This application for a Mentored Research Scientist Development Award is designed to provide me with training in selected aspects of cellular and molecular biology, and to facilitate the development of skills necessary to accomplish my long-term objective of an independent research career focused on the study of G protein-coupled receptor (GPCR) neurotransmission and neuroadaptation. The scientific experiments proposed will focus on the interaction between dopamine receptors and a novel class of proteins that are termed regulators of G protein signaling (RGS). Guidance will be provided by Dr. Richard Mailman, an internationally known expert in the dopamine field, and by Dr. David Siderovski, a pioneer and leader of the newly recognized field of RGS proteins. The research will be carried out in the laboratories of these scientists at the UNC Neuroscience Center and Department of Pharmacology at the University of North Carolina at Chapel Hill. The proposed activities will provide me with opportunities to acquire additional important molecular and cellular technical expertise while focusing on a research problem that will provide the foundation for my independent career. In addition to didactic and career development activities, my training will occur through the conduct of a series of experiments that test the hypothesis that dopamine regulates the expression of RGS2. I propose that RGS2, in turn, regulates the activity of dopamine or other receptors involved in dopaminergic signaling and neuronal adaptation.
The first aim i n this proposal will explore the role of dopamine in mediating increases in RGS2 expression using quantitative in situ hybridization histochemistry. In these studies, the RGS2 induction that occurs in response to dopaminergic agents will be measured in subregional and cellular compartments of selected brain areas.
The second aim i s to identify potential interacting partners of RGS2 that may regulate its function. These experiments will also identify important structural characteristics and localize RGS2 subcellularly, in order to hypothesize a discrete role of RGS2 in GPCR signaling. In the third aim, studies will be performed to determine possible roles of RGS2 as a modulator of receptor signaling in dopaminergic brain regions. The studies outlined in Aims 1 and 2 will be accompanied by coursework in cellular and molecular neurobiology and neuroanatomy. The research to be conducted will broaden our understanding of the long-term consequences of dopamine receptor activation, and should provide insights for future studies and treatment of dopamine-related disorders such as Parkinson's disease, schizophrenia, and drug abuse.
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