ABSTRACTS OF K99/R00 PATHWAY TO INDEPENDENCE AWARDS
Date Run: 11/30/06 PUBLIC ABSTRACTS
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Grant: |
1K99AA016731-01 |
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Program Director: |
GRANDISON, LINDSEY |
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Principal Investigator: |
SABINO, VALENTINA |
PHD |
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Title: |
Role of sigma receptors in ethanol reinforcement |
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Institution: |
SCRIPPS RESEARCH INSTITUTE |
LA JOLLA, CA |
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Project Period: |
2006/12/01-2008/11/30 |
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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of excess ethanol intake will be studied in Specific Aims 1 and 3 -- genetically selected alcohol-preferring rats and withdrawn outbred rats made dependent during chronic, intermittent exposure to ethanol vapor, emphasizing positive and negative reinforcing properties of ethanol,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 |
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Program Director: |
BUCKHOLTZ, NEIL |
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Principal Investigator: |
TOWN, TERRENCE C |
PHD |
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Title: |
Blocking TGF-Beta immune signaling as a therapeutic target for Alzheimer's diseas |
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Institution: |
YALE UNIVERSITY |
NEW HAVEN, CT |
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Project Period: |
2006/12/01-2007/11/30 |
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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 |
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Program Director: |
KOHANSKI, RONALD |
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Principal Investigator: |
ROSSI, DERRICK J. |
PHD |
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Title: |
Stem Cell Aging: Functional Decline, DNA damage and Therapeutic Targets |
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Institution: |
STANFORD UNIVERSITY |
STANFORD, CA |
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Project Period: |
2006/12/01-2008/11/01 |
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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 |
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Program Director: |
PETERS, N. KENT |
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Principal Investigator: |
GALONIC, DANICA P |
PHD |
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Title: |
Methylation in Antibiotic Biosynthesis: Methylcobalamin-Radical SAM Enzymes |
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Institution: |
HARVARD UNIVERSITY (MEDICAL SCHOOL) |
BOSTON, MA |
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Project Period: |
2006/12/01-2007/11/30 |
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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 |
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Program Director: |
PROGRAIS, LAWRENCE J. |
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Principal Investigator: |
KAGAN, JONATHAN C |
PHD |
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Title: |
Cellular and molecular aspects of Toll-like receptor signal transduction. |
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Institution: |
YALE UNIVERSITY |
NEW HAVEN, CT |
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Project Period: |
2006/12/01-2007/11/30 |
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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 |
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Program Director: |
WASSEF, NABILA M. |
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Principal Investigator: |
ALTER, GALIT |
PHD |
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Title: |
Anergizing effect of NK cell receptor expression on HIV-specific CD8+ T cells |
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Institution: |
MASSACHUSETTS GENERAL HOSPITAL |
BOSTON, MA |
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Project Period: |
2006/12/01-2007/11/30 |
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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 |
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Program Director: |
ECKSTEIN, DAVID J |
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Principal Investigator: |
XIN, LI |
PHD |
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Title: |
Characterization of prostatic stem cells and prostate cancer-initiating cells |
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Institution: |
UNIVERSITY OF CALIFORNIA LOS ANGELES |
LOS ANGELES, CA |
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Project Period: |
2006/12/01-2008/11/30 |
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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 |
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Program Director: |
ECKSTEIN, DAVID J |
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Principal Investigator: |
LI, ZIQIANG |
PHD |
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Title: |
Dissect roles of mismatch repair proteins in Lymphomagenesis and Ig diversity |
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Institution: |
YESHIVA UNIVERSITY |
BRONX, NY |
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Project Period: |
2007/03/01-2009/02/28 |
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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 |
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Program Director: |
ECKSTEIN, DAVID J |
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Principal Investigator: |
ZHANG, YOU-WEI |
PHD |
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Title: |
Roles of the Checkpoint Kinase Chk1 in Cancer Biology and Therapy |
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Institution: |
SALK INSTITUTE FOR BIOLOGICAL STUDIES |
LA JOLLA, CA |
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Project Period: |
2006/12/01-2008/11/30 |
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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 |
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Program Director: |
ECKSTEIN, DAVID J |
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Principal Investigator: |
HE, LIN |
PHD |
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Title: |
Functions of microRNAs in lymphomagenesis |
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Institution: |
COLD SPRING HARBOR LABORATORY |
COLD SPRING HARBOR, NY |
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Project Period: |
2006/12/01-2008/11/30 |
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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 |
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Program Director: |
WU, DA-YU |
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Principal Investigator: |
XU, XIANGMIN |
PHD |
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Title: |
Local Connections and In Vivo Physiology of Inhibitory Cortical Neurons |
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Institution: |
SALK INSTITUTE FOR BIOLOGICAL STUDIES |
LA JOLLA, CA |
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Project Period: |
2006/12/01-2008/11/30 |
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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
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Grant: |
1K99DE018088-01 |
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Program Director: |
AVILA, ALBERT |
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Principal Investigator: |
EBERHART, JOHANN |
PHD |
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Title: |
Genetic Hierarchies and Cellular Behaviors during Zebrafish Palatogenesis |
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Institution: |
UNIVERSITY OF OREGON |
EUGENE, OR |
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Project Period: |
2006/12/01-2008/11/30 |
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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.
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Date Run: 11/30/06 PUBLIC ABSTRACTS
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Grant: |
1K99DK077427-01 |
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Program Director: |
HYDE, JAMES F. |
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Principal Investigator: |
SRINIVASAN, SUPRIYA |
PHD |
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Title: |
The Role of Serotonin in Energy Homeostasis in C. elegans |
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Institution: |
UNIVERSITY OF CALIFORNIA SAN FRANCISCO |
SAN FRANCISCO, CA |
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Project Period: |
2007/07/01-2009/06/30 |
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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.
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Date Run: 11/30/06 PUBLIC ABSTRACTS
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Grant: |
1K99DK077445-01 |
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Program Director: |
HYDE, JAMES F. |
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Principal Investigator: |
ZHOU, QAIO |
PHD |
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Title: |
Diversity and Specification of Pancreatic Progenitor Cells |
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Institution: |
HARVARD UNIVERSITY |
CAMBRIDGE, MA |
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Project Period: |
2006/12/01-2008/11/30 |
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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.
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Date Run: 11/30/06 PUBLIC ABSTRACTS
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Grant: |
1K99DK077573-01 |
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Program Director: |
HYDE, JAMES F. |
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Principal Investigator: |
HOSTETLER, HEATHER A |
PHD |
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Title: |
The role of long chain acyl-CoAs in nuclear receptor regulation |
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Institution: |
TEXAS A&M UNIVERSITY SYSTEM |
COLLEGE STATION, TX |
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Project Period: |
2007/04/01-2009/03/31 |
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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.
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Date Run: 11/30/06 PUBLIC ABSTRACTS
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Grant: |
1K99EB007129-01 |
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Program Director: |
BAIRD, RICHARD |
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Principal Investigator: |
ALLEN, MATTHEW J |
MB, PHD |
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Title: |
Increasing the Utility of Contrast Agents for MRI |
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Institution: |
UNIVERSITY OF WISCONSIN MADISON |
Madison, WI |
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Project Period: |
2006/12/01-2007/11/30 |
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