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

转化研究和不断发展的酒精性肝炎治疗 (TREAT-IU)

基本信息

批准号：
8427105
负责人：
NAGA P CHALASANI
金额：
$ 94.85万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
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/8427105
关键词：
Acids Acute Alcoholic Hepatitis Address Adrenal Cortex Hormones Adult Affect Age Agonist Alcohol consumption Alcoholic Hepatitis Alcoholic Liver Diseases Alcoholic beverage heavy drinker Alcohols Antibodies Back Bacterial Translocation Bile Acids CYP2E1 gene Caspase Inhibitor Cells Clinic Clinical DNA Drug Kinetics Enrollment Fatty Liver Feces Fibroblast Growth Factor Foundations Functional disorder Gender Genomics Glossary Goals Heavy Drinking Hepatic Hepatocyte Histologic Homeostasis Hospitalization Human Immune response Impairment Incidence Indiana Individual Inflammation Injury to Liver Kupffer Cells Laboratories Length of Stay Lipopolysaccharides Liver Liver diseases Metabolism Modeling Mononuclear Morbidity - disease rate Multiple Abnormalities Natural Immunity Nuclear Receptors Observational Study Oral Oral cavity Oxidative Stress Pathogenesis Pathway interactions Patient Care Patients Peripheral Permeability Placebo Control Placebos Plasma Public Health Questionnaires Race Randomized Randomized Controlled Trials Recording of previous events Research Personnel Safety Sample Size Sampling Serious Adverse Event Severities Signal Transduction Staging Testing Therapeutic Studies Time Tissues Translational Research Universities Urine Virginia alcohol research bile salts case control cohort cytokine drinking effective therapy meetings member mortality named group novel novel strategies patient oriented research prospective receptor repository response therapy development translational study

项目摘要

DESCRIPTION (provided by applicant): In response to the RFA-AA-12-007, Indiana University (IU), Mayo Clinic (Mayo), and Virginia Commonwealth University (VCU) have formed a consortium "Translational Research and Evolving Alcoholic Hepatitis Treatments"(TREAT). Central hypotheses of this application are: (a) a large cohort of patients with well-characterized acute alcoholic hepatitis (AH) and matched controls greatly enhances our ability to conduct translational studies in humans to better understand its pathogenesis and to develop novel treatments, and (b) alcohol-induced impairment of signaling via bile salt receptors impairs gut integrity, permits activation of Kupffer cells, enhances oxidative stress in the liver, stimulates fatty liver, and sensitizes hepatocytes to cytokine-induced necroapoptosis, and that these abnormalities can be reversed with the FXR agonist, obeticholic acid (OCA). We will address these hypotheses by conducting the following patient- oriented studies. Specific Aim 1: To conduct a prospective multicenter observational study of patients with well-characterized AH and suitable controls that serves as the foundation for conducting novel mechanistic and therapeutic studies. A robust central bio-repository of serum/plasma, peripheral mononuclear cells, genomic DNA, urine, stool samples, and liver tissue (where available) will be developed from both cases and controls. Specific Aim 2: To test the hypothesis that alcohol-induced impairment of signaling via farnesoid X receptor (FXR, the bile salt nuclear receptor) interrupts normal bile salt homeostasis, and that this will be reversed with an FXR agonist, obeticholic acids (OCA). A secondary hypothesis is that altered FXR signaling impairs gut integrity, promotes activation of the innate immune response, enhances hepatic oxidative stress, and sensitizes hepatocytes to cytokine-induced necroapoptosis. . To address these hypotheses, we will conduct a study of bile salt metabolism and effects of OCA in heavy drinkers without liver disease (n=15), moderate drinkers (n=15), and non-drinkers (n=15). Specific Aim 3: To test the hypothesis that FXR agonists are effective in treating AH by correcting multiple abnormalities implicated in its pathogenesis. We will test this hypothesis by conducting a proof-of-concept multicenter, placebo-controlled randomized controlled trial of OCA in patients with moderately severe AH. Sixty adults with AH of moderate severity will be randomized to receive either obeticholic acid (10 mg once daily by mouth) or placebo for 4 weeks. Primary efficacy end point is change in MELD score at 4 weeks [5] and the primary safety end point is the incidence of serious adverse events (SAE) at 4 weeks. Specific aim 4: To participate in the two other proof-of-concept studies proposed by the other two members of the TREAT consortium. PUBLIC HEALTH RELEVANCE: Alcoholic Hepatitis is a major public health problem and it causes significant morbidity and mortality. It is not known why some individuals develop acute alcoholic hepatitis and also there are no effective treatments. In this application, investigators are proposing to conduct studies to better understand its pathogenesis and to develop novel treatments.

描述（由申请人提供）：响应RFA-AA-12-007，印第安纳大学（IU），梅奥诊所（Mayo）和弗吉尼亚联邦大学（VCU）成立了一个财团，“转化研究并发展了酒精性肝炎治疗”（治疗）。 Central hypotheses of this application are: (a) a large cohort of patients with well-characterized acute alcoholic hepatitis (AH) and matched controls greatly enhances our ability to conduct translational studies in humans to better understand its pathogenesis and to develop novel treatments, and (b) alcohol-induced impairment of signaling via bile salt receptors impairs gut integrity, permits activation of Kupffer cells, enhances oxidative stress in the肝脏，刺激脂肪肝，并使肝细胞对细胞因子诱导的坏死型敏感，并且可以用FXR激动剂Obeticholic Acid（OCA）将这些异常逆转。我们将通过进行以下以患者为导向的研究来解决这些假设。具体目的1：对具有良好特征AH的患者和合适的对照组进行前瞻性多中心观察研究，该研究是进行新型机械和治疗研究的基础。血清/血浆，周围单核细胞，基因组DNA，尿液，粪便样品和肝组织的强大中央生物依赖性（可用的情况下）。具体目的2：测试酒精诱导的通过Farnesoid X受体（FXR，胆汁盐核受体）的信号损害的假说中断了正常的胆汁盐稳态，并且它将用FXR激动剂，肥胖酸（OCA）逆转。次要假设是，改变的FXR信号传导会损害肠道完整性，促进先天免疫反应的激活，增强肝氧化应激，并使肝细胞对细胞因子诱导的坏死性凋亡敏感。。为了解决这些假设，我们将研究胆汁盐代谢和OCA对无肝病饮酒者（n = 15），中等饮酒者（n = 15）和非饮用者（n = 15）的胆汁盐代谢和影响。特定目的3：检验FXR激动剂可以通过纠正与其发病机理有关的多种异常来治疗AH的假设。我们将通过对中度严重AH的患者进行OCA的概念证明多中心，安慰剂对照对照试验来检验这一假设。六十名患有中等严重性的成年人将被随机分配，以接受obeticholic酸（每天10 mg一次）或安慰剂4周。主要功效终点是4周的MELD评分的变化[5]，主要安全终点是4周严重不良事件（SAE）的发生率。特定目的4：参与其他两名治疗联盟成员提出的另外两项概念验证研究。公共卫生相关性：酒精性肝炎是一个主要的公共卫生问题，它会引起大量的发病率和死亡率。尚不清楚为什么有些人会患上急性酒精性肝炎，而且没有有效的治疗方法。在此应用中，研究人员提议进行研究，以更好地了解其发病机理并开发新的治疗方法。