Our interdisciplinary team of 18 scientists/clinicians and 18 research fellows will continue studies on the metabolism and metabolic effects of ethanol and the pathogenesis and treatment of medical disorders associated with chronic ethanol consumption, both with the animal models developed in this Center and in judicious clinical investigations. Our immediate goals are to determine the regulatory mechanism of the induction of the ethanol- specific cytochrome P450IIE1 in cultured human hepatocytes and placental tissue. We will assess the contribution of P450IIE1 to the oxidation of pyrazole and glycerol derivatives and the mechanisms (and consequences) of altered gastric bioavailability of ethanol. We shall continue our studies on changes in hepatic lipid and serum lipoprotein metabolism, and the toxicity of acetaldehyde, including its role in alcohol-induced fibrosis. Liver cells involved and molecular mechanisms by which alcohol stimulates fibrogenesis and modulates collagen breakdown will be determined, including the role of the tissue inhibitor of metalloproteinases (TIMP), interleukin- 1, tumor necrosis factor and transforming growth factor-Beta1, studied by molecular """"""""in situ"""""""" hybridization techniques. The baboon model will also be used to determine the reversibility of alcoholic liver fibrosis and to explore the antifibrotic properties of polyunsaturated phospholipids, colchicine, allopurinol and vitamin E. We will assess the impact of alterations in nutrient utilization, including ethanol-vitamin A interactions (especially those with Beta-carotene), and corresponding therapeutic implications, particularly those pertaining to cancer. We will delineate the ability of ethanol to influence initiation of carcinogenesis through inhibition of the DNA repair protein 06-alkylguanine transferase, and determine whether ethanol potentiates chemotherapy of cancer with DNA alkylating agents. Inhibition of DNA methylation and alteration of gene expression in the esophagus and colorectum will be studied in conjunction with site specific carcinogens. Another GI complication to be investigated is the possibility that alcoholic gastritis has an infectious etiology amenable to antibacterial treatment. Our ultimate target is to decrease the significant morbidity and mortality associated with the medical complications of alcoholism by promoting early recognition through markers of alcohol consumption, by elucidating the structural changes and biochemical mechanisms of the pathological effects of ethanol, and by applying this newly acquired knowledge to the successful prevention and treatment of alcohol related hepatic and GI disorders. The Center also actively pursues an educational mission at the regional, national and international level and offers post-doctoral fellows (M.D.'s or Ph.D.'s) the opportunity to acquire specialized research training in the filed of alcohol metabolism and alcoholism.
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