PSYCHOTROPIC DRUG RESPONSIVE TRANSCRIPTION FACTORS

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DESCRIPTION (Applicant's Abstract): Drug addiction is one of the major public health problems in the United states and is largely resistant to currently available prevention and treatment strategies. Accordingly, in recent years, there has been intense interest in numberous laboratories, including my own, in defining the intracellular signalling pthways that regulate and mediate the long-term adaptation of neurons to a wide variety of physiological and pharmacological stimuli, including drugs of abuse. As part of this ongoing effort, I am requesting renewal of my K02 award. This renewal will enable me to gain further expertise in molecular biological approaches I have employed in previous studies. The specific aims of the research outlined in this proposal focus on defining novel aspects of regulation of the Egr family of immediate early gene transcripiton factors. In particular, we have obtained evidence in preliminary studies that there are distinct acute and delayed phases to the transcriptional responses mediated by the Egr response element. As the delayed phase may be especially relevant to understanding the long-term effects of drugs of abuse on neuronal funciton, we plan to conduct experiments aimed at: 1) defining the Egr family members experessed durng the "delayed" wave of Egr family expression, and 2) determine how these two phases of Egr family member expression are influenced by repeated or chronic stimulation. In addition, in preliminary studies aimed at identifying the Egr family members expresed during the delayed phase, we have obtained evidence that one of these, Egr-3, is phosphorylated in vivo. As little is known about how Egr family members are regulated by phosphorylation, we plan to 3) map the sites of phosphorylation of Egr-3 under basal conditions and following activation of second messenger pathways, and 4) to assess the effects of phosphorylation on its transcriptional regulatory activity. Acquiring further expertise in molecular biological approaches by carrying out the studies outlined in this proposal will provide a firm foundation for pursuing future studies aimed at defining the signalling pathways that regulate neuronal plasticity and psychotropic drug actions. The close interaction among members of the Department of Neuroscience at Johns Hopkins, which include leading experts in molecular neurobiology, provides an ideal environment for my scientific development.