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.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
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Special Emphasis Panel (ZRG1-DIG-F (02))
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Guo, Qingbin
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University of Louisville
Internal Medicine/Medicine
Schools of Medicine
United States
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