Alcoholic liver disease remains a highly prevalent and often lethal complication of alcohol abuse, whoseetiology is incompletely understood. Understanding the basis of alcoholic liver disease could improve thehealth of millions of Americans afflicted by this problem. The overall objective of this exploratory alcoholresearch center is to elucidate the pathogenesis of alcoholic liver injury and fibrosis due to oxidant stress byincorporating novel models of disease and promoting unique synergistic interactions among a diverse rangeof investigators with complementary interests and strengths. This will advance our commitment todeveloping an Alcohol Research Center (P50). Specifically, we will: 1) Elucidate the mechanisticunderpinnings of alcoholic liver disease by studying the roles of oxidant stress, cell-cell interactions and anovel transcriptional regulator, KLF6, in mediating liver injury and fibrogenesis; 2) Define novel models ofalcoholic 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) Forgenew, synergistic interactions among investigators at the Mount Sinai School of Medicine to create novelapproaches to understanding alcoholic liver injury and fibrosis; 4) Create new educational and trainingopportunities 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 ModelsCore that will include both mammalian and zebrafish reagents and animal models; and a Morphology Coreled by a highly experienced hepatopathologist); Two Exploratory Projects: a) Hepatic injury, fibrosis andalternative splicing of the KLF6 gene in response to oxidant stress; b) zebrafish as a model for alcoholic liverdisease; Three Pilot Feasibility Projects; a) Effects of alcohol-mediated liver injury on growth hormonebiology; b) Cdc37 an early biomarker of alcohol induced hepatocellular carcinoma and the role Hsp90inhibitors as therapeutic agents; c) Effect of alcohol on mouse and human embryonic stem cell-derivedhepatoblasts. Collectively, the highly collaborative nature of the program promises to yield important newinsights into the molecular basis of alcoholic liver injury using novel models and state-of-the-art methods.
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