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）：此申请对RFA-AA-12-007做出了响应，创建了一个用于酒精性肝炎的转化研究联盟（AH），我们将其命名为“治疗：转化研究和不断发展的酒精性肝炎治疗”。 AH是大量饮酒的相对罕见的并发症，但具有很高的早期死亡率，并且如果患者继续大量酒精饮酒，则是对肝硬化的发展的非常有力的预测指标。当前的严重AH疗法是不令人满意的，因此需要更好的基于机械的疗法。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）的这个长期目标是开发AH的AH疗法，以防止早期死亡率并降低急诊症的进展率。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是由以下原因引起的：a）肠道完整性和门户内毒素血症受损，b）激活先天免疫系统，c）通过氧化胁迫和异常的胆汁盐代谢和d）Necropoptosis of Hepatocatocysess敏化肝细胞对凋亡胁迫的敏化。我们建议通过口服对LP的抗体，FXR信号通路的激活和抑制caspase的抗体可以阻止这些途径，这将改善结果。此应用程序的目的是：1）创建一个 AH和控制重饮酒的患者注册中没有肝损伤，这将为机械研究，试点项目和临床试验提供患者和患者样本，从而使我们能够测试有关发病机理，危险因素，预后指标以及对AH治疗的反应的假设； 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能够改善AH的预后的能力。 公共卫生相关性：该协议由印第安纳大学，梅奥诊所和弗吉尼亚联邦大学的调查人员组成。它的建立是为了更好地了解酒精性肝炎的发病机理并开发新疗法。酒精性肝炎是一个主要的公共卫生问题。