My application for a K02 award reflects a natural progression of my scientific development, first as a child psychiatrist and then as a molecular biologist. From the beginning of my career as a research fellow in psychiatry and in molecular biology, and more recently as a faculty member in the Yale Child Study Center, the focus of my research has been on understanding underlying mechanisms in signaling pathways within the basal ganglia. Disruption of the normal signal transduction pathways within this region occurs in a number of neuropsychiatric disorders, including Tourette's syndrome and obsessive compulsive disorder, as well as being the site of action of the unwanted side effects of the major neuroleptics. The central goal of the proposed investigation is to study the structure and function of a family of protein tyrosine phosphatases, termed STEP. The family consists of both cytosolic and membrane-associated isoforms, as well as truncated variants that lack an active catalytic site. A striking feature is that some STEP isoforms contain transmembrane domains, PEST sequences, and polyproline-rich sequences. We hypothesize that these domains provide a mechanism for the subcellular targeting, as well as determining their substrate specificity and enzymatic activity. These hypotheses require additional investigations beyond my expertise in molecular biology. Specifically, there are four areas of career development that I have arranged over the course of the next five years. These include the identification of interacting proteins that form complexes with STEP members using both the yeast 2 hybrid system, as well as affinity chromatography to biochemically purify associated proteins. STEP knockout mice will also be characterized. The proposed investigations will be done in the supportive environment of the Child Study Center with its commitment to clinically informed basic science research.
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