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of excess ethanol intake will be studied in Specific Aims 1 and 3 -- genetically selected alcohol-preferring rats and withdrawn outbred rats made dependent during chronic, intermittent exposure to ethanol vapor, emphasizing positive and negative reinforcing properties of ethanol,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 |