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

描述（由申请人提供）：本申请响应RFA-AA-12-007创建酒精性肝炎（AH）转化研究联盟，我们将其命名为“TREAT：转化研究和不断发展的酒精性肝炎治疗”。AH是一种相对不常见的重度饮酒并发症，但具有很高的早期死亡率，如果患者继续重度饮酒，AH是肝硬化发展的一个强有力的预测因素。目前治疗严重AH的方法并不令人满意，因此需要更好的、基于机械的治疗方法。这个由印第安纳大学（TREAT- iu）、梅奥诊所（TREAT- Mayo）和弗吉尼亚联邦大学（TREAT- vcu）组成的联盟的长期目标是开发治疗AH的方法，防止早期死亡并降低向肝硬化发展的速度。由于缺乏令人满意的动物模型，我们选择将重点放在人类生物学上。中心假设是AH的原因是：a)肠道完整性受损和门静脉内毒素血症，b)先天免疫系统激活，c)肝细胞通过氧化应激和胆盐代谢异常对凋亡细胞因子的敏化，d)肝细胞坏死凋亡。我们提出，这些途径可以通过口服LPS抗体、激活FXR信号通路和抑制半胱天冬酶来阻断，这将改善结果。这个应用程序的目标是：1)创建一个

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.