This application is for an ADAMHA (NIMH) Scientist Development Award. The University of California, San Francisco is the nominating institution and the site of training and research. The main objective of this proposal is to provide advanced training in molecular and cellular biological techniques to the PI to permit him to establish an independent research career investigating cell biological processes relevant to psychiatric disease. Elucidating the molecular basis of neuronal shape and its regulation is a primary goal of neuroscience research. Neuronal shape and motility derive from the regulated activity of the cytoskeleton. The external environment is a primary source of signals that regulate the cytoskeleton; how these signals are transduced is largely unknown. The cytoskeleton is also an important regulator of neurotransmission. Altered neurotransmission is thought to be etiologically important in many psychiatric illnesses. Elucidating how signals are transduced to the cytoskeleton is directly relevant to understanding how neurotransmission is altered in severe mental illnesses. The goal of this proposal is to investigate the roles of the signal transducing G proteins in the regulation of the neuronal cytoskeleton. First, G protein-species that regulate actin dynamics will be identified using mutationally activated G proteins. Next, chemical cross-linking and actin affinity chromatography will identify G protein effector sites in the cytoskeleton. Finally, biochemical assays will characterize the cytoskeletal activities regulated by G proteins. Identifying the mechanisms by which G proteins regulate actin dynamics will enable a greater understanding of how neural cells regulate their shape and how the cytoskeleton may mediate the effects of altered neurotransmission in mental illness.
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