Translational Research and Evolving Alcoholic hepatitis Treatment (TREAT-ADMIN)

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DESCRIPTION (provided by applicant): This application responds to RFA-AA-12-007 creating a Consortium for translational research on alcoholic hepatitis (AH), which we have named "TREAT: Translational Research and Evolving Alcoholic hepatitis Treatment." AH is a relatively uncommon complication of heavy alcohol use, but carries a high early mortality rate and is a very strong predictor of the development of cirrhosis if the patient continues heavy alcohol use. Current therapies for severe AH are unsatisfactory, and therefore better, mechanistically-based therapies are needed. The long term goal of this consortium of Indiana University (TREAT-IU), Mayo Clinic (TREAT- Mayo), and Virginia Commonwealth University (TREAT-VCU) is to develop therapies for AH that prevent early mortality and reduce the rate of progression to cirrhosis. Because of the lack of satisfactory animal models, we have chosen to focus on human biology. The central hypothesis is that AH results from: a) impaired gut integrity and portal endotoxinemia, b) activation the innate immune system, c) sensitization of hepatocytes to apoptotic cytokines through oxidative stress and abnormal bile salt metabolism, and d) necroapoptosis of the hepatocytes. We propose that these pathways can be blocked with oral administration of antibody to LPS, activation of the FXR signaling pathways, and inhibition of caspases, and that this will improve outcomes. The objective of this application is: 1) to create a registry of patients with AH and control heavy drinkers without liver injury, which will supply patients and patient samples for the mechanistic studies, pilot projects, and clinical trials, allowing us to test hypotheses about pathogenesis, risk factors, prognostic indicators, and response to therapy of AH; 2) to study interrelated pathophysiological mechanisms of liver injury; and 3) to test the ability of drugs reversing these abnormalities to improve outcomes in AH. PUBLIC HEALTH RELEVANCE: The TREAT Consortium consists of investigators from Indiana University, Mayo Clinic, and Virginia Commonwealth University. It is established to better understand the pathogenesis of alcoholic hepatitis and to develop new treatments. Alcoholic hepatitis is a major public health problem.