? The proposed 4-year training award is intended to provide the applicant with additional training in three areas: microarray study design and analysis, bioinformatic techniques, and translational genetics. Experts in all of these fields have agreed to participate in the training program. Additionally, structured course work is proposed that addresses the trainee's deficiencies. The proposed training environment is an interdisciplinary center established by Columbia University to promote interaction among biologists, geneticists, statisticians, computational biologists, bioinformaticians, and engineers for the purpose of forging interdisciplinary """"""""genomic"""""""" solutions to biomedical problems. Experts in all relevant fields are already working on closely related projects under the umbrella of a program project grant that has been awarded to the sponsor of this training program. Thus, the environment is ideally suited to the training goals. The applicant is already expert in the tools of classical behavioral genetics, such as quantitative trait locus (QTL), analysis and the creation of selected lines. The research plan is designed to identify genes that influence naturally occurring variability in a genetically tractable form of fear learning in mice. Short term selected mouse lines will be created and used to identify QTL, and gene expression differences. Specific polymorphisms related to genes and gene expression will be identified by the synergistic application of traditional (QTL mapping) and modern (microarray and bioinformatics) techniques. By using the latter techniques, which are the training component of this application, specific genes will be rapidly identified. This proposal addresses the major weakness of traditional mouse QTL studies, which is that they are seldom powerful enough to identify specific genes. We predict that some of the identified genes will also control fear learning and anxiety disorders in human subjects. To test these hypotheses, the strongest candidate genes, gene classes, and pathways will be examined for polymorphisms in a large population (approximately 1000) of unrelated normal human subjects scored for fear learning, and other anxiety dimensions, as well as in a population of anxiety disorder patients. Our collaborators are ascertaining these human subjects as one component of the sponsor's program project grant. This training program will prepare the candidate for an academic career focused on the use of endophenotypes, animal models and bioinformatics to elucidate the genetic basis of psychiatric disease. ? ?
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