Liver disease due to alcohol is both a serious and prevalent complication of alcohol abuse. At present, there is little specific treatment to offer patients with alcoholic liver disease except to advise abstinence. Unfortunately, sustained abstinence is impossible for most alcoholics; and development of other successful treatments for alcoholic liver injury has been hampered by a lack of understanding about the pathophysiology of liver injury and recovery in patients with alcoholic liver disease. A better understanding of the effect of ethanol consumption on liver injury and clarify the pathogenesis of chronic liver disease in the alcoholic patient. This proposal will begin to explore the effects of ethanol on polyamine synthesis and proto-oncogene expression, two processes essential for liver regeneration. Preliminary data indicate that chronic consumption of ethanol inhibits polyamine synthesis by inhibiting the activity of ornithine decarboxylase (ODC), the rate limiting enzyme for polyamine synthesis. Acute treatment with ethanol also inhibits expression of the proto-oncogene c-myc. This proposal will: 1) define the mechanism by which chronic ethanol treatment inhibits ODC activity by determining ethanol effects on ODC apoenzyme levels and post- translational enzyme inhibitory processes (e.g., phosphorylation); 2) determine whether chronic ethanol treatment alters the expression of c- myc and/or other proto-oncogenes (c-fos, P-53, ras) associated with liver regeneration and; 3) test whether ethanol effects on polyamine synthesis and proto-oncogene expression and related to each other or to ethanol associated inhibition of liver regeneration. The results of this project will enhance general knowledge about regulation of regenerative growth and may also suggest rational, new treatment for alcoholic liver disease.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
First Independent Research Support & Transition (FIRST) Awards (R29)
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Alcohol Biomedical Research Review Committee (ALCB)
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George Washington University
Schools of Medicine
United States
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