diseases, allow for targeting
  specific proteins encoded by identified genes during drug development,
  and allow small molecule drugs to be prescribed based on individual
  genomic content. In short, the proposed single-molecule based
  genotyping technology will catalyze the start of the era of
  personalized medicine.

  -----------------------------------------------------------------------

Date Run: 11/30/06 **PUBLIC ABSTRACTS**

  ------------------ ------------------------------- ---------------------
  **Grant:**         1K99HL087462-01                 

  **Program          VARGHESE, JAMIE                 
  Director:**                                        

  **Principal        TIKUNOVA, SVETLANA B            PHD
  Investigator:**                                    

  **Title:**         Influence of Troponin C on the  
                     Rate of Cardiac Muscle          
                     Relaxation                      

  **Institution:**   OHIO STATE UNIVERSITY           COLUMBUS, OH

  **Project          2006/12/01-2008/11/30           
  Period:**                                          
  ------------------ ------------------------------- ---------------------

  -----------------------------------------------------------------------
  DESCRIPTION (provided by applicant): Up to 40% of heart failure
  patients have impaired relaxation, known as diastolic dysfunction.
  Cardiac muscle relaxation is not merely a passive reversal of
  contraction, but a complex process requiring a series of events: 1)
  decline in intracellular Ca2+, 2) dissociation of Ca2+ from troponin C
  (TnC), and 3) cross-bridge detachment. There is controversy regarding
  the relative importance of each of these events in controlling
  relaxation. Despite the fact that Ca2+ must dissociate from the
  regulatory domain of TnC to allow relaxation, contribution of TnC to
  the rate of relaxation is in dispute. The objective of this project is
  to test the overriding hypothesis that the rate of Ca2+ dissociation
  from the regulatory domain of TnC is a major determinant of cardiac
  relaxation. To test this hypothesis, the proposed study will utilize
  the following AIMs: AIM 1: Elucidate and manipulate factors controlling
  Ca2+ binding and exchange with TnC in increasingly structured systems,
  ranging from isolated TnC to reconstituted thin filaments. The goal of
  this aim is to determine how Tnl, thin and thick filament proteins and
  key residues in TnC affect Ca2+ affinity and Ca2+ dissociation rate
  from the regulatory domain of TnC. TnC proteins, generated in this AIM
  by mutagenesis of key residues in TnC, will be used in AIMs 2 and 3 to
  test the overriding hypothesis. AIM 2: Determine the contribution of
  Ca2+ dissociation from TnC to the rate of relaxation in skinned rabbit
  trabeculae. This study will probe the contribution of Ca2+ dissociation
  from TnC to the rate of relaxation at the level of the myofilaments.
  Relaxation of skinned trabeculae reconstituted with TnC mutants,
  possessing dramatically faster or slower Ca2+ dissociation rates, will
  be induced by rapid laser photolysis of the caged Ca2+ chelator
  diazo-2. AIM 3: Determine the contribution of Ca2+ dissociation from
  TnC to the rate of relaxation in intact, continuously contracting
  rabbit trabeculae in culture. These studies will probe the contribution
  of TnC to the rate of relaxation, under the conditions where Ca2+
  sequestration can be a determinant of relaxation. TnC mutants with
  dramatically faster or slower Ca2+ dissociation rates will be
  introduced into intact cultured trabeculae by adenoviral gene transfer.
  These experiments should clarify whether TnC should be a target for the
  treatment of diastolic dysfunction. (End of Abstract)

  -----------------------------------------------------------------------

Date Run: 11/30/06 **PUBLIC ABSTRACTS**

  ------------------ ------------------------------- ---------------------
  **Grant:**         1K99HL087513-01                 

  **Program          VARGHESE, JAMIE                 
  Director:**                                        

  **Principal        MAHONEY, WILLIAM M              PHD BIOCHEMISTRY
  Investigator:**                                    

  **Title:**         Molecular Characterization of   
                     Arterially-Restricted RGS5      

  **Institution:**   UNIVERSITY OF WASHINGTON        SEATTLE, WA

  **Project          2006/12/01-2008/11/30           
  Period:**                                          
  ------------------ ------------------------------- ---------------------

  -----------------------------------------------------------------------
  DESCRIPTION (provided by applicant): Arteries and veins must have very
  distinct properties responsible for each vessel\'s unique functional
  demands. For example, arteries, unlike veins, transmit the pressure
  wave and constrict to maintain pressure and to control blood flow. We
  propose that these different properties are regulated by a unique gene,
  or genes, found in arteries. We discovered that Regulator of G-Protein
  Signaling - 5 (RGS5), a member of the highly homologous R4 subfamily of
  RGS proteins, uniquely identifies smooth muscle cells (SMCs) from
  arteries relative to veins. The RGS family of proteins functions to
  control the duration of cellular signals mediated through G-Protein
  Coupled Receptors (GPCRs). RGS proteins act as GTPase Activating
  Proteins (GAPs) for specific GPCRs by facilitating the exchange of GDP
  for GTP upon G-alpha subunits of the heterotrimeric G-protein complex
  (Galpha/beta/gamma), thereby returning the complex to its inactive
  state. Our preliminary results demonstrate that arterial SMCs, relative
  to vein SMCs, specifically overexpress RGS5. In addition, arteries
  differentially express RGS5 (i.e., some arteries express RGS5 to a
  higher degree than others). Finally, RGS5 expression is dynamically
  regulated in response to vascular injury, and therefore, RGS5 may be
  dynamically regulated as cardiovascular disease develops. Based on
  these preliminary data, we hypothesize that artery-specific
  differences - either in physical forces acting on each vessel segment
  or local factors such as cell lineage or in nervation - act through
  specific promoter sequences to determine RGS5 protein expression level.
  The proposed experiments will identify and characterize the expression
  mechanism controlling RGS5 expression in arteries. Specifically, the
  experiments proposed will: (1) characterize the transcriptional
  regulatory mechanism controlling RGS5 mRNA expression in vitro; (2)
  characterize the RGS5 promoter in vivo; (3) investigate the activity of
  RGS5 during development an in response to vascular injury; (4) use the
  RGS5 promoter as a molecular model to address larger pathophysiologic
  questions, focusing on the likely hypothesis that functional adaptation
  of arteries is determined by a coordinate control mechanisms for
  transcription of mRNA for proteins that are key to differential
  arterial function. The latter goal-defining the mechanism defining
  arterial gene expression in response to specific local demands-is
  intended to provide the basis for an independent research career. (End
  of Abstract)

  -----------------------------------------------------------------------

Date Run: 11/30/06 **PUBLIC ABSTRACTS**

  ------------------ ------------------------------- ---------------------
  **Grant:**         1K99HL087560-01                 

  **Program          ROTHGEB, ANN E.                 
  Director:**                                        

  **Principal        DESHPANDE, DEEPAK A             DVM, PHD
  Investigator:**                                    

  **Title:**         Molecular Mechanisms of Airway  
                     Smooth Muscle Relaxation        

  **Institution:**   WAKE FOREST UNIVERSITY HEALTH   WINSTON-SALEM, NC
                     SCIENCES                        

  **Project          2006/12/01-2008/11/30           
  Period:**                                          
  ------------------ ------------------------------- ---------------------

  -----------------------------------------------------------------------
  DESCRIPTION (provided by applicant): Although inhaled beta-agonist is a
  first-line therapy for treatment and prophylaxis of acute bronchospasm
  that occurs with asthma, its mechanisms of action are poorly
  understood. In this Pathway to Independence application we propose of
  series of hypothesis-driven experiments, as well as the development of
  new approaches, to clarify mechanisms mediating airway smooth muscle
  (ASM) relaxation. The proposed studies will utilize both murine and
  human tissue and cells to explore mechanisms by which two relevant
  agents, beta-agonist and prostaglandin E2 (PGE2), mediate inhibition of
  ASM tension generation. Two sets of Specific Aims for the mentored and
  independent phases of this award are proposed. Mentored Phase I studies
  will provide important, new data establishing the relationship between
  regulation of calcium flux, contraction, and agonist-stimulated
  signaling events in both murine and human ASM. Independent Phase II
  studies will provide greater mechanistic insight into the Phase I
  outcomes by identifying the specific intracellular targets of
  beta-agonist signaling that antagonize calcium flux and contraction,
  and how modulation of these targets is influenced with chronic agonist
  treatment. Upon completion of Phase II studies, the PI should have both
  an empirical basis and powerful methodologies to pursue highly relevant
  research in the field of ASM physiology and biology. (End of Abstract)

  -----------------------------------------------------------------------

Date Run: 11/30/06 **PUBLIC ABSTRACTS**

  ------------------ ------------------------------- ---------------------
  **Grant:**         1K99HL087561-01                 

  **Program          COMMARATO, MICHAEL              
  Director:**                                        

  **Principal        SILVA, RANASINGHE A             PHD
  Investigator:**                                    

  **Title:**         The Role of Apolipoprotein A-II 
                     in the Modulation of HDL        
                     Function                        

  **Institution:**   UNIVERSITY OF CINCINNATI        CINCINNATI, OH

  **Project          2006/12/01-2008/11/30           
  Period:**                                          
  ------------------ ------------------------------- ---------------------

  -----------------------------------------------------------------------
  DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) is
  the number one killer in the United States, taking nearly a million
  lives each year. It is well established that high density lipoprotein
  (HDL) and its major protein constituent apolipoprotein (apo) A-l play a
  major role in reducing the risk of CVD. However the function of
  apolipoprotein A-l I, the second most abundant protein in HDL, has not
  been determined. Studies on apoA-ll have led to mixed conclusions
  concerning the pro- or antiatherogenicity of apoA-ll in HDL. This study
  will test the hypothesis that apoA-ll interacts with apoA-l in HDL in a
  site-specific manner to modulate HDL function. Furthermore, the effect
  is based on the relative amounts of apoA-l: apoA-ll present in a given
  HDL particle. In the Mentored Phase of this project, I will determine
  how the incorporation of apoA-ll affects apoA-l structure in discoidal
  reconstituted HDL particles. Relative changes in the solvent
  accessibility of specific apoA-l sequences in mixed particles vs apoA-l
  only HDL will be assessed using the hydrogen deuterium exchange
  technique combined with mass spectrometry (HDX-MS). I will then extend
  the studies in the Independent Phase to locate conformational changes
  in apoA-l caused by apoA-ll in HDL particles from human plasma. This
  will be accomplished in stages. First, I will reconstitute spherical
  HDL particles that resemble native HDL by incorporating varying ratios
  of apoA-l:apoA-ll along with native HDL lipids. I will also generate
  native hybrid HDL particles by incorporating isolated apoA-ll into
  native HDL particles containing apoA-l only. The apoA-ll induced
  modifications of apoA-l solvent exposure will then be correlated to
  functional properties including activation of various HDL remodeling
  factors including lecithin:cholesterol acyl transferase (LCAT), hepatic
  lipase (HL), and endothelial lipase (EL). I anticipate that this work
  will provide significant new information on the role of apoA-ll in
  lipoprotein metabolism and may suggest new therapeutic approaches for
  fighting CVD. (End of Abstract)

  -----------------------------------------------------------------------

Date Run: 11/30/06 **PUBLIC ABSTRACTS**

  ------------------ ------------------------------- ---------------------
  **Grant:**         1K99HL087591-01                 

  **Program          COMMARATO, MICHAEL              
  Director:**                                        

  **Principal        O\'CONNELL, KRISTEN M           PHD
  Investigator:**                                    

  **Title:**         Cell Biology of Cardiac Kv      
                     Channels                        

  **Institution:**   COLORADO STATE UNIVERSITY-FORT  FORT COLLINS, CO
                     COLLINS                         

  **Project          2006/12/01-2008/11/30           
  Period:**                                          
  ------------------ ------------------------------- ---------------------

  -----------------------------------------------------------------------
  DESCRIPTION (provided by applicant): Kv channels play a crucial role in
  determining the resting membrane potential, shaping action potential
  repolarization and setting spike frequency. It is becoming increasingly
  clear that the subcellular localization of these channels is an
  important component of cellular excitability. However, very little is
  known; about the localization of specific ion channels within cardiac
  myocytes. Kv2.1 is one of the delayed rectifier K+ channels expressed
  in both atria and ventricle, where it plays an important role in the
  late phase of repolarization of the cardiac action potential and helps
  set the QT interval. Kv2.1 is unusual among the voltage-gated K+
  channels in that its function is modulated by hypoxia/ischemia, redox,
  mitochondrial Ca2+ and muscarinic agonists. It is intriguing that
  channel localization is also altered by these stimuli, suggesting a
  tight relationship between channel function and localization. In the
  brain, the altered function of Kv2.1 following ischemic insult appears
  to be neuroprotective. It is therefore likely that Kv2.1 plays a
  similar role in the heart. The hypothesis of this proposal is that the
  localization of Kv2.1 to subcellular microdomains places the channel in
  proximity to the singaling pathways that modulate its function in
  response to cellular stimuli, permitting dynamic regulation of cardiac
  excitability on a beat-to-beat basis. Because it is unknown where in a
  cardiac myocyte Kv2.1 is expressed, the goal of the mentored phase of
  this proposal is to establish cardiac myocytes from both atria and
  ventricle as a model system for studying the trafficking of Kv2.1.
  AdenoviraI-mediated expression of tagged channels will be used to study
  the localization and dynamics of Kv2.1 in living myocytes, thus
  building a foundation for the independent phase research. During the
  second phase, the emphasis will be on investigating the role of Kv2.1
  in the cardiac cellular response to ischemia and intracellular Ca2+. We
  propose that the localization of Kv2.1, and consequently channel
  function will be altered by these stimuli. Idiopathic arrhythmias and
  cardiac ischemia are serious threats to human health whose underlying
  causes are not well understood. Therefore, defects in ion channel
  localization may be an as-yet unrecognized cause of human cardiac
  disease, emphasizing the importance of understanding how these proteins
  are trafficked and localized in the heart. (End of Abstract)

  -----------------------------------------------------------------------

Date Run: 11/30/06 **PUBLIC ABSTRACTS**

  ------------------ ------------------------------- ---------------------
  **Grant:**         1K99HL087607-01                 

  **Program          VARGHESE, JAMIE                 
  Director:**                                        

  **Principal        WANG, MEIJING                   MD
  Investigator:**                                    

  **Title:**         Testosterone in TNFR1 Signaling 
                     During Acute Myocardial Injury  

  **Institution:**   INDIANA UNIV-PURDUE UNIV AT     INDIANAPOLIS, IN
                     INDIANAPOLIS                    

  **Project          2006/12/01-2008/11/30           
  Period:**                                          
  ------------------ ------------------------------- ---------------------

  -----------------------------------------------------------------------
  DESCRIPTION (provided by applicant): Myocardial ischemia is a leading
  cause of heart failure and death in both men and women. Restoration of
  blood flow to ischemic myocardium results in ischemia / reperfusion
  (I/R) injury. Sex-specific differences have been noted in myocardial
  I/R. Clinically, when compared to women, men experience: a higher
  overall incidence of heart failure, more rapid heart failure
  progression, worse age-matched cardiac contractility, and less
  preservation of myocardial mass as they age. These differences may be
  attributable to the effects of the sex hormone testosterone.
  Surprisingly, little information exists regarding the effect of
  testosterone on myocardial injury. Myocardial inflammation occurs
  following cardiac I/R injury and plays a crucial role in myocardial
  dysfunction. Tumor necrosis factor-alpha (TNF) is increased in
  myocardial tissue following I/R, and contributes to post-ischemic
  myocardial dysfunction, proinflammatory signaling and myocyte
  apoptosis. The effect of testosterone on TNFR1 and TNFR2 signaling
  following myocardial I/R remains unknown. Nearly simultaneously,
  ischemia results in the activation of JAK/STAT and p38 MARK signaling
  pathways, both of which are responsible for subsequent inflammatory
  cytokine production and apoptosis. Suppressors of cytokine signaling
  (SOCS) proteins, that are induced by various cytokines and stresses,
  exert negative effects on cytokine production and apoptosis. It remains
  unknown whether cross talk exists between the STAT/SOCS pathway and
  TNFR1 or TNFR2 signaling in the heart, and if so, whether testosterone
  amplifies or suppresses this link following myocardial I/R. A
  therapeutic approach to the treatment of heart failure may be to
  unbalance TNF signaling to diminish its deleterious effects while
  enhancing its salutary effects, towards a therapeutic benefit for both
  sexes. Utilizing endogenous mechanisms, such as SOCS mediated
  disruption of TNFR1 signaling, is appealing. We hypothesize that: 1)
  testosterone exacerbates acute myocardial ischemia and reperfusion
  injury by unbalancing TNFR1/TNFR2 signaling in favor of TNFR1; and 2)
  testosterone does so by disrupting the SOCS-3/STAT3 regulatory balance
  of TNFR1 signaling in the heart. Several specific aims are proposed to
  test these hypotheses which will be accomplished within the context of
  a detailed training plan, with the ultimate goal being a
  repeatedly-funded independent investigator at the faculty level. (End
  of Abstract)

  -----------------------------------------------------------------------

Date Run: 11/30/06 **PUBLIC ABSTRACTS**

  ------------------ ------------------------------- ---------------------
  **Grant:**         1K99HL087614-01                 

  **Program          VARGHESE, JAMIE                 
  Director:**                                        

  **Principal        ENNIS, DANIEL B                 PHD
  Investigator:**                                    

  **Title:**         Myocardial Structure, Function, 
                     and Remodeling in Mitral        
                     Regurgitation                   

  **Institution:**   STANFORD UNIVERSITY             STANFORD, CA

  **Project          2006/12/01-2008/11/30           
  Period:**                                          
  ------------------ ------------------------------- ---------------------

  -----------------------------------------------------------------------
  DESCRIPTION (provided by applicant): The clinical consequence of
  severe, uncorrected mitral regurgitation (MR) is excess mortality and
  morbidity. The timing of surgical intervention in chronic MR remains
  one of the most challenging clinical decisions in cardiac surgery. A
  refinement in our understanding of the pathogenesis of ventricular
  remodeling in mitral regurgitation is clearly needed to improve
  clinical outcomes. The canonical model of ventricular remodeling in
  volume overload hypertrophy does not account for transmural differences
  in hypertrophic remodeling. We now have exciting preliminary results
  that demonstrate a transmural gradient in ventricular wall remodeling
  wherein the epicardium thins by 30% and the endocardium thickens by
  nearly 10% during chronic MR. The overall hypothesis of the work is
  that transmural differences in the hypertrophic response to chronic
  mitral regurgitation may portend a poor clinical outcome. My immediate
  career goal is to develop the necessary experimental, computational,
  and theoretical tools to test hypotheses about transmural differences
  in cardiac structure, function, and remodeling in mitral regurgitation.
  A unique research environment is available to me through an
  inter-disciplinary collaboration between the Departments of
  Cardiothoracic Surgery and Radiology at Stanford University. This
  opportunity affords the ability to gain a deep understanding of cardiac
  pathophysiology research in addition to further developing my expertise
  in cardiac magnetic resonance imaging. My career plan includes gaining
  considerable expertise in experimental cardiac physiology research,
  quantitative histologic methods, diffusion tensor magnetic resonance
  imaging (DTMRI), and computational techniques for integrating structure
  and function data. My long-term career goal is to secure a tenure-track
  faculty position so that I can continue to answer questions about
  cardiac structure, function, and remodeling in disease. Work during the
  Independent Phase will develop the first finite element model of
  integrated cardiac structure and function from a rodent model of mitral
  regurgitation using data acquired from MRI tissue displacement and
  DTMRI. The relevance of this research proposal regards improving our
  understanding of mitral regurgitation, a common cause of heart failure.
  The results of this research may help elucidate important changes that
  underlie the progression from chronic mitral regurgitation to over
  heart failure and may spur the development of innovative therapies to
  aid in the treatment of this disease. (End of Abstract)

  -----------------------------------------------------------------------

Date Run: 11/30/06 **PUBLIC ABSTRACTS**

  ------------------ ------------------------------- ---------------------
  **Grant:**         1K99HL087618-01                 

  **Program          SARKAR, RITA                    
  Director:**                                        

  **Principal        MOSNIER, LAURENT OLIVIER        
  Investigator:**                                    

  **Title:**         Direct Cellular Effects of      
                     Blood Coagulation Proteases     

  **Institution:**   SCRIPPS RESEARCH INSTITUTE      LA JOLLA, CA

  **Project          2006/12/01-2007/11/30           
  Period:**                                          
  ------------------ ------------------------------- ---------------------

  -----------------------------------------------------------------------
  DESCRIPTION (provided by applicant): The major scientific goal of this
  Pathway to Independence (K99/R00) Career Development Award application
  is to understand the molecular pathophysiology of thrombotic and
  inflammatory disorders by studying novel mechanisms for cytoprotective
  actions of vitamin K-dependent coagulation proteases. This application
  focuses initially on the role of membrane receptors in the regulation
  of the cellular protein C pathway and later on the exploration of novel
  mechanisms for cytoprotective activities of coagulation proteases. The
  major career development goal of the applicant is to expand his
  technical and academic experience required for a successful transition
  into an independent investigator. These studies will provide the
  opportunity and solid basis to apply successfully for future
  independent NIH R01 funding focused on the molecular mechanistic
  studies centered on the crossroads of coagulation and inflammation.
  Novel hypotheses on the functional proteomics of cytoprotective actions
  by blood coagulation proteases will be tested using biochemical and
  cellular biology methods. The clinical and therapeutic implications of
  the proposed studies are clear from the large clinical trials, where
  activated protein C (ARC), but not other anticoagulants reduced
  mortality in severe sepsis patients and implied that the unique
  combination of APC\'s anticoagulant activity and direct activity on
  cells is the basis for APC\'s success. My published work and
  unpublished preliminary data lead directly to the proposed studies and
  provide strong support for my hypotheses. In testing these hypotheses,
  I propose: 1) To characterize the formation of endothelial cell
  membrane receptor complexes between thrombomodulin, endothelial protein
  C receptor and protease activated receptor-1 required for APC
  generation and APC\'s direct effects on cells; 2) To clarify the
  potential beneficial and detrimental functional properties of platelet
  factor 4 for APC generation and APC\'s direct effects on cells; 3) To
  identify novel themes and mechanisms for APC and fVlla cytoprotective
  actions on cells by exploration of the similarities and differences
  between APC and fVlla anti-apoptotic activities; and 4) To establish
  whether meizothrombin has anti-apoptotic activity, as predicted, and if
  this activity requires cofactor-dependent and PAR-dependent mechanisms.
  If the proposed studies are successful, they will increase our
  knowledge and may lead to improved treatment of a variety of disorders
  in which thrombosis, apoptosis and inflammation contribute to
  pathogenesis. (End of Abstract)

  -----------------------------------------------------------------------

Date Run: 11/30/06 **PUBLIC ABSTRACTS**

  ------------------ ------------------------------- ---------------------
  **Grant:**         1K99HL087621-01                 

  **Program          VARGHESE, JAMIE                 
  Director:**                                        

  **Principal        GRIFFIN, COURTNEY T             PHD
  Investigator:**                                    

  **Title:**         ATP-Dependent                   
                     Chromatin-Remodeling Complexes  
                     and Vascular Development        

  **Institution:**   UNIVERSITY OF NORTH CAROLINA    CHAPEL HILL, NC
                     CHAPEL HILL                     

  **Project          2006/12/01-2008/11/30           
  Period:**                                          
  ------------------ ------------------------------- ---------------------

  -----------------------------------------------------------------------
  DESCRIPTION (provided by applicant): ATP-dependent chromatin-remodeling
  complexes are thought to play important roles in a number of
  developmental processes. We propose to ablate the catalytic subunits of
  the three best-known classes of mammalian chromatin-remodeling
  complexes in mouse endothelium in order to understand their influence
  on vascular development. Our preliminary data indicate that at least
  one class of these complexes (SWI/SNF) is necessary for normal vascular
  development and for embryonic viability. We also propose strategies for
  identifying genomic targets of these complexes that might mediate their
  activities during vascular development. We believe these studies will
  clarify the role of epigenetics in vascular morphogenesis and will lead
  to the discovery of new genes and signaling pathways involved in
  vascular development. This Award will advance the candidate\'s goal of
  establishing an independent lab for the study of vascular development.
  The mentor\'s lab provides a rich environment for learning techniques
  necessary for the discovery of target genes of chromatin-remodeling
  complexes in the developing vasculature. The candidate will identify
  such targets in a mouse endothelial cell line during the mentored phase
  of the Award and will verify those targets in mice lacking vascular
  chromatin-remodeling complexes during the independent phase of this
  Award. Additionally, the candidate will refine techniques for the
  phenotypic analysis of SWI/SNF deficient embryonic vasculature during
  the mentored phase of this Award, which will be useful while evaluating
  embryonic vasculature deficient for the two other classes of
  chromatin-remodeling complexes during the independent phase of this
  Award. Many of the processes that occur during vascular development in
  the embryo are recapitulated when new blood vessels are formed in the
  adult. New vessel formation can be beneficial (e.g., during wound
  healing) or detrimental (e.g., during tumor growth) in the adult.
  Therefore, this project provides an important approach to defining
  genes that could lead to novel therapies to promote insufficient
  vascular growth or to disable pathogenic vascular growth. (End of
  Abstract)

  -----------------------------------------------------------------------

Date Run: 11/30/06 **PUBLIC ABSTRACTS**

  ------------------ ------------------------------- ---------------------
  **Grant:**         1K99HL087927-01                 

  **Program          COMMARATO, MICHAEL              
  Director:**                                        

  **Principal        NORTHCOTT, CARRIE A             PHD
  Investigator:**                                    

  **Title:**         Paraventricular Nucleus         
                     Signaling Mechanisms in         
                     Hypertension                    

  **Institution:**   MICHIGAN STATE UNIVERSITY       EAST LANSING, MI

  **Project          2006/12/01-2008/11/30           
  Period:**                                          
  ------------------ ------------------------------- ---------------------

  -----------------------------------------------------------------------
  DESCRIPTION (provided by applicant): My career goal is to have an
  independent research laboratory exploring the direct neuronal signaling
  pathways in the paraventricular nucleus (PVN) that influence
  hypertension. The PVN is an integrative region of the hypothalamus
  involved in the regulation of metabolic processes, stress responses,
  cardiovascular function/blood pressure regulation and the autonomic
  nervous system. The overall hypothesis is that sodium-dependent
  hypertension is associated with increased excitatory neurotransmission
  and hypertension that is the result of changes within the PVN. In part
  due to altered paracrine signaling, specifically nitric oxide (NO) and
  superoxide (O2-) interactions, influencing neurotransmitters. In
  addition, an upregulation of intracellular signaling families,
  phosphatidylinositol 3-kinase (PI3-kinase) and mitogen activated
  protein kinase (MARK), further amplifies excitatory neurotransmission
  resulting in hypertension. The goal is to use an integrative approach,
  using biochemical, gene transfer and physiological studies, to examine
  how both paracrine and intracellular signaling changes in the PVN to
  increase excitatory sympatho-adrenal function and elevate blood
  pressure. To achieve this goal 4 hypotheses will be addressed (2 during
  the mentored period and 2 during the independent portion of the grant):
  Hypothesis #1: NAD(P)H oxidase is present in the PVN and its activity
  is increased by Ang II and glutamate, thus elevating O2- levels in
  renal wrap hypertension. Hypothesis #2: In renal wrap hypertension,
  there is elevated O2- which combines with NO, reducing bioavailable NO
  and ultimately increasing sympathoadrenal function and blood pressure.
  Hypothesis #3: Ang II via the AT1 receptor and Glutamate via the NMDA
  receptor utilize common signaling pathways involving an upregulated
  PI3-kinase signaling cascade, increasing O2-, in turn, elevating
  excitatory neurotransmission in hypertension. Hypothesis #4: Enhanced
  O2- levels act as signaling molecules that lead to the activation of
  the MAPK signaling cascade in the PVN, ultimately elevating excitatory
  neurotransmission in hypertension. Identifying the changes in paracrine
  and intracellular signaling pathways is significantly important for
  understanding the impact signaling pathways have on neurotransmitter
  activity and hypertension. In addition, due to the integrative nature
  of the PVN, these data will also provide a glimpse at the role of
  signaling in other physiological conditions, such as obesity. (End of
  Abstract)

  -----------------------------------------------------------------------

Date Run: 11/30/06 **PUBLIC ABSTRACTS**

  ------------------ ------------------------------- ---------------------
  **Grant:**         1K99HL087936-01                 

  **Program          WERNER, ELLEN                   
  Director:**                                        

  **Principal        CHING-CHENG, CHEN               PHD
  Investigator:**                                    

  **Title:**         Paired lg-Like Receptor as a    
                     Regulator of Hematopoietic Stem 
                     Cell Function                   

  **Institution:**   STANFORD UNIVERSITY             STANFORD, CA

  **Project          2006/12/01-2008/11/30           
  Period:**                                          
  ------------------ ------------------------------- ---------------------

  -----------------------------------------------------------------------
  DESCRIPTION (provided by applicant): Hematopoietic stem cells (HSCs)
  are a rare population of cells in blood forming tissues that can
  self-renew and differentiate into all blood cell lineages. The
  long-term objective of the candidate is to understand the underlying
  mechanisms and regulators of HSC fate decision and survival. We propose
  to study a pair of activating and inhibitory receptors named paired
  Ig-like receptors (PIRs) that are expressed in HSC. PIR-A (activating)
  and PIR-B (inhibitory) form a novel MHC class I recognition system that
  can constitutively regulate the activation threshold in cells that
  express them. PIR is involved in the regulation of cytokine, integrin,
  and chemokine receptor signaling pathways that are crucial for HSC and
  progenitor functions. Thus we hypothesize that PIRs are major
  regulators of hematopoietic stem cell self-renewal, migration and
  survival. Our preliminary findings have demonstrated that: 1) PIR
  expression is specifically regulated among hematopoietic HSC and
  progenitor cell subsets; 2) Perturbing PIR expression, using a
  lentiviral shRNA knockdown strategy, dramatically reduces HSC
  re-engraftment capability; 3) PIR-A knockdown HSCs display selective
  reduction in responsiveness to the CXCR4 ligand SDF-1a in in vitro
  chemotaxis assays; and 4) Knocking down PIR expression in mast cell and
  HSCs greatly alters their responses to SCF and IL-3, cytokines
  important for their survival. Based on these observations, we plan
  first to investigate whether altering expression levels of PIRs or PIR
  ligands will influence HSC engraftment capacity. Then we will try to
  unravel the underlying mechanisms of how PIR regulate HSC functions.
  Lastly, we will determine the role of PIR, as the only known MHC
  recognition system expressed on HSC, in HSC engraftment resistance
  between MHC-match and allogeneic mouse strains. Elucidating the roles
  of PIRs in the regulation of HSC function will increase our
  understanding of the underlying mechanisms controlling the
  proliferation and fate of HSCs. This knowledge is important for both
  understanding hematopoietic disorders and for the therapeutic use of
  HSCs. This award will provide the candidate two years of mentored and
  three years independent research in the field of stem and mast cell
  biology. Research collaborations and resources will assist the
  candidate in the development of the skills and autonomy required to
  become a successful independent investigator. (End of Abstract)

  -----------------------------------------------------------------------

Date Run: 11/30/06 **PUBLIC ABSTRACTS**

  ------------------ ------------------------------- ---------------------
  **Grant:**         1K99HL088000-01                 

  **Program          COLOMBINI-HATCH, SANDRA         
  Director:**                                        

  **Principal        FUCHS, SEBASTIEN                MD, PHD
  Investigator:**                                    

  **Title:**         Importance of the Two Catalytic 
                     Sites of ACE in                 
                     Bleomycin-Induced Lung Injury   

  **Institution:**   EMORY UNIVERSITY                ATLANTA, GA

  **Project          2006/12/01-2008/11/30           
  Period:**                                          
  ------------------ ------------------------------- ---------------------

  -----------------------------------------------------------------------
  DESCRIPTION (provided by applicant): Project Summary. The phenotype of
  angiotensin converting enzyme (ACE) knockout mice is a complex
  combination of cardiovascular, reproductive, hematologic and renal
  defects. This diversity of abnormalities supports the idea that ACE and
  angiotensin II influence many physiologic processes beyond simple blood
  pressure control. ACE is a zinc metalloproteinase composed of two
  regions termed N- and C-terminal domains. These domains are highly
  homologous but have somewhat different properties. In particular, while
  both domains can cleave angiotensin I, the tetrapeptide AcSDKP is
  exclusively cleaved by the N domain. To investigate the in vivo roles
  of each domain, I created two new strains of mice. These mice were
  generated by homologous recombination in order to mutate the specific
  amino acids responsible for zinc binding (and thus catalysis) in each
  domain. In mice termed N-KO, the N-terminal domain of ACE is
  inactivated. In C-KO mice, it is the C-terminal domain that is no
  longer catalytic. The cardiovascular and renal phenotypes of N-KO and
  C-KO mice are indistinguishable from this of wild-type. These mouse
  models are ideal to study specific functions of ACE independent of
  blood pressure changes, a typical bias in studying the RAS with
  pharmacologic manipulations. My first aim is to complete the
  characterization of the C-KO mice. This investigation will be performed
  during the mentored phase of this grant. The next aims will be fully
  developed during the independent phase. The second aim is to
  investigate the in vivo function of the two catalytic sites of ACE in
  the progression of pulmonary fibrosis using bleomycin-induced lung
  injury as a model. My hypothesis is that ACE controls the concentration
  of both pro-fibrotic (angiotensin II) and anti-fibrotic (AcSDKP)
  molecules. My preliminary data strongly suggest that the N-KO mice are
  protected against bleomycin-induced lung injury. I find this in studies
  using both low and high doses of bleomycin. The third aim is to
  identify the mechanism responsible of this resistance. My hypothesis is
  that AcSDKP, elevated in N-KO mice, inhibits the progression of lung
  fibrosis. Relevance: This proposal will yield fundamental knowledge
  about the importance of ACE and its multiple substrates in tissue
  injury. Finally, my studies are both interesting and relevant to a
  variety of human diseases, including diseases of the lung, heart and
  kidney. (End of Abstract)

  -----------------------------------------------------------------------

Date Run: 11/30/06 **PUBLIC ABSTRACTS**

  ------------------ ------------------------------- ---------------------
  **Grant:**         1K99HL088017-01                 

  **Program          PRATT, CHARLOTTE                
  Director:**                                        

  **Principal        ROVNIAK, LIZA                   PHD
  Investigator:**                                    

  **Title:**         WalkLink: Email-Based Walking   
                     Program for Cardiovascular      
                     Disease Risk-Reduction          

  **Institution:**   SAN DIEGO STATE UNIVERSITY      SAN DIEGO, CA

  **Project          2006/12/01-2008/11/30           
  Period:**                                          
  ------------------ ------------------------------- ---------------------

  -----------------------------------------------------------------------
  DESCRIPTION (provided by applicant): RESEARCH PROJECT: About 90% of
  people who develop cardiovascular disease have prior exposure to risk
  factors that could be targeted through lifestyle interventions. E-mail
  based walking programs that promote sustainable ecological supports for
  active lifestyles hold promise for cardiovascular disease
  risk-reduction, but few such programs have been developed or evaluated
  with objective outcomes. The purpose of this study is to conduct a
  randomized controlled trial to evaluate the effects of three walking
  programs: (1) Usual Care: walking information; (2) WalkLink: 12-week
  e-mail based walking program; and (3) WalkLink+: 12-week e-mail based
  walking program with ecological supports, among 220 sedentary adults
  with risk factors for cardiovascular disease recruited through primary
  care settings. Primary specific aims include: (1) To evaluate the
  effects of the three programs on change in aerobic fitness, blood
  pressure, body composition, body mass index, and moderate and vigorous
  walking and physical activity from baseline to posttest, and at 6-month
  follow-up; (2) To evaluate the effect of selected moderator/mediator
  variables on program outcomes, including: self-management skills (e.g.,
  goal-setting, self-monitoring), social support (e.g., number of walking
  partners, social cues), and physical support (e.g., neighborhood
  walkability, physical cues). The proposed research builds upon an
  email-based walking program Dr. Rovniak previously conducted, and her
  current research in implementing ecological supports to promote AIDS
  prevention and tobacco control. CANDIDATE AND ENVIRONMENT: Liza S.
  Rovniak received her Ph.D. in Clinical Health Psychology in 2003. Her
  long-term goal is to launch an independent research career with
  emphasis on designing economically sustainable lifestyle change
  interventions to promote physical activity and reduce risk of
  cardiovascular disease. To achieve this goal, Dr. Rovniak proposes to
  complement her psychology training with population based public health
  approaches important for developing sustainable interventions through:
  (1) training at Dr. Mel Novell\'s Center for Behavioral Epidemiology
  and Community Health; (2) training at Dr. James Sallis'Active Living
  Research Center; and (3) completing an MPH at San Diego State
  University. RELEVANCE: Sustainable physical activity programs are
  urgently needed, as 70% of U.S. adults are inactive. Email-based
  walking programs could be widely disseminated to reduce risk of
  cardiovascular disease. (End of Abstract)

  -----------------------------------------------------------------------

Date Run: 11/30/06 **PUBLIC ABSTRACTS**

  ------------------ ------------------------------- ---------------------
  **Grant:**         1K99HL088021-01                 

  **Program          MONDORO, TRACI                  
  Director:**                                        

  **Principal        SORROR, MOHAMED                 MDOT (MB CHB)
  Investigator:**                                    

  **Title:**         Impact of Comorbidities on      
                     Outcomes of Allogeneic          
                     Transplantation                 

  **Institution:**   FRED HUTCHINSON CANCER RESEARCH SEATTLE, WA
                     CENTER                          

  **Project          2006/12/01-2008/11/30           
  Period:**                                          
  ------------------ ------------------------------- ---------------------

  -----------------------------------------------------------------------
  DESCRIPTION (provided by applicant): Project Summary: Allogeneic
  hematopoietic cell transplantation (HCT) is a potentially curative
  therapy for various hematological diseases. However, many patients who
  could potentially benefit from HCT have been ineligible for the
  procedure due to comorbidities and age. With the development of
  reduced-intensity regimens and improvements in supportive care after
  myeloablative HCT, increasing numbers of elderly patients and those
  with comorbidities have been offered allogeneic HCT. Dr. Sorror, and a
  collaborator, Dr. R. Diaconescu, have published the first reports
  describing the importance of comorbidities in predicting HCT outcomes.
  Dr. Sorror went on to develop a new and more sensitive tool to assess
  comorbidities specific for recipients of allogeneic HCT. The
  HCT-specific-comorbidity index (HCT-CI) has created unique
  opportunities to better understand the impact of comorbidities on HCT
  outcomes and it forms the basis for this proposal. The proposal is
  focused on further evaluating and developing the prognostic value of
  comorbidities for outcomes in HCT recipients with the eventual aim of
  creating a universally applicable comorbidity index. During the
  Mentored Phase, the reliability and validity of the HCT-CI will be
  retrospectively tested among patients transplanted at multiple centers.
  In addition, scores weighting the impact of age intervals on HCT
  outcomes will be developed to form composite scores with the HCT-CI.
  Results of these studies will guide Dr. Sorror to proceed into the
  Independent Phase, which will address two parallel major aims. First,
  the biological impact of comorbidities on causes of death, particularly
  those associated with acute graft-versus-host disease and organ
  failures, and quality of life after HCT will be assessed comparing
  scores from the HCT-CI to those from the comorbidity-aging composite
  index. This will involve both retrospective reviews of medical records
  of previously transplanted patients and analyses of prospective
  clinical trials to include larger number of patients and to ensure
  prospective reproducibility of the impacts of comorbidities. The second
  aim will prospectively investigate three different methods aimed at
  simplifying collection of comorbidity data and develop an educational
  program for evaluation of comorbidities by data registrars and,
  thereby, facilitate the more wide-spread incorporation of comorbidity
  assessment at HCT centers. Relevance: The goal of the proposal is to
  improve pretransplant prognostic assessment of survival and quality of
  life in patients with malignant and non-malignant blood disorders who
  are treated with allogeneic HCT and eventually establish a universally
  applicable comorbidity index, which will facilitate comparing results
  of clinical trials conducted at different academic centers. (End of
  Abstract)

  -----------------------------------------------------------------------

Date Run: 11/30/06 **PUBLIC ABSTRACTS**

  ------------------ ------------------------------- ---------------------
  **Grant:**         1K99HL088048-01                 

  **Program          MONDORO, TRACI                  
  Director:**                                        

  **Principal        RODRIGUEZ-PORCEL, MARTIN        MD
  Investigator:**                                    

  **Title:**         Role of Oxidative Stress in     
                     Stem Cell Differentiation and   
                     Survival                        

  **Institution:**   MAYO CLINIC COLL OF MEDICINE,   ROCHESTER, MN
                     ROCHESTER                       

  **Project          2006/12/01-2008/11/30           
  Period:**                                          
  ------------------ ------------------------------- ---------------------

  -----------------------------------------------------------------------
  DESCRIPTION (provided by applicant): Stem cell transplantation offers
  much promise as a potential treatment for myocardial salvation at the
  end stages of coronary artery disease (CAD), and much interest has been
  placed in the differentiation capacity of different population of stem
  cells. However, little is known about the regulatory mechanisms of stem
  cell differentiation in vivo, and under hostile conditions, like
  myocardial infarction. Myocardial infarction leads to changes in the
  local microenvironment and increases oxidative stress, which can
  regulate cellular differentiation and survival. The long-term goal of
  our program is to study the biology of stem cells after transplantation
  to the heart. Our primary hypothesis in this proposal is that changes
  in oxidant status play a role in stem cell differentiation and survival
  in the mycoardium. To test that hypothesis we have the following
  specific aims: in Specific Aim 1 we will differentiate bone marrow
  stromal cells into cells with myocyte characteristics, both in cell
  culture and in living subjects, and we will use molecular techniques to
  track this differentiation non-invasively, something that could be done
  until recently. For that purpose we will use reporter imaging
  technology and optical imaging. In Specific Aim 2, we will examine if
  increased oxidative stress is involved in stem cell differentiation and
  survival. For that, will be induced in cell culture and in living
  subjects (after myocardial infarction), after which stem cell
  differentiation and survival will be tracked using molecular imaging
  techniques (optical imaging). In addition, we will study pathways
  related to oxidative stress (i.e. nitric oxide), and examine their role
  in stem cell differentiation. Lastly in Specific Aim 3, we will learn
  from Aims 1 and 2 and \"genetically engineer\" stem cells so they are
  better prepared to differentiate and survive in hostile condition, like
  the one found in states of myocardial ischemia and infarction. The
  studies proposed in this grant will provide invaluable information on
  the role that the micro-environment plays in stem cell differentiation
  and survival and can lead to novel and improved therapeutic strategies.
  Stem cell therapy provides a great opportunity to re-constitute a
  damaged heart, but we first need to elucidate the mechanisms that
  regulate stem cell differentiation and survival. In this study we
  propose that specific biological pathways (i.e., oxidant status) can be
  involved in such response. Understanding these mechanisms that regulate
  stem cell survival will lead to better and improved therapies. (End of
  Abstract)

  -----------------------------------------------------------------------

Date Run: 11/30/06 **PUBLIC ABSTRACTS**

  ------------------ ------------------------------- ---------------------
  **Grant:**         1K99HL088317-01                 

  **Program          VARGHESE, JAMIE                 
  Director:**                                        

  **Principal        ARJUN, DEB                      
  Investigator:**                                    

  **Title:**         Role of Sfrp2 in Cardiac        
                     Regeneration                    

  **Institution:**   DUKE UNIVERSITY                 DURHAM, NC

  **Project          2006/12/01-2008/11/30           
  Period:**                                          
  ------------------ ------------------------------- ---------------------

  -----------------------------------------------------------------------
  DESCRIPTION (provided by applicant): The static view of the heart as a
  terminally differentiated organ incapable of any regeneration has
  undergone considerable change with the discovery of multipotent cardiac
  progenitor cells (CPCs) residing within the heart. However despite
  their existence, it is apparent that the regenerative ability of
  resident cardiac progenitors is not sufficient to regenerate myocardium
  and prevent ventricular dysfunction after myocardial infarction. The
  signals regulating differentiation of resident CPCs are currently
  unclear. The long-term goals of the project are to identify and
  understand factors that determine myogenic differentiation of resident
  CPCs after myocardial injury. We show here that secreted frizzled
  related protein 2 (Sfrp2), a Wnt modulator, inhibits cardiomyogenic
  differentiation of P19CL6 cells, a murine embryonal cell line, well
  studied for mammalian myogenesis. We demonstrate that resident CPCs
  express Sfrp2 and cardiomyocytes increase Sfrp2 expression following
  hypoxic injury. We have thus hypothesized that Sfrp2 in an autocrine or
  paracrine fashion inhibits differentiation of resident CPCs. The
  specific aims include: 1) Determining the effects of Sfrp2 on myogenic
  differentiation of CPCs, 2) Determining whether alteration of Sfrp2
  expression in CPCs or in the heart after myocardial injury affects
  myocardial regeneration, and 3) Determining whether Sfrp2 modulates
  canonical Wnt signaling in mediating its effects on differentiation of
  CPCs. We have isolated CPCs from the adult mouse heart and will
  initially determine the effects of Sfrp2 on myogenic differentiation of
  these cells in vitro. Subsequently, we will use RNA interference
  techniques to alter Sfrp2 expression on isolated CPCs as well as in the
  heart following injury to elucidate the role of Sfrp2 in regulating
  myogenesis in vivo. Finally, we will use molecular and biochemical
  assays to interrogate the effects of Sfrp2 on canonical Wnt signaling
  in CPCs. The candidate wishes to work on cardiac regeneration as a long
  term goal; this project thus serves as an ideal platform to transition
  to independence. Duke University Medical Center provides a rich
  collaborative and integrated environment for training of
  physician-scientists. Relevance: Owing to the limited regenerative
  capacity of the heart, heart disease often results in dreaded sequelae
  of congestive heart failure. This proposal aims to determine how stem
  cells within the heart can be coaxed to form new heart muscle and could
  lead to the design of novel regenerative therapies of heart disease.
  (End of Abstract)

  -----------------------------------------------------------------------

Date Run: 11/30/06 **PUBLIC ABSTRACTS**

  ------------------ ------------------------------- ---------------------
  **Grant:**         1K99HL088514-01                 

  **Program          VARGHESE, JAMIE                 
  Director:**                                        

  **Principal        KONTARIDIS, MARIA IRENE         PHD
  Investigator:**                                    

  **Title:**         Molecular Pathogenesis of the   
                     Cardiomyogenic Defects in       
                     LEOPARD Syndrome                

  **Institution:**   BETH ISRAEL DEACONESS MEDICAL   BOSTON, MA
                     CENTER                          

  **Project          2006/12/01-2008/11/30           
  Period:**                                          
  ------------------ ------------------------------- ---------------------

  -----------------------------------------------------------------------
  DESCRIPTION (provided by applicant): SUMMARY: Recently, mutations in
  the SH2 domain-containing protein tyrosine phosphatase Shp2, have been
  implicated in cardiac disease. Shp2 was identified as the gene mutated
  in approximately 50% of cases of Noonan Syndrome (NS) and all cases of
  LEOPARD Syndrome (LS). NS and LS share several clinical features,
  including congenital heart defects, and, as such, were viewed as
  overlap syndromes. However, LS is NOT a disease variant of NS;
  LS-associated mutations in Shp2 are catalytically inactive and behave
  as dominant negatives, whereas Shp2 mutations in NS are catalytically
  hyperactive. This proposes a model in which LS mutations are
  loss-of-function and NS mutations are gain-of-function. Moreover, most
  LS patients develop a hypertrophic cardiomyopathy (HCM), which is
  unique to LS; few NS patients with Shp2 mutations develop HCM. The
  central hypothesis, therefore, is that biochemical differences between
  these two syndromic disorders give rise to distinct cardiac defects.
  This proposal will define the mechanism(s) by which Shp2 LS mutants
  interfere with positive signaling events upstream and/or downstream of
  Ras in the Erk/MAPK pathway, will determine the signaling pathways that
  are aberrantly regulated by LS in the heart, will identify the
  developmental interval in which Shp2 is required during cardiogenesis,
  and will generate and functionally analyze a murine model of LS.
  CANDIDATE: Maria Kontaridis will receive advanced training in the field
  of cardiology and will further develop skills in molecular and
  developmental biology, biochemistry, and mouse genetics during the
  mentored phase of this award. Benjamin Neel, her sponsor, is an expert
  in Shp2 and mouse genetics. Her advisory panel (Drs. Jonathan Seidman,
  Jeffrey Saffitz, Lewis Cantley and James Chang), all experts in cardiac
  development/pathophysiology and/or signal transduction, will contribute
  substantially to her training and career development. Long-term, she
  plans to become an independent research scientist at an academic
  institution and to direct her own lab in cardiac development, with an
  emphasis on the signaling mechanisms (and mutations therein) that lead
  to congenital heart disease. RELEVANCE: This work will further define
  the mechanisms by which genetic mutations lead to cardiac disease.
  These findings will advance our knowledge of cardiac function and
  pathogenesis through better understanding of the fundamental signaling
  mechanisms that mediate these processes. (End of Abstract)

  -----------------------------------------------------------------------

Date Run: 11/30/06 **PUBLIC ABSTRACTS**

  ------------------ ------------------------------- ---------------------
  **Grant:**         1K99HL088528-01                 

  **Program          COMMARATO, MICHAEL              
  Director:**                                        

  **Principal        TEMEL, RYAN E                   PHD
  Investigator:**                                    

  **Title:**         Mechanisms For PPARdelta        
                     Agonist-Induced Elevation of    
                     HDL in Non-Human Primates       

  **Institution:**   WAKE FOREST UNIVERSITY HEALTH   WINSTON-SALEM, NC
                     SCIENCES                        

  **Project          2006/12/01-2008/11/30           
  Period:**                                          
  ------------------ ------------------------------- ---------------------

  -----------------------------------------------------------------------
  DESCRIPTION (provided by applicant): Reduction of LDL-cholesterol
  through the use of statins has been shown to significantly decrease the
  rate of mortality and morbidity caused by coronary heart disease (CHD).
  Nevertheless, CHD remains the leading cause of death for men and women
  in the United States. One reason for the persistence of CHD may be the
  lack of therapies that increase HDL-cholesterol (HDL-C). It is well
  established that HDL-C concentration is a strong, independent,
  inversely related risk factor for CHD. Because of data indicating that
  a 1 mg/dl increase in HDL-C decreases CHD risk by 2-3%, many
  pharmaceutical companies are attempting to develop therapies that will
  effectively elevate HDL-C levels. One class of compounds that may have
  great therapeutic potential are PPAR-delta agonists, which in non-human
  primates can elevate HDL-C by 43-79% and apoA-l, the major
  apolipoprotein of HDL, by 43%. In this application, we propose to
  define the mechanisms by which PPAR-delta agonists induce HDL-C
  elevation in non-human primates. For the mentored research phase, we
  will determine whether PPAR-delta agonists increase HDL-C by: 1)
  altering HDL production or catabolism; 2) changing the activity of
  plasma lipases, lipid transfer proteins, and LCAT; 3) modulating the
  mRNA and protein expression of genes involved in HDL metabolism. For
  the independent research phase, we propose to determine whether
  PPAR-delta agonists elevate HDL-C in monkeys that have been treated
  with antisense oligonucleotides (ASOs) that suppress hepatic expression
  of PPAR-delta. We feel confident that these studies will provide
  insights for the development of more-potent PPAR-delta agonists or
  other therapies that effectively increase HDL-C, which in turn could
  prevent CHD in hundreds of thousands of people each year in the United
  States and around the world. Scientific data indicates that increasing
  HDL cholesterol may decrease the risk of heart disease, the leading
  cause of death for men and women in the United States. We propose to
  determine the mechanisms by which a new class of drugs, known as PPAR
  delta agonists, increase HDL-cholesterol in monkeys. Because of the
  high degree of similarity between the bodies of humans and monkeys, we
  feel confident that these studies will provide insights for the
  development of therapies that could increase HDL and prevent the deaths
  of hundreds of thousands of people each year from heart disease. (End
  of Abstract)

  -----------------------------------------------------------------------

Date Run: 11/30/06 **PUBLIC ABSTRACTS**

  ------------------ ------------------------------- ---------------------
  **Grant:**         1K99HL088692-01                 

  **Program          SARKAR, RITA                    
  Director:**                                        

  **Principal        BRUNETTI-PIERRI, NICOLA         MD
  Investigator:**                                    

  **Title:**         HDAd-mediated gene therapy for  
                     hemophilia B                    

  **Institution:**   BAYLOR COLLEGE OF MEDICINE      HOUSTON, TX

  **Project          2006/12/01-2008/11/30           
  Period:**                                          
  ------------------ ------------------------------- ---------------------

  -----------------------------------------------------------------------
  DESCRIPTION (provided by applicant): HDAd are attractive gene therapy
  vectors that can mediate long-term, high level FIX expression from
  transduced hepatocytes leading to sustained phenotypic correction of
  FIX-deficiency in mice and dogs with no chronic toxicity. However,
  systemic high dose administration, required for efficient hepatic
  transduction, results in activation of an acute inflammatory response
  with potentially severe and lethal consequences. The mechanism
  responsible for Ad-mediated activation of the acute inflammatory
  response is not known, however, it is clearly dose-dependent. We have
  developed an in vivo gene therapy delivery approach for HDAd which has
  proven to be very successful in a large animal model. This method
  entails the use of balloon occlusion catheters to deliver HDAd
  preferentially to the liver of nonhuman primates. During the mentored
  phase, I propose to complete the nonhuman primate studies already
  initiated to establish dose-response relationship and vector
  biodistribution following vector delivery with this novel method. In
  Specific Aim 1, I will investigate the dose-response relationship
  ranging from 1x1010 to 1x1011 vp/kg of HDAd expressing baboon
  (-fetoprotein (bAFP) under the control of a liver specific promoter. In
  Specific Aim 2, I will investigate the biodistribution of HDAd vector
  delivered through balloon catheter-assisted delivery in nonhuman
  primates and to carry out formal toxicity studies, both performed under
  conditions to satisfy the requirements of the FDA for a phase I
  clinical trial. In the independent phase, I propose to investigate
  safety and efficacy of the balloon catheter-assisted delivery of HDAd
  into the clinically relevant animal model of hemophilia B. The proposed
  experiments are designed to generate the data necessary to progress
  towards human clinical trials for the treatment of hemophilia B
  (Specific Aim 3). In Specific Aim 4, I will investigate HDAd expressing
  genetically engineered FIX molecules with greater catalytic activity.
  This strategy is specifically designed to achieve therapeutic FIX
  levels using low vector doses. If superior, these catalytically
  enhanced FIX molecules will not only increase the safety and efficacy
  of HDAd-mediated hemophilia B gene therapy, but will also be valuable
  for other vector systems as well as for recombinant protein replacement
  therapy. During the independent phase I also propose to investigate, in
  nonhuman primates, the efficacy and safety of liver-directed gene
  therapy using naked plasmid DNA vector (pDNA) delivered through the
  balloon catheter-assisted delivery (Specific Aim 5).

  -----------------------------------------------------------------------

Date Run: 11/30/06 **PUBLIC ABSTRACTS**

  ------------------ ------------------------------- ---------------------
  **Grant:**         1K99MD002271-01                 

  **Program          HUNTER, DELORIS                 
  Director:**                                        

  **Principal        CARSWELL, STEVEN BERNARD        PHD
  Investigator:**                                    

  **Title:**         Risk Factors for HIV Among      
                     Urban African American Youth    

  **Institution:**   FRIENDS RESEARCH INSTITUTE,     BALTIMORE, MD
                     INC.                            

  **Project          2006/12/01-2008/11/30           
  Period:**                                          
  ------------------ ------------------------------- ---------------------

  -----------------------------------------------------------------------
  DESCRIPTION (provided by applicant): The candidate is a sociologist,
  and a former recipient of a Minority Investigator Award from NIDA, with
  knowledge and experience regarding community and environmental factors
  and their relationship to youth involvement in health-compromising
  behaviors in urban areas. The Social Research Center (SRC), where the
  candidate is currently employed as a research scientist, is the
  research campus of Friends Research Institute (FRI), a private
  non-profit institution established in 1955. The Center promotes
  pre-doctoral training experiences designed to facilitate careers in
  behavioral, public health, and public policy research, providing
  entry-level positions for talented graduate and undergraduate students
  in the behavioral sciences. The candidate\'s long-term career objective
  is to become an independent investigator. He would like to focus his
  professional career on developing and testing intervention models that
  place urban African American youth and adults at-risk for HIV/AIDS. The
  candidate proposes to be mentored by his primary sponsor Dr. Jeannette
  Johnson, a Native American, cross-cultural psychologist, who has
  extensive prevention research knowledge and expertise regarding
  individual, social, and cultural risk and protective factors associated
  with HIV/AIDS in minority communities. During the mentored phase, he
  also proposes to take courses regarding HIV/AIDS at the Bloomberg
  School of Public Health at John\'s Hopkins University and attend NIH
  and other HIV/AIDS related conferences. The primary aim of the proposed
  three-year cross-sectional study is to examine the extent to which
  specific risk and protective factors predict both perceptions of HIV
  risk and participation in risky sexual behavior among high-risk African
  American youth. These youth, currently attending Baltimore City
  Alternative Learning Centers (BCALC), have been expelled from
  traditional public schools for committing violent acts or for engaging
  in other serious infractions, with many engaging in risky sexual
  behavior. Half of the participants will be assessed the first project
  year and the remainder assessed in the second year. Participants will
  be 200 male and female students, between the ages of 11 and 17 randomly
  selected from two BCALC school sites. Assessment data will be collected
  from January through May during each of the two data collection years.
  The research study proposed has the potential to provide a greater
  understanding of issues related to perceptions of HIV risk and
  participation in risky sexual behaviors among high-risk urban African
  American youth. Findings from the study will be of significance to the
  field of public health by filling important knowledge gaps in terms of
  risk for HIV infection among such youth.

  -----------------------------------------------------------------------

Date Run: 11/30/06 **PUBLIC ABSTRACTS**

  ------------------ ------------------------------- ---------------------
  **Grant:**         1K99MH080599-01                 

  **Program          DESMOND, NANCY L                
  Director:**                                        

  **Principal        YE, BING                        PHD NEUROSCIENCE
  Investigator:**                                    

  **Title:**         Mechanisms Differentiating      
                     Dendrite Development form Axon  
                     Development                     

  **Institution:**   UNIVERSITY OF CALIFORNIA SAN    SAN FRANCISCO, CA
                     FRANCISCO                       

  **Project          2006/09/25-2008/08/31           
  Period:**                                          
  ------------------ ------------------------------- ---------------------

  -----------------------------------------------------------------------
  DESCRIPTION (provided by applicant): My career goal is to understand
  the mechanisms of neuronal compartmentalization and how this process
  contributes to nervous system function and to the pathogenesis of
  neurological disorders. I will pursue this goal by working in an
  academic institution as an independent investigator. During my
  postdoctoral training in the laboratory of Dr. Yuh Nung Jan at UCSF, I
  have been using Drosophila PNS neurons as a model system to study the
  mechanisms that differentiate the development of dendrite from axon,
  two major compartments of a neuron. This training complements my
  doctoral training in vertebrate neurobiology. I plan to combine the
  strength of Drosophila (in vivo and superb genetics) and cultured rat
  hippocampal neurons (well- characterized cell biology) to study
  neuronal compartmentalization. The objective of this research is to
  examine the roles of the secretory pathway in differentiating dendrite
  and axon development. From a genetic screen in Drosophila, we isolated
  several mutants (dar mutants) with reduced dendritic arbors but normal
  axons. Dar2, 3, and 6 regulate the secretory pathway, suggesting that
  this pathway differentiates dendritic and axonal growth. I propose two
  aims. First, I will determine cell biological mechanisms through which
  the secretory pathway differentially controls dendritic and axonal
  growth. New techniques will be developed to complement existing ones to
  identify such mechanisms. Membrane traffic through the secretory
  pathway will be monitored in live wild-type and mutant Drosophila
  embryos/larvae and cultured hippocampal neurons. Second, I will
  identify and characterize genes that control the differential
  development of dendrites and axons by regulating key players of the
  secretory pathway. Dar7 (genetically interacts with dar2 and 3), darl
  (genetic interaction untested), and Trailer Hitch (regulates the
  secretory pathway) will be studied. Their mammalian homologs will be
  examined in cultured neurons to determine if the mechanisms are
  conserved in mammals. This research will provide much-needed
  information for understanding the causes of neurological disorders
  characterized by preferential damage to dendrites (e.g., Rett\'s
  syndrome) or by defective Golgi function (e.g., amyotrophic lateral
  sclerosis). Such information will also allow the design of therapeutic
  approaches.

  -----------------------------------------------------------------------

Date Run: 11/30/06 **PUBLIC ABSTRACTS**

  ------------------ ------------------------------- ---------------------
  **Grant:**         1K99NS057906-01                 

  **Program          MAMOUNAS, LAURA                 
  Director:**                                        

  **Principal        CUI, BIANXIAO                   
  Investigator:**                                    

  **Title:**         Imaging nerve growth factor     
                     signal transduction in live     
                     neurons                         

  **Institution:**   STANFORD UNIVERSITY             STANFORD, CA

  **Project          2006/12/01-2008/11/30           
  Period:**                                          
  ------------------ ------------------------------- ---------------------

  -----------------------------------------------------------------------
  DESCRIPTION (provided by applicant): Our broad objective is to
  understand the mechanisms by which the nerve growth factor (NGF) signal
  is propagated from the axon terminal to the cell body. NGF retrograde
  signaling is critical for the survival, differentiation, and
  maintenance of certain types neurons. Disrupted NGF retrograde
  transport was reported to contribute to the loss of the basal forebrain
  cholinergic (BFC) neurons in the brains of patients with Alzheimer\'s
  Disease or Down\'s Syndrome. This project will use advanced imaging
  techniques to directly visualize NGF transport in live neurons in real
  time. We focus on exploring dynamic features of NGF transport in normal
  and Down\'s Syndrome mice. The aims are: 1. Characterize the movement
  of NGF-containing endosomes in axons and define their pausing
  mechanism(s), by using quantum dot conjugated NGF to track endosomal
  movements with nanometer resolution. 2. Determine whether NGF-lacking
  endosomes are present, whether they are relevant for NGF signaling, and
  whether there are alternative signaling pathways independent of
  endosomal transport, by marking the NGF-lacking endosomes with
  photo-activatable green fluorescence proteins that are fused to the
  C-terminal of TrkA receptor. 3. Identify the abnormal features of
  disrupted NGF transport in Down Syndrome mouse neurons, by
  characterizing individual features of transport dynamics, which include
  the average speed, the moving speed, the pausing duration, and the
  pausing frequency. 4. Determine how amyloid precursor protein
  overexpression leads to the abnormal NGF retrograde transport in Down
  Syndrome mouse by examining how overexpression of amyloid precursor
  protein in DS mice might cause defective structural or axonal features
  that lead to disrupted NGF transport. Achieving those aims will
  increase our understanding of how NGF signal is propagated in normal
  and degenerative neurons. More broadly, those studies will contribute
  to elucidate the pathogenesis of Alzheimer\'s disease and Down
  syndrome.

  -----------------------------------------------------------------------

Date Run: 11/30/06 **PUBLIC ABSTRACTS**

  ------------------ ------------------------------- ---------------------
  **Grant:**         1K99NS057931-01                 

  **Program          TALLEY, EDMUND M                
  Director:**                                        

  **Principal        COLON-RAMOS, DANIEL A           PHD
  Investigator:**                                    

  **Title:**         Synaptic target selection in    
                     the thermotaxis neural circuit  
                     of C. elegans                   

  **Institution:**   STANFORD UNIVERSITY             STANFORD, CA

  **Project          2006/12/01-2008/11/30           
  Period:**                                          
  ------------------ ------------------------------- ---------------------

  -----------------------------------------------------------------------
  DESCRIPTION (provided by applicant): The human brain consists of
  approximately 100 billion neurons, which form over 100 trillion
  synapses with specific targets. How neurons find the correct targets
  and how the correct wiring of the brain influences behavior are central
  questions, and the focus of this proposal. The nematode C. elegans
  offers an excellent model system to explore how synaptic specificity is
  achieved in vivo, and how correct synaptic choices influence the
  formation of neuronal circuits, and behavior. AIY, an important
  interneuron in the C. elegans brain, receives inputs from multiple
  sensory neurons to modulate behaviors such as thermotaxis, chemotaxis
  and learning. During development AIY contacts many neurites, but
  selects only three neurons (RIA, RIB and AIZ) as its postsynaptic
  partners. The molecular mechanisms used by AIY to discriminate between
  potential targets and form functional neuronal circuits are not
  understood. Here I propose to characterize how synaptogenesis is
  regulated in the complex environment of the C. elegans brain by
  studying synaptic formation in the thermotaxis neural circuit. A visual
  forward genetic screen on AIY synapses has yielded multiple mutants
  with abnormal synaptic patterns. I will identify AIY synaptic
  specificity molecules by characterizing these mutants. Initial
  characterization of one class of mutants indicates that immunoglobulin
  superfamily protein UNC-40/DCC directs AIY synaptogenesis in a cell
  autonomous manner. In unc-40 mutant, AIY exhibits normal axon
  trajectory with abnormal presynaptic locations. UNC-40 localizes to AIY
  presynaptic sites in wild type animals. Furthermore, mislocalization of
  UNC-40 leads to ectopic presynaptic terminal formation at the location
  of mislocalized UNC-40. Further experiments will identify the mechanism
  by which unc-40 directs synaptic target selection in AIY. Future
  characterization of mutants with similar AIY phenotype as unc-40 will
  determine the molecular signaling pathway that leads to correct AIY
  synaptogenesis. Together our work promises to lend us insights into the
  molecular components that direct correct synaptogenesis in the C.
  elegans brain. Altered synaptogenesis might lead to a number of
  neurodevelopmental disorders and human diseases such as schizophrenia
  and autism. Understanding correct synaptogenesis should provide
  insights into how functional neuronal circuits are constructed during
  development and how the correct formation of these circuits affects
  behavior.

  -----------------------------------------------------------------------

Date Run: 11/30/06 **PUBLIC ABSTRACTS**

  ------------------ ------------------------------- ---------------------
  **Grant:**         1K99NS057934-01                 

  **Program          GWINN-HARDY, KATRINA            
  Director:**                                        

  **Principal        ROLL-MECAK, ANTONINA            PHD
  Investigator:**                                    

  **Title:**         Elucidation of the Biochemical  
                     Mechanism and In Vivo Functions 
                     of Spastin                      

  **Institution:**   UNIVERSITY OF CALIFORNIA SAN    SAN FRANCISCO, CA
                     FRANCISCO                       

  **Project          2006/12/01-2008/11/30           
  Period:**                                          
  ------------------ ------------------------------- ---------------------

  -----------------------------------------------------------------------
  DESCRIPTION (provided by applicant): The objective of this award is to
  complete my training and to establish a highly interdisciplinary lab at
  an academic institution in the U.S., focused on the study of the
  mechanism of cytoskeletal regulators. My lab will take a comprehensive,
  multifaceted approach by linking atomic resolution structural
  information with single molecule dynamics in vitro and in the larger
  context of the cell. The research focus of this award is to dissect the
  biochemical and cellular mechanisms of spastin. Mutations in the
  spastin gene are the leading cause of hereditary spastic paraplegias, a
  group of poorly understood neurodegenerative disorders characterized by
  axonopathy. I have discovered that spastin severs microtubules
  (Roll-Mecak and Vale, 2005). Disease mutations impair severing, linking
  spastin\'s remodeling of the microtubule cytoskeleton to
  neurodegeneration. The research plan outlined here is highly
  interdisciplinary, integrating techniques and concepts from structural
  biology, biophysics and cell biology to answer three fundamental
  questions about spastin function: 1) What is spastin\'s atomic
  structure throughout its ATPase cycle and how does it bind and break
  the microtubule; 2) How does it use the energy of ATP hydrolysis to
  disassemble the microtubule; and 3) How does spastin affect microtubule
  architecture and dynamics in the living cell and what are the cellular
  consequences incurred when spastin is depleted or mutated ? Despite its
  importance for neuronal survival very little is known about spastin. A
  detailed understanding of its mechanism and basic cell biology are
  critical to understanding the causes of the disease and this proposal
  sets the fundamental mechanistic groundwork that is needed to develop
  therapies further down the road. Perturbation of microtubule dynamics
  and architecture has emerged as a common theme in a variety of
  neurodegenerative diseases and an understanding of spastin\'s effects
  will have implications for the etiologies of all these disorders. Lay
  Summary: The goal of this research is to understand the function of an
  enzyme, spastin, that is defective in the majority of patients with
  hereditary spastic paraplegias, a group of poorly understood
  neurodegenerative disorders. I discovered that spastin breaks a central
  component of the cell\'s skeleton. This research will provide the basic
  groundwork needed for the development of treatments for this group of
  disorders and also increase our understanding of other
  neurodegenerative disorders.

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Date Run: 11/30/06 **PUBLIC ABSTRACTS**

  ------------------ ------------------------------- ---------------------
  **Grant:**         1K99NS058111-01                 

  **Program          MURPHY, DIANE                   
  Director:**                                        

  **Principal        WEST, ANDREW B                  PHD
  Investigator:**                                    

  **Title:**         The Role of LRRK2 in the        
                     Pathogenesis of Parkinson\'s    
                     Disease                         

  **Institution:**   JOHNS HOPKINS UNIVERSITY        BALTIMORE, MD

  **Project          2006/12/01-2008/11/30           
  Period:**                                          
  ------------------ ------------------------------- ---------------------

  -----------------------------------------------------------------------
  DESCRIPTION (provided by applicant): Parkinson\'s disease (PD) is a
  common progressive neurodegenerative disorder. Current therapeutic
  approaches initially alleviate symptoms but eventually cause
  deleterious side effects and fail to halt disease progression. A
  significant genetic component to disease was recently identified as
  mutations in the leucine- rich repeat kinase 2 gene (LRRK2). LRRK2
  mutations cause a highly-penetrant dominant disease phenotype
  indistinguishable from typical PD. Preliminary data suggest that LRRK2
  mutations perturb the normal enzymatic activity of LRRK2 by increasing
  kinase activity. Such increases in kinase activity are associated with
  neurotoxicity. The mentored phase of this proposal dissects LRRK2
  toxicity using a combination of approaches including inducible gene
  expression, RNA interference, and viral-delivery of mutant LRRK to
  primary neurons. The goal is to define LRRK2-mediated kinase dependent
  cell death cascades. Complementary to understanding the role of LRRK2
  in health and disease will be the identification of LRRK2 kinase
  substrates in relevant cells. As the first of two independent phase
  projects, LRRK2 kinase substrates will be identified using a
  combination of novel technologies to assess the complete set of LRRK2
  interacting proteins in an unbiased manner. The functional impact of
  LRRK2 mediated kinase activity on protein substrates will be evaluated,
  particularly in existing and emerging models of PD. Finally, the second
  independent phase aim utilizes the tools and techniques developed in
  this proposal to perform high-throughput screening to identify
  small-molecule LRRK2 kinase inhibitors. Small molecule inhibitors will
  be used to definitively assess the role of LRRK2 kinase activity in
  causing neurotoxicity. LRRK2 may represent a far upstream element in
  the pathogenesis of PD. Through the understanding of LRRK2, other genes
  involved in PD may fall into a common biochemical pathway where disease
  intervention is possible. Mutations in the leucine-rich repeat kinase 2
  (LRRK2) gene are a common cause of Parkinson\'s disease. This proposal
  explores the role of LRRK2 in neurodegeneration with a focus on
  identifying pathways and drugs to intervene in the disease process.

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Date Run: 11/30/06 **PUBLIC ABSTRACTS**

  ------------------ ------------------------------- ---------------------
  **Grant:**         1K99RR024110-01                 

  **Program          CHANG, MICHAEL                  
  Director:**                                        

  **Principal        BHALLA, NEEDHI                  PHD
  Investigator:**                                    

  **Title:**         Characterization of the Synapis 
                     Checkpoint in C. elegans        
                     Meiosis                         

  **Institution:**   UNIVERSITY OF CALIFORNIA        BERKELEY, CA
                     BERKELEY                        

  **Project          2006/12/01-2008/11/30           
  Period:**                                          
  ------------------ ------------------------------- ---------------------

  -----------------------------------------------------------------------
  DESCRIPTION (provided by applicant): Meiosis generates haploid gametes
  from a diploid cell such that a diploid genome is restored upon
  fertilization. The proper segregation of chromosomes during the meiotic
  divisions depends on events in meiotic prophase, such as the pairing
  and synapsis of homologous chromosomes and crossover recombination.
  Errors in chromosome segregation are usually fatal to the fertilized
  zygote but can also result in cancer predisposition or serious
  developmental disorders. I have identified a meiotic checkpoint that
  responds to defects in homolog synapsis, independent of a DNA
  damage/recombination checkpoint, and activates apoptosis to avoid the
  generation of aneuploid gametes. Not all unsynapsed sequences have the
  capacity to trigger this checkpoint; rather, this pathway is
  specifically activated by unsynapsed pairing centers (PCs), chromosome
  sites that promote synapsis in C. elegans. Furthermore, the checkpoint
  requires the C. elegans homolog of PCH-2, a budding yeast pachytene
  checkpoint gene, suggesting that the molecular mechanism that detects
  synaptic failure is widely conserved. I plan to further characterize
  this synapsis checkpoint. I am particularly interested in the PC\'s
  contribution to synapsis checkpoint activation. The identification and
  characterization of proteins that interact with factors required for PC
  function will provide insight into how this locus activates the
  checkpoint when unsynapsed. Studies that address the regulation of
  heterochromatin on unsynapsed chromosomes and how the PC may inhibit
  the DNA damage checkpoint will also be undertaken. I will determine the
  role of the synaptonemal complex (SC) in the synapsis checkpoint by
  characterizing two genes that interact with the SC and appear to be
  required for the checkpoint by preliminary RNA inteferference (RNAi)
  experiments. I will investigate the function and regulation of the
  known checkpoint component, pch-2; a GFP-PCH-2 fusion protein will be
  localized in a variety of genetic backgrounds and a reagent will be
  provided to identify interacting proteins biochemically. Furthermore, I
  will identify additional components of the checkpoint by undertaking an
  RNAi screen that will focus on candidate genes that fulfill specific
  expression and phenotypic profile criteria. These complementary
  approaches will enable me to gain a molecular and mechanistic
  understanding of how homolog synapsis is monitored and how an
  unsynapsed or inappropriately synapsed homolog generates a checkpoint
  signal that is ultimately translated into an apoptotic response.
  Meiosis produces gametes, such as eggs and sperm. Checkpoints monitor
  meiotic events to ensure that gametes have the correct number of
  chromosomes. If a gamete has an incorrect number of chromosomes, the
  embryo that results from fertilization is often inviable. Occasionally,
  an embryo inherits an extra chromosome that is not lethal but can cause
  cancer predisposition or serious developmental defects.

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Date Run: 11/30/06 **PUBLIC ABSTRACTS**

  ------------------ ------------------------------- ---------------------
  **Grant:**         1K99RR024119-01                 

  **Program          CHANG, MICHAEL                  
  Director:**                                        

  **Principal        LIN, FANG                       PHD PHARMACOLOGY &
  Investigator:**                                    PHYSIOLOGY

  **Title:**         G-protein Signaling in          
                     Zebrafish Primordial Germ Cell  
                     Migration                       

  **Institution:**   VANDERBILT UNIVERSITY           NASHVILLE, TN

  **Project          2006/12/01-2008/11/30           
  Period:**                                          
  ------------------ ------------------------------- ---------------------

  -----------------------------------------------------------------------
  DESCRIPTION (provided by applicant): Diverse cell movements during
  animal development contribute significantly to the establishment and
  maintenance of normal body plan and organogenesis. G protein signaling
  is one of many molecular genetic mechanisms that control these
  processes. Previously I showed that Ga12/13 is required for distinct
  cell behaviors that drive zebrafish gastrulation. In the mentored
  phase, I will work under supervision of Drs. Lila Solnica-Krezel and
  Heidi Hamm to continue characterizing the cell behaviors mediated by
  Ga12/13 signaling to identify the downstream and upstream regulators of
  Ga12/13 during gastrulation. These studies will provide new insights
  into the molecular mechanism by which Ga12/13 modulate cell movements
  during embryogenesis. Knowledge and crucial techniques obtained during
  this period will provide me a solid foundation to launch my own
  independent research as proposed below. I have recently discovered that
  G protein signaling is also involved in migration of the progenitors of
  the gametes, primordial germ cells (PGCs). As in many other organisms,
  PGCs in zebrafish migrate from the position where they are specified
  toward the region where the gonad develops. It has been shown that this
  migration is governed by a chemokine G protein-coupled receptor,
  CXCR4b, and its ligand, SDF1a. However, whether signaling proceeds
  through Ga? or Ga subunits, and their downstream effectors that are
  involved in PGC migration remain largely unknown. My preliminary
  results indicated that Ga?, Ga12/13 and probably Gaq are involved in
  the PGC movements. I hypothesize that PGC migration in zebrafish is
  mediated by diverse G protein signaling pathways probably through
  multiple receptors. I will employ a combination of genetic, cellular,
  pharmacological and biochemical approaches to test this hypothesis. In
  aim 1, I will characterize Ga? function in PGC migration, and test my
  hypothesis that Ga? transmit the SDF1a/CXCR4 signal. I will also
  identify the downstream effectors of Ga? that are required for PGC
  migration. In aim 2, I will determine the roles of Ga subunits during
  PGC migration and investigate the involvement of cell adhesion and RhoA
  in this process. Based on my findings that multiple G proteins may be
  involved in PGC migration, my aim 3 is to identify G protein coupled
  receptors other than Cxcr4b that regulate PGC migration, which may
  uncover unknown signaling pathways that control PGC migration. Given
  that the signaling pathways of cell migration are conserved during
  embryogenesis, immune response, and cancer cell metastasis, our study
  using an in vivo model with a vertebrate body plan will provide new
  insights into cell movement behaviors in normal development and
  disease.

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