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创建的酒精性肝炎(AH)翻译研究联盟，我们已将其命名为“治疗：翻译研究和演变的酒精性肝炎治疗”。AH是大量饮酒的一种相对不常见的并发症，但具有较高的早期死亡率，如果患者继续大量饮酒，它是发展为肝硬变的非常强的预测因子。目前治疗重症急性胰腺炎的方法并不令人满意，因此需要更好的机械性治疗方法。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预防早期死亡和降低进展为肝硬变的治疗方法。由于缺乏令人满意的动物模型，我们选择关注人类生物学。中心假说是：a)肠道完整性受损和门静脉内毒素血症，b)激活天然免疫系统，c)氧化应激和异常胆盐代谢使肝细胞对凋亡细胞因子敏感，d)肝细胞坏死。我们认为，口服内毒素抗体、激活FXR信号通路和抑制caspase可以阻断这些通路，这将改善结果。此应用程序的目标是：1)创建一个 这将为机制研究、试点项目和临床试验提供患者和患者样本，使我们能够检验关于AH的发病机制、危险因素、预后指标和治疗反应的假说；2)研究肝损伤的相互关联的病理生理机制；3)测试逆转这些异常的药物改善AH预后的能力。

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.