Oxidant Stress and Fibrosis in Alcoholic Liver Injury

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DESCRIPTION (provided by applicant): Alcoholic liver disease remains a highly prevalent and often lethal complication of alcohol abuse, whose etiology is incompletely understood. Understanding the basis of alcoholic liver disease could improve the health of millions of Americans afflicted by this problem. The overall objective of this exploratory alcohol research center is to elucidate the pathogenesis of alcoholic liver injury and fibrosis due to oxidant stress by incorporating novel models of disease and promoting unique synergistic interactions among a diverse range of investigators with complementary interests and strengths. This will advance our commitment to developing an Alcohol Research Center (P50). Specifically, we will: 1) Elucidate the mechanistic underpinnings of alcoholic liver disease by studying the roles of oxidant stress, cell-cell interactions and a novel transcriptional regulator, KLF6, in mediating liver injury and fibrogenesis; 2) Define novel models of alcoholic liver injury, non-alcoholic steatohepatitis (NASH) and fibrosis through the use of zebrafish, engineered mammalian cell lines, and transgenic models of alcohol-induced liver injury in mice; 3) Forge new, synergistic interactions among investigators at the Mount Sinai School of Medicine to create novel approaches to understanding alcoholic liver injury and fibrosis; 4) Create new educational and training opportunities to study alcoholic liver injury and fibrosis by leveraging existing NIH-funded training programs, and by establishing annual symposia and regular seminars in topics related to alcoholic liver disease. To address these aims, the Center will include an Administrative and two Research Cores (a Models Core that will include both mammalian and zebrafish reagents and animal models; and a Morphology Core led by a highly experienced hepatopathologist); Two Exploratory Projects: a) Hepatic injury, fibrosis and alternative splicing of the KLF6 gene in response to oxidant stress; b) zebrafish as a model for alcoholic liver disease; Three Pilot Feasibility Projects; a) Effects of alcohol-mediated liver injury on growth hormone biology; b) Cdc37 an early biomarker of alcohol induced hepatocellular carcinoma and the role HspQO inhibitors as therapeutic agents; c) Effect of alcohol on mouse and human embryonic stem cell-derived hepatoblasts. Collectively, the highly collaborative nature of the program promises to yield important new insights into the molecular basis of alcoholic liver injury using novel models and state-of-the-art methods.