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Grant Abstract

Grant Number: 1R01AA014371-01A1
PI Name: Shirish Barve
Project Title: Mechanisms of Alcohol-Induced Immunosuppression

Abstract: DESCRIPTION (provided by applicant): Alcohol abuse imposes a heavy burden on the U.S. health care system. Immune dysfunction associated with chronic alcohol abuse is linked to increased clinical morbidity, such as infectious diseases and neoplasia. A critical factor in the alcohol abuse associated immune impairment is the loss of CD4+ T lymphocytes. Based on our substantial preliminary data, we hypothesize that a decrease in S-adenosylmethionine (SAMe) caused by ethanol-induced inhibition of methionine adenosyl transferase (MAT2A) enhances the susceptibility of CD4+ T-cells to Fas- and activation (T cell receptor - TCR) - mediated apoptotic death. To test this hypothesis we will examine the effect of ethanol on PBMCs/CD4+ T-cells obtained from alcoholic patients and abstinent, healthy control subjects. The overall goals of this proposal are: (i) to elucidate the molecular mechanisms underlying ethanol mediated depletion of CD4+ T lymphocytes and ensuing immune dysfunction and (ii) to provide a basis for clinically relevant paradigms for the development of potential therapeutic intervention(s) using S-adenosylmethionine (SAMe) in alcoholic patients. Accordingly, the effects of ethanol on Fas- and TCR-induced apoptotic signaling components will be determined. We will perform systematic analyses of the effects of ethanol on MAT2A gene expression and activity and SAMe levels in CD4+ T-cells in order to determine the relevance of MAT2A and SAMe as molecular targets of ethanol-induced CD4+ T-cell toxicity. We will also determine the efficacy of exogenous SAMe supplementation in attenuating CD4+ T-cell death induced by ethanol. Overall, we expect our studies to elucidate critical molecular mechanisms underlying CD4+ T-cell depletion associated with chronic alcohol abuse. Moreover, the data from these studies would support our future goals by providing a basis for relevant clinical paradigms for the development of potential therapeutic intervention(s) for alcoholic patients.

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