Murine Genetic Models of Autism

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DESCRIPTION (provided by candidate): This proposal outlines a five year program to train a child psychiatrist to study the molecular pathophysiology of autism. Autism spectrum disorders affect as many as 1 in 160 children. Little is known concerning the genetic determinants of autism pathophysiology, limiting treatment and prevention strategies. The candidate has completed clinical training in child psychiatry and concurrent research training in human molecular genetics. He proposes to learn a new set of scientific skills to use transgenic mice to model alterations of the serotonin system in autism. The training program centers on techniques to analyze the brain and platelet serotonin system, as well as methodology to study resulting changes in mouse brain morphology and behavior. Recent genetic and biochemical studies implicate genetic and physical interactions of the integrin 33 and serotonin transporter genes in the determination of platelet serotonin levels as well as autism traits. The candidate proposes to use transgenic mice to understand the impact of variation in these two genes. The Specific Aims include brain and behavioral analyses of: 1) Mice with decreased or absent expression of integrin (33; 2) Mice expressing an overactive serotonin transporter 425Leu variant; and 3) Mice heterozygous for both integrin p3 and serotonin transporter variants to model interaction effects of common human variation. The candidate's mentor, Dr. Randy Blakely, is an internationally respected researcher in the field of neurotransmitter transporters and has an active, well-funded laboratory in the candidate's field of interest. He has trained numerous graduate students and postdoctoral fellows in the study of monoamine transporter proteins, including the production and characterization of transgenic mice. To add further expertise, Dr. Jacqueline Crawley, a specialist in murine models of autism, will advise on mouse behavioral studies, and Dr. Elaine Sanders-Bush will advise on serotonin receptor studies. The Department of Psychiatry and the Center for Molecular Neuroscience at Vanderbilt present an ideal setting for the candidate's development. Vanderbilt's collective expertise in molecular research on the serotonin system and strong commitment to autism research provide an unparalleled opportunity to advance the candidate's career development toward the goal of developing an independent research program relevant to child psychiatry.