Cirrhosis, which is the 9th leading cause of death in the United States. It develops over a period of years to decades because chronic necro-inflammatory activity gradually transforms the normal architecture into nodules. This proposal is focused on the ductular reaction, which is important predictor of the development of cirrhosis and refers to the preferential growth of biliary epithelial cells over hepatocytes, recognized at the interface zone of diseased livers. By either favoring biliary epithelial cell or inhibiting hepatocyte proliferation some cytokines and growth factors hasten the development of cirrhosis, whereas others that stimulate hepatocytes (IL-6/gp130, HGF) and inhibiting biliary epithelial cell proliferation prevent architectural distortion and liver failure. In this proposal we plan to: a. Characterize the effect of IL-6/gp130/STAT3 signaling, extracellular matrix and immunosuppressive drugs on biliary epithelial cell mitogenesis, apoptosis and maintenance of intercellular junctions, in vitro. b. Further characterize an experimental animal model of decompensated biliary cirrhosis in IL-6-/- mice after bile duct ligation using gene chip expression array analysis. Determine the role of p21 in hepatocyte proliferation and apoptosis during the development of cirrhosis and whether administration or exogenous recombinant growth factors, or transient transfection of vectors containing growth factors can influence the ductular reaction. c. Determine in humans, whether cytokine polymorphisms influence the susceptibility or the rate of progression of various chronic inflammatory liver diseases. The ultimate goal is to understand molecular mechanisms of differential biliary epithelial cell and hepatocyte growth control in diseased livers, which will serve as a rational basis for therapeutic intervention with cytokines and growth factors.
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