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

转化研究和不断发展的酒精性肝炎治疗 (TREAT-ADMIN)

• 批准号: 8544963
• 负责人: DAVID W CRABB
• 金额: $ 3.63万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-15 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8544963
• 关键词: Adrenal Cortex Hormones; Agonist; Alcoholic Hepatitis; Alcoholic beverage heavy drinker; Alcohols; Animal Model; Antibodies; Apoptosis; Apoptotic; Caspase; Caspase Inhibitor; Cirrhosis; Clinic; Clinical Trials; Clinical Trials Data Monitoring Committees; Communities; Complication; Data; Development; Double-Blind Method; Foundations; Functional disorder; Future; Goals; Heavy Drinking; Hepatocyte; Human Biology; Immune system; Indiana; Information Dissemination; Lipopolysaccharides; Liver; Liver diseases; Medical; Metabolism; Names; Natural Immunity; Necrosis; Observational Study; Oral Administration; Outcome; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Permeability; Pharmaceutical Preparations; Pilot Projects; Prognostic Marker; Public Health; Randomized; Research; Research Personnel; Risk Factors; Role; Sampling; Serum; Signal Pathway; Specimen; Sterility; Supportive care; Testing; Therapeutic Studies; Tissues; Translational Research; Universities; Virginia; alcohol effect; base; bile salts; cytokine; improved; liver injury; microbial; microbiome; mortality; novel; operation; patient registry; prevent; programs; prospective; repository; response; therapy development

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.

描述（由申请人提供）：本申请响应 RFA-AA-12-007，创建了一个酒精性肝炎 (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大量饮酒并发症，但早期死亡率很高，如果患者继续大量饮酒，它是肝硬化发展的强烈预测因素。目前严重 AH 的治疗方法并不令人满意，因此需要更好的、基于机制的治疗方法。该联盟由印第安纳大学 (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 AH 疗法，预防早期死亡并降低进展为肝硬化的速度。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) 激活先天免疫系统，c) 通过氧化应激和异常胆汁盐代谢使肝细胞对凋亡细胞因子敏感，以及 d) 肝细胞坏死性凋亡。我们建议可以通过口服 LPS 抗体、激活 FXR 信号通路和抑制半胱天冬酶来阻断这些通路，这将改善结果。该应用程序的目标是：1）创建一个 登记 AH 患者和无肝损伤的对照重度饮酒者，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，使我们能够检验有关 AH 发病机制、危险因素、预后指标和治疗反应的假设； 2）研究肝损伤的相关病理生理机制； 3) 测试药物逆转这些异常以改善 AH 结局的能力。