Targeting DAMPs in Alcoholic Hepatitis

针对酒精性肝炎中的 DAMP

• 批准号: 8669780
• 负责人: WAJAHAT Zafar MEHAL
• 金额: $ 38.53万
• 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/8669780
• 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，死亡率很高。然而，引发AH的分子途径仍然未知，并且酒精性肝炎的治疗方法在过去30年中没有改变。值得注意的是，针对炎性细胞因子，如TNF！或减少ROS的产生都不成功，非特异性抗炎治疗用皮质类固醇仅是中等有效。在这个提议中，我们将