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: 8427520
• 负责人: DAVID W CRABB
• 金额: $ 3.9万
• 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/8427520
• 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; Injury; 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; 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; microbial; microbiome; mortality; novel; operation; patient registry; prevent; prognostic indicator; 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. 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.

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是重度饮酒的一种相对罕见的并发症，但具有较高的早期死亡率，如果患者继续重度饮酒，则是肝硬化发展的一个非常强的预测因素。目前针对重度AH的治疗不能令人满意，因此需要更好的基于机械的治疗。这个由印第安纳州大学（印第安纳-IU）、马约诊所（TREAT-马约）和弗吉尼亚联邦大学（弗吉尼亚-VCU）组成的联盟的长期目标是开发AH的治疗方法，以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，我们选择将重点放在人类生物学上。中心假设是AH由以下因素引起：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盐代谢使肝细胞对凋亡细胞因子敏感，d）肝细胞坏死性凋亡。我们认为，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，这将改善预后。本申请的目的是：1）创建一个 登记无肝损伤的AH患者和对照重度饮酒者，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，使我们能够检验关于AH的发病机制、危险因素、预后指标和对治疗的反应的假设; 2）研究肝损伤的相关病理生理机制;和3）测试药物逆转这些异常以改善AH结果的能力。 公共卫生相关性：TREAT联盟由来自印第安纳州大学、马约诊所和弗吉尼亚联邦大学的研究人员组成。它的建立是为了更好地了解酒精性肝炎的发病机制，并开发新的治疗方法。酒精性肝炎是一个重大的公共卫生问题。