This proposal seeks to provide Edward S. Brodkin, M.D. with a five-year period of supervised research training that will enable him to become an independent investigator, with a research focus on the genetic dissection of aggressive behaviors in mice. The candidate will gain training and experience in high resolution genetic mapping of quantitative trait loci (QTLs), candidate gene analysis, and mutagenesis methods. Background: Aggressive behaviors are a major source of morbidity and mortality in patients with severe neuropsychiatric disorders. A propensity towards aggression is substantially heritable in mammals. Genetic dissections of aggressive behaviors in mice can identify biological pathways that underlie mammalian aggression and that may be involved in the pathophysiology of human psychiatric disorders. Dr. Brodkin has previously identified aggression QTLs on chromosome 10 (Aggr1) and chromosome X (Aggr2) in NZB/B1NJ and A/J mice; however he has had no previous experience with high-resolution (fine) mapping of QTLs, candidate gene analysis, or mutagenesis methodologies. Training in these methodologies is important for the candidate's career development and is necessary for his future research independence.
Specific Aims of Research Plan: 1. Fine-mapping aggression QTLs. Using NZB/B1NJ and AJ mice as progenitor strains, interval-specific congenic strains will be bred for the Aggr1 and Aggr2 QTL intervals and will be used to fine map the QTL intervals. 2. Candidate gene analysis. Within the finely mapped QTL intervals, candidate genes that are expressed in brain will be sequenced in the progenitor strains to look for functional polymorphisms. Expression level of the candidate genes in brain regions will be compared in the progenitor strains. 3. Initiation of mutagenesis studies of aggressive behaviors. ENU mutagenesis and gene-trap studies of aggressive behaviors in mice will be initiated. ENVIRONMENT: The training will be conducted at the Center for Neurobiology and Behavior, Department of Psychiatry, University of Pennsylvania School of Medicine. RESEARCH CAREER DEVELOPMENT: The candidate will take relevant courses at Penn and elsewhere and will attend research meetings. Dr. Wade Berrettini will be the mentor, and Drs. Maja Bucan, Russell Buono, Thomas Ferraro, and Irwin Lucki will provide additional consultation in genetics and behavioral analysis.
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