1998 — 2002 |
Gershenfeld, Howard K |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Positional Cloning of a Pleiotropic Locus For Behavior @ University of Texas SW Med Ctr/Dallas
Decades of twin, adoption, and family studies have delineated a significant genetic predisposition for psychiatric disorders and epilepsy. Segregation analyses of the inheritance in pedigrees strongly suggest that genetic transmission is multigenic where several genes contribute to a liability for illness. The pursuit of disease loci for bipolar and seizure disorders have underscored the complexity and difficulties in mapping genes for behaviors in humans. As an alternative, we have focused on a mouse model of complex behaviors measuring multiple behavioral dimensions, namely fear-like, exploratory (open field), and generalized seizure behavior. A mouse system offers the advantages of planned matings, good genetic maps, mature genomic resources, and robust transgenic techniques. We propose to positionally clone a major locus affecting several complex behaviors, capitalizing on our recent genetic mapping of a chromosome 10 quantitative trait locus (exq1 QTL) influencing multiple traits, namely open-field behaviors, fear-like behavior, and generalized seizures induced by a beta carboline, methyl-b-carboline-3-carboxylate (b-CCM). Most importantly, this exq1 QTL is a dominantly acting locus and affects multiple traits. Specifically, using strains that differ markedly in their fear-like, exploratory, and drug-induced seizure behavior, we will genetically further localize this chromosome 10 QTL region by generating a series of nested congenic strains. These congenic strains will establish the QTL's range of influence on complex behavior and further delimit the locus. We will positionally clone this exq1 QTL by serially employing recombinational fine mapping of the congenic strains, YAC transgenics, direct selection of cDNA, and evaluation of candidate genes. About 26.9 million Americans suffer from an anxiety disorder, costing an estimated $46.6 billion per year. We interpret rodent exploratory, fear-like, and beta-carboline induced seizure behavior as models of human anxious temperament, anxiety, and seizure vulnerability, respectively. The goal is to understand the biological basis of individual differences in behavior and the etiology of vulnerability to anxiety disorders and seizures in humans. We hypothesize that the characterization of this exq1 locus will delineate a novel mechanism for regulating behavior and neuronal excitability and may lead to a target for rational drug design.
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0.914 |
2003 — 2007 |
Gershenfeld, Howard K |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Neurogenetics of Stress Vulnerability @ University of Texas SW Med Ctr/Dallas
[unreadable] DESCRIPTION (provided by applicant): Depression and anxiety are common psychiatric illnesses in the U.S. with about 23 million and 28 million people suffering annually. In the1990's, the annual economic burden to society of depressive disorders and anxiety disorders were each estimated at $43 billion dollars. We aim to understand the neurobiology of "stress vulnerability," which leads to anxiety and depressive disorders. Stress is a well known "common factor" contributing to many disorders. While the causal association with stress is more direct for depressive and anxiety disorders, evidence has accumulated for stress aggravating cardiovascular and inflammatory diseases. Stress responses vary greatly among individuals. This project proposes to explore the mechanism of vulnerability to acute stress. The mouse tail suspension test (TST) reflects these individual differences in behavior to an uncontrollable stressor. This acute stress model has become a facile model of individual differences in stress reactivity (including psychogenic fever/hyperthermia) and antidepressant responses. This project focuses on the genetic factors predisposing to differences in stress responses induced by TST. The specific aims include: 1) positionally cloning a confirmed locus (Tsti1) on chromosome 5,2) performing secondary and tertiary screens of ENU mutagenized, mutant mice with altered TST behavior, and 3) dissecting the role of gender and cytokines in TST behaviors via selected transgenic mice. The ENU mutant screens will include TST-induced hyperthermia, antidepressant response, and neural activity mapping. Despite the effectiveness of antidepressants, we know little about how these treatments work. The goal is to define robust factors influencing the fundamental biology of individual differences in "stress reactivity," favoring assumption free genetic strategies. We hypothesize that the TST paradigm in mice may probe a genetic shared liability for "general distress," which is a risk factor for psychiatric disorders. An understanding of the molecular pathophysiology of the mammalian stress response will contribute to integration of established genes and pathways, attach functions to unknown genes, and define new pathways for improved therapy. Ultimately, this work may contribute to our etiological understanding of stress vulnerability, identifying individuals at high risk for stress-induced disorders, and provide rational drug design to sever the link between acute stress and pathological consequences.
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0.914 |