Targeting DAMPs in Alcoholic Hepatitis

针对酒精性肝炎中的 DAMP

基本信息

批准号：
8851461
负责人：
WAJAHAT Zafar MEHAL
金额：
$ 37.76万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8851461
关键词：
ATP Receptors ATP phosphohydrolase Acute Adrenal Cortex Hormones Affect Alcoholic Hepatitis Alcoholic Liver Diseases Alcohols Anti-Inflammatory Agents Anti-inflammatory Antibodies Apyrase Bone Marrow Cell Proliferation Cells Chronic Clinical Collaborations Cyclosporins Data Evaluation Glycyrrhizic Acid HMGB1 Protein Health Hepatic Hepatocyte Human Inflammation Inflammatory Injury Knockout Mice Link Liver Liver Regeneration Liver diseases Measures Mitochondria Mitochondrial DNA Modeling Molecular Mus Natural regeneration Necrosis Neutrophil Infiltration Organ Outcome Pathway interactions Patients Pattern Prevention Process Production RNA RNA Sequences Receptor Inhibition Research Role Salvage Therapy Sepsis Sepsis Syndrome Serum Stem cells Sterility Symptoms TLR9 gene Testing Tissues Transgenic Mice Tumor Necrosis Factor-alpha base biobank cellular targeting cytokine deep sequencing fMet-Leu-Phe receptor formyl peptide inhibitor/antagonist injured knockout animal liver inflammation liver injury mortality mouse model next generation novel pre-clinical preclinical study problem drinker receptor receptor for advanced glycation endproducts research study response signature molecule transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): Alcoholic hepatitis (AH) is particularly severe form of alcoholic liver disease (ALD) that affects up to 20% of alcoholics and has a high mortality rate. However, the molecular pathways that trigger AH remain unknown, and therapy for alcoholic hepatitis has not changed over the past 30 years. Notably, targeting inflammatory cytokines such as TNFα or decreasing ROS production have been unsuccessful, and non-specific anti- inflammatory therapy with corticosteroids is only moderately effectively. In this proposal, we will investigate the hypothesis that signature molecules from dying cells, termed damage-associated molecular patterns (DAMPs), contribute to hepatic and systemic inflammation in AH, progenitor cell proliferation, and worsen liver injury and outcome. The proposed research will investigate several DAMPs with known role in sterile inflammation and neutrophil recruitment in the liver with a particular focus on (i) mitochondrial (mt) DAMPs due to their abundance in hepatoyctes and mitochondrial changes in ALD, and (ii) HMGB1, a key DAMP in necrotic liver injury. Our application will employ a combination of human studies in patients with AH and functional mouse studies, to identify key and druggable DAMP pathways with high relevance to AH. The proposed human studies will be performed in collaboration with Project 1, the Human Biorepository Core and the 10 clinical centers of the InTeam Consortium. For functional studies, we will test DAMP pathways in acute-on-chronic models of AH developed together with and performed in part by the Mouse Models Core of this consortium. We will determine the contribution of HMGB1 to AH by measuring HMGB1 levels in AH patients, and determining the contribution of HMGB1 and its receptor RAGE in two acute-on-chronic models of AH in novel conditional HMGB1 knockout mice and RAGE-deficient mice, respectively (Aim 1). To determine the contribution of mtDAMPs formyl peptide, mtDNA and ATP to AH, we will measure mtDNA, formyl peptide receptor 1 (FPR1), P2X7 receptor and Toll-like receptor 9 in patients, and determine their functional contribution in murine AH models using P2X7, FPR1 and TLR9 knockout mice (Aim 2). For both Aim 1 and Aim 2, DAMP and DAMP receptor levels measured in AH patients will be also correlated with clinical parameters and next generation RNA sequencing data generated in Project 1 of this consortium. Finally, we will determine the effect of pharmacologic DAMP and DAMP receptor inhibition for the prevention and treatment of murine AH focusing on inhibition of those pathways that showed the most significant contribution in Aims 1 and 2 (Aim 3). We anticipate to unravel the contribution of DAMPs to hepatic and systemic inflammation in AH, and to establish select DAMPs and their receptors as "druggable" targets in AH.

描述（由申请人提供）：酒精性肝炎 (AH) 是一种特别严重的酒精性肝病 (ALD)，影响高达 20% 的酗酒者，死亡率很高。然而，引发 AH 的分子途径仍然未知。酒精性肝炎的治疗在过去 30 年里没有改变，值得注意的是，针对 TNFα 等炎症细胞因子或减少 ROS 产生的非特异性抗炎治疗并不成功。在本提案中，我们将研究这样的假设：来自死亡细胞的特征分子（称为损伤相关分子模式（DAMP））会导致 AH 中的肝脏和全身炎症、祖细胞增殖以及肝损伤恶化。拟议的研究将调查几种在肝脏无菌炎症和中性粒细胞募集中具有已知作用的 DAMP，特别关注 (i) 线粒体 (mt) DAMP，因为它们在肝细胞中含量丰富。 (ii) HMGB1（坏死性肝损伤中的关键 DAMP）我们的应用将结合 AH 患者的人体研究和功能性小鼠研究，以确定与 AH 高度相关的关键且可药物化的 DAMP 途径。拟议的人体研究将与项目 1、人类生物库核心和 InTeam 联盟的 10 个临床中心合作进行。对于功能研究，我们将在以下环境中测试 DAMP 通路。 AH 的慢性急性模型是与该联盟的小鼠模型核心共同开发并部分执行的。我们将通过测量 AH 患者的 HMGB1 水平并确定 HMGB1 及其受体的贡献来确定 HMGB1 对 AH 的贡献。分别在新型条件 HMGB1 敲除小鼠和 RAGE 缺陷小鼠的两种 AH 急性加慢性模型中进行 RAGE（目标 1）以确定 mtDAMP 的贡献。甲酰肽、mtDNA 和 ATP 对 AH 的影响，我们将测量患者的 mtDNA、甲酰肽受体 1 (FPR1)、P2X7 受体和 Toll 样受体 9，并使用 P2X7、FPR1 和 TLR9 敲除小鼠确定它们在小鼠 AH 模型中的功能贡献（目标 2）对于目标 1 和目标 2，AH 患者中测量的 DAMP 和 DAMP 受体水平也将与临床参数相关。最后，我们将确定药理 DAMP 和 DAMP 受体抑制对小鼠 AH 的治疗和治疗的效果，重点关注在目标 1 和目标 1 中表现出最显着贡献的那些途径的抑制。 2（目标 3）我们期望揭示 DAMP 对 AH 中肝脏和全身炎症的影响，并确定选择 DAMP 及其受体作为 AH 中的“药物”靶点。