METABOTROPIC GLUTAMATE RECEPTOR EXPRESSION AND FUNCTION

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I am currently an Associate Professor (tenure-track) in the department of Pharmacology at Georgetown University and hold a joint appointment in the Fidia-Georgetown Institute for the Neurosciences. My long-term research goal is to understand the role of G-protein coupled metabotropic glutamate receptors in neuronal function. My career goal is to establish a strong research program and gain expertise and knowledge allowing me to combine the techniques of neurochemistry, pharmacology, cell biology and molecular biology to study receptor functional expression and intracellular signalling. I obtained my Ph.D. from the Department of Neurochemistry, Polish Academy of Sciences in Warsaw in 1979. My postdoctoral training in neuropharmacology was with Dr. E. Costa at NIMH. I joined the faculty at Georgetown University in 1985 and have established at FGIN, under the direction of Dr. E. Costa, a research program in the field of pharmacology and signal transduction of excitatory amino acid receptors. This work has been the basis for my participation in the Program Project "Excitatory Amino Acids: Role in CNS Disorders" (P01-NS28130, R. A. Gillis, Program Director) for 3 years as a Core Director, and since 1993 as a principal investigator of one of the projects which has been funded through 3/31/98. The current RCDA application is submitted to enable me to expand my expertise in neurosciences and to devote additional time to my research program. By minimizing my teaching and administrative responsabilities, the award will allow for personal growth at several levels and for in-depth training in molecular biology an antibody preparation techniques. The research plan (based on the funded Program Project grant) focuses on the expression and function of metabotropic glutamate receptors (mGluRs) in primary cultures of neurons. The specific aims are: to evaluate the functional expression of mGluRTs coupled to phosphoinositide (PI) hydrolysis by determining the developmental pattern of expression of mRNA, receptor protein, and of the appearance of the PI response in neurons cultured in media enhancing receptor expression and by establishing the agonist and antagonist pharmacology of these receptors; to determine the role of mGluRs in PI metabolism by identifying the specific substrates and products of phospholipase C coupled to mGluRs; to determine the role of PI- coupled mGluRs in intracellular calcium homeostasis; and to determine the role of ionotropic glutamate receptors (NMDA and AMPA) interacting with mGluRs in the regulation of PI hydrolysis. An important goal of the current RCDA application is to extend the proposed studies to the entire family of mGluRs, including those negatively coupled to adenylate cyclase. Thus, I propose to study the expression of mRNA and receptor protein for all PI and cAMP-coupled mGluRs in primary neuronal cultures and to establish the selective pharmacology of the receptor-induced responses. These studies will provide information fundamental for the understanding of the pharmacological and neurochemical properties of mGluRs, their role in neuronal function, and for development of future therapeutic strategies.