This application presents a career development award proposal spanning the fields of child psychiatry, molecular cytogenetics and molecular genetics. The near-term objective of this submission is to develop an independent program in patient-oriented research that focuses on identifying genes that contribute to serious psychiatric disorders. The ultimate aim of the applicant is to contribute to the translation of advances in genetics into improvements in diagnosis, treatment and prevention of childhood developmental and neuropsychiatric illnesses. After completing clinical training in adult and child psychiatry, the applicant participated in a three-year NIMH funded patient-oriented research fellowship at the Yale Child Study Center (YCSC). During this time, he simultaneously pursued an expertise in molecular genetics by enrolling in the Ph.D. program in the Department of Genetics at Yale. Dr. State was appointed Assistant Professor in the Child Study Center (Department of Child Psychiatry) in July of 2000. He currently divides his time between attending in the Tourette syndrome (TS) and Obsessive Compulsive Disorder (OCD) clinics and conducting research in the laboratory. This career award will provide vital support for his efforts to bridge clinical and basic science research. It will facilitate his continued patient-oriented research training, allow him to develop further expertise in relevant areas of molecular genetics and molecular cytogenetics, and provide the opportunity to achieve full scientific independence. The research plan presented below centers on the identification and characterization of genes that reside within a small region around a chromosomal inversion breakpoint found in a patient with a Tourette syndrome/Obsessive Compulsive Disorder (TS/OCD) phenotype. The developmental expression pattern of these genes will be assessed and the transcripts will be prioritized for further study with respect to their role in the TS/OCD spectrum of disorders. The proposal also plans for the development of a repository of cytogenetic abnormalities in well- characterized patients with TS/OCD phenotypes. The overarching objective of the award proposal, comprising both the career development and research plans, is to identify candidate genes in childhood neuropsychiatric disorders as a prelude to further investigations within the Child Study Center and the Children's Clinical Research Center (CCRC) that will focus on the relevance of these genes for the diagnosis, treatment, and natural history of TS/OCD. To help reach his long-term career objectives, the applicant has arranged for an outstanding group of mentors and advisors to provide guidance with respect to the design and conduct of his research, assistance in mastering the organizational challenges of running a successful research program, and training in the ethical issues attending research. He has formulated a plan for additional didactics and intensive workshops that will deepen his understanding of clinical statistical methodology, population genetics, gene expression analysis, genomics, and bioinformatics. Finally, his overall career development plan is made possible by the existence at Yale of a multidisciplinary team conducting translational research into the pathogenesis and treatment of childhood neuropsychiatnc disorders including TS/OCD, as well as the availability of the Children's Clinical Research Center (CCRC) which serves as a key resource in the conduct of this ongoing research.
