The overall goal of this Mentored Research Career Award (K08) application is to provide training in innovative techniques that will permit the applicant to ask and answer the largest possible questions in translational mental health research. This research training plan has two overall objectives. The first is to train the applicant in new cutting-edge techniques to study gene expression in postmortem tissue. The second is for the applicant to learn how to perform and evaluate inducible gene deletion or overexpression in the rodent brain. To achieve these objectives, the applicant has planned a series of complementary educational and research training experiences, including formal coursework in biostatistics, bioinformatics, clinical epidemiology, genetics and signal transduction, as well as extended laboratory experiences with consultants to learn electrophysiology, laser capture microscopy (LCM), quantitative PCR, and gene manipulation techniques with viral vectors. In concert with this application's overall objectives, we have designed a research project that maximizes the applicant's exposure to innovative research methodologies and builds on his previous findings of glutamate transporter transcript abnormalities in schizophrenia. These data suggest abnormalities of glutamate transporter expression in corticothalamic circuits in schizophrenia. Accordingly, we hypothesize that expression and regulation of excitatory amino acid transporters (EAATs) is altered in corticothalamic circuits in schizophrenia, contributing to psychopathology in this illness. To evaluate this hypothesis we will measure EAAT mRNA expression in populations of microdissected cells and examine post-translational modification of EAAT proteins in subjects with schizophrenia and a control group. Guided by these human studies, we will then characterize the electrophysiological and neurochemical consequences associated with corticothalamic alterations of transporter gene expression generated using viral mediated gene transfer and/or the cre-loxP recombinase system. These studies will link identified changes in gene expression in schizophrenia with circuit specific alterations in glutamate synapse composition and function. At the conclusion of this set of experiments, the applicant will have learned innovative, state-of-the-art techniques for investigating abnormalities of gene expression and regulation in severe psychiatric illness, providing the tools needed to develop an independent research program.
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