Targeting DAMPs in Alcoholic Hepatitis

针对酒精性肝炎中的 DAMP

• 批准号: 8427971
• 负责人: WAJAHAT Zafar MEHAL
• 金额: $ 42.02万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8427971
• 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; 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; TNF gene; Testing; Tissues; Transgenic Mice; 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; public health relevance; receptor; receptor for advanced glycation endproducts; research study; response; signature molecule

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 TNF! 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，死亡率高。然而，触发AH的分子途径仍然未知，酒精性肝炎的治疗在过去30年中没有改变。值得注意的是，靶向炎症细胞因子，如TNF！或减少ROS产生的方法都不成功，并且用皮质类固醇进行的非特异性抗炎治疗仅是中等有效的。在本提案中，我们将 研究来自死亡细胞的标记分子（称为损伤相关分子模式（DAMP））有助于AH中的肝脏和全身炎症、祖细胞增殖以及恶化肝损伤和结局的假设。拟议的研究将调查几种已知在肝脏中无菌炎症和中性粒细胞募集中起作用的DAMP，特别关注（i）线粒体（mt）DAMP，因为它们在肝细胞中的丰度和ALD中的线粒体变化，以及（ii）HMGB 1，坏死性肝损伤中的关键DAMP。我们的申请将采用AH患者的人体研究和功能性小鼠研究的组合，以确定与AH高度相关的关键和可药物化的DAMP途径。拟定的人体研究将与项目1、人类生物储存库核心和InTeam联盟的10个临床中心合作进行。对于功能研究，我们将在与该联盟的小鼠模型核心共同开发并部分执行的急性-慢性AH模型中测试DAMP通路。我们将通过测量AH患者中的HMGB 1水平来确定HMGB 1对AH的贡献，并分别在新的条件性HMGB 1敲除小鼠和RAGE缺陷小鼠的两种急性慢性AH模型中确定HMGB 1及其受体α的贡献（目的1）。为了确定mtDAMP甲酰基肽、mtDNA和ATP对AH的贡献，我们将测量患者的mtDNA、甲酰基肽受体1（FPR 1）、P2 X7受体和Toll样受体9，并使用P2 X7、FPR 1和TLR 9敲除小鼠确定它们在小鼠AH模型中的功能贡献（目的2）。对于目标1和目标2，AH患者中测量的DAMP和DAMP受体水平也将与该联盟项目1中生成的临床参数和下一代RNA测序数据相关。最后，我们将确定药物DAMP和DAMP受体抑制对预防和治疗小鼠AH的作用，重点是抑制在目的1和2（目的3）中表现出最显著贡献的那些途径。我们期望阐明DAMPs对AH中肝脏和全身炎症的贡献，并建立选择DAMPs及其受体作为AH中的“可用药”靶点。!