The major theme in this Program Project application is the study of ethanol-induced changes in signal transduction cascades and gene expression in cells from alcoholics and in model cell systems. All of the investigators in this Program Project use cellular systems to investigate biochemical and molecular mechanisms of pathophysiologic significance in alcoholism, and all are experienced in various aspects of signal transduction and second messenger cascades, a major target for ethanol in the cell. This program will examine the cell biology, molecular biology, and morphology of responses to ethanol that are of pathophysiologic and/or genetic significance in alcoholism. Ethanol-induced changes in second messenger systems and gene expression are also likely to account for the pleiotropic effects of ethanol in many organs and tissues. This program Project addresses some of these major problems related to signal transduction. These include biologic and genetic markers the molecular basis of tolerance and physical dependence at a cellular level, neuronal differentiation, and the pathogenesis of alcoholic cardiomyopathy. The projects are: the role of adenosine in ethanol-induced changes in lymphocytes from alcoholics; Studies in cultured lymphocytes to identify a genetic marker for alcoholism: Ethanol-responsive gene expression in lymphocytes from alcoholics; Ethanol modulation of NGF-mediated signal transduction and neural differentiation in cultured cells: and, Ethanol modulation of signal transduction in cardiac myocytes. We expect that advances in understanding ethanol-induced changes in signal transduction and gene expression in human cells and in model cell systems will lead to new approaches to prevent or reverse alcohol dependence and the medical complications of alcohol abuse.
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