BASES OF CIRRHOSIS IN ALCOHOLIC LIVER DISEASE

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This proposal represents a continuation and expansion of our initial objective of attempting to understand the molecular mechanisms responsible for hepatic fibrogenesis. We are defining specific factors that may initiate the fibrotic events, agents that may ameliorate the condition, and a test that may diagnose who develops it. By better understanding the interaction of the elements that influence the fibrogenic process, it becomes possible to design rational therapeutic intervention. Specific Aims: 1) To identify the cell(s) responsible for the synthesis of collagen in the liver. 2) To determine how two cytokines, tumor necrosis factor (TNF) and transformation growth factor beta (TGF-beta) initiate and promote the fibrogenic process. 3) To delineate the antifibrogenic effects of gamma-interferon and corticosteroids. 4) To establish how genetic variation in a type I collagen gene may be associated with the development of alcoholic cirrhosis. Methods: 1) Procollagen mRNA will be located in specific cells by in situ hybridization. 2) The effects of TNF and TGF-beta on matrix protein synthesis will be studied in cultured cells and in animal models of cirrhosis by Northern hybridization analysis, nuclear run-on assays, and in situ hybridization. 3) Cells and cirrhotic animals will be treated with gamma-interferon to delineate the basis of its anti-fibrogenic effects. A transients expression vector system will be used to define the mechanisms by which dexamethasone inhibits collagen synthesis. 4) Analysis of restriction fragment length polymorphisms of a collagen gene will be undertaken in an extended family of alcoholics to define a genetic basis for cirrhosis. Health relatedness: By accomplishing the aims of this proposal we will formulate a general model for the pathogenesis of alcoholic liver disease and therapy aid in the formulation of therapy. Identification of a haplotype clearly associated with a propensity for a specific alcoholic to develop cirrhosis will establish a clinically relevant test. Defining the antifibrogenic actions of corticosteroids and gamma-interferon may help determine which patients with chronic liver disease will prosper from intervention with one of these therapeutic agents.