This competitive renewal of my KO2 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 STEP family is specifically expressed in the CNS, and within the brain is found enriched within neurons of the basal ganglia, amygdala, nucleus accumbens and related structures. The family consists of both cytosolic and membrane-associated isoforms, as well as truncated variants that lack an active catalytic site. Recent work in the lab has identified several substrates of STEP. STEP regulates the tyrosine phosphorylation level of NMDA receptor subunits, the MAP kinase proteins, ERK1/2, and the tyrosine kinase, Fyn. Striking features of STEP include the findings that it contains a MAP kinase binding domain, PEST sequences, polyproline-rich sequences, and two transmembrane domains. We hypothesize that these domains target STEP to subcellular compartments, determine substrate specificity, and enzymatic activity. We have recently demonstrated that STEP is itself phosphorylated at two regulatory serines in a dopamine/D 1/cAMP/PKA pathway. STEP is dephosphorylated in response to glutamate signaling. Additional investigations are now needed that are beyond my expertise in molecular biology. Specifically, there are three areas of career development that I have arranged over the course of the next five years. These include the identification of additional proteins that are substrates of STEP, continued work on the neurotransmitter pathways that regulate STEP activity through phosphorylation/dephosphorylation, and the identification of the kinases and phosphatases that phosphorylate STEP, and their sites. STEP knock-out mice will also be characterized. The proposed investigations will be done in the supportive environment of the Child Study Center with its commitment to cliniclaly informed basic science research.
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