Gain of function mutations in inflammasome related genes in human and experimental alcoholic liver disease

人类和实验性酒精性肝病中炎症小体相关基因功能突变的获得

基本信息

批准号：
9756246
负责人：
Ariel Feldstein
金额：
$ 32.92万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-20 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9756246
关键词：
Address Affect Alcohol abuse Alcoholic Liver Diseases Alcoholic steatohepatitis American Apoptosis Archives Biological Markers Biology Bone Marrow CASP1 gene Caspase Cell Death Chronic Cirrhosis Clinical Complex Crohn&apos s disease Data Development Disease Disease Progression Environmental Risk Factor Ethanol Fatty Liver Fibrosis General Population Genes Genetic Polymorphism Genetic Risk Genetic Variation Genetically Engineered Mouse Germany Glucocorticoids Goals Grant Hepatic Hepatitis Hepatocyte Human Immune response Immunity Immunology Inflammasome Inflammation Inflammation Mediators Inflammatory Inflammatory Response Innate Immune System Interleukin-1 Interleukin-1 Receptors Interleukin-1 beta Interleukin-18 International Kupffer Cells Lead Liver Liver diseases Mediating Minority Molecular Monitor Morbidity - disease rate Mus Pathologic Pathology Patients Pattern Pattern recognition receptor Periodicity Phenotype Play Predisposition Production Proteins Research Personnel Resources Rheumatoid Arthritis Role Sampling Scientist Serum Severities Severity of illness Steatohepatitis Syndrome Testing Tissues Treatment Efficacy Treatment outcome Universities Wound Healing alcohol effect autoinflammatory base cohort cytokine design effective therapy gain of function gain of function mutation genetic association improved in vivo macrophage marenostrin mortality nonalcoholic steatohepatitis novel novel diagnostics novel therapeutics problem drinker recruit response small molecule inhibitor

项目摘要

Alcohol abuse is a leading cause of morbidity and mortality worldwide. The deleterious effects of alcohol abuse on the liver leads to pathologically distinct entities: steatosis, steatohepatitis (ASH), fibrosis and cirrhosis. NLRP3 inflammasome is a multi-protein cytoplasmic complex that serves as pattern recognition receptor and has emerged as key mediator of inflammation, and cell death. The NLRP3 inflammasome senses damage- associated molecular patterns and induces secretion of IL-1β and IL-18 that may be destructive to tissues. We, and others, have recently shown that hepatic caspase 1 activation occurs during the development of ASH and nonalcoholic steatohepatitis (NASH) and this activation appears to be mediated through the NLRP3 inflammasome. These studies demonstrated that caspase 1 plays an important role in inflammation and fibrosis during ASH and NASH development while IL-1 receptor antagonist ameliorates ASH in mice. A role for NLRP3 inflammasome gain-of-function mutations was initially described in a group of rare autoinflammatory monogenic conditions. Subsequently, multiple gene polymorphisms have been described and some have been implicated in common chronic inflammatory conditions including Crohn's disease and rheumatoid arthritis. In particular, two common polymorphisms affecting 15-20% of general population have been shown to result in gain-of-function phenotype associated with moderately increased IL-1β levels. Based on these preliminary data we propose the CENTRAL HYPOTHESIS that 1) NLRP3 is required for the progression of ethanol-induced fatty liver to ASH and fibrosis in mice; 2) Genetic variation in NLRP3-inflammasome expression predicts progression and/or severity of ALD and response to IL-1-based therapy in ASH. To investigate this hypothesis our proposal has following SPECIFIC AIMS. First: Determine the role of NLRP3 inflammasome activation on ALD progression from fatty liver to steatohepatitis and fibrosis. Second: Determine the role of genetic variations of NLRP3 inflammasome resulting in gain-of-function phenotypes in susceptibility to ALD and response to IL-1-based therapy in patients with ALD. To address these central issues, we have put together a Multi-PI investigative team including a Pioneered Scientist in Inflammasome Biology, and Experts in Cell Death, Fibrosis and Alcoholic Liver Disease Pathology. The results of these studies will uncover crucial aspects of NLRP3 inflammasome biology and its contribution to liver pathology in ALD that may lead to novel diagnostic and therapeutic strategies for patients with this disease.

酗酒是全世界发病和死亡的主要原因。酗酒对肝脏的影响会导致病理上不同的实体：脂肪变性，脂肪性肝炎 (ASH)、纤维化和肝硬化 NLRP3 炎性体是一种多蛋白。细胞质复合物作为模式识别受体并已成为关键 NLRP3 炎症小体是炎症和细胞死亡的介质。相关的分子模式并诱导 IL-1β 和 IL-18 的分泌，这可能是我们和其他人最近发现肝 caspase 1 激活。发生在 ASH 和非酒精性脂肪性肝炎 (NASH) 的发展过程中，这这些研究似乎是通过 NLRP3 炎症小体介导的。 Caspase 1 在 ASH 期间的炎症和纤维化中发挥重要作用和 NASH 的发展，而 IL-1 受体拮抗剂可改善小鼠的 ASH。 NLRP3 炎症小体功能获得性突变最初是在一组罕见的随后，出现多基因多态性。已被描述，其中一些与常见的慢性炎症有关尤其是克罗恩病和类风湿性关节炎这两种常见的多态性。影响 15-20% 的普通人群已被证明可导致功能获得表型与中度升高的 IL-1β 水平相关。基于这些初步数据，我们提出中心假设 1) NLRP3 是小鼠乙醇诱导的脂肪肝进展为 ASH 和纤维化所需的 2) NLRP3炎症体表达的遗传变异可预测进展和/或严重程度酒精性肝病 (ALD) 和对 ASH 中基于 IL-1 的治疗的反应为了研究这一假设，我们进行了研究。该提案有以下具体目标：首先：确定 NLRP3 炎性体的作用。激活 ALD 从脂肪肝进展为脂肪性肝炎和纤维化的作用第二：确定 NLRP3 炎性体遗传变异在功能获得中的作用 ALD 患者对 ALD 的易感性表型以及对基于 IL-1 的治疗的反应。为了解决这些核心问题，我们组建了一个多 PI 调查团队，其中包括炎症体生物学领域的先驱科学家，细胞死亡、纤维化和细胞死亡领域的专家这些研究的结果将揭示酒精性肝病病理学的关键方面。 NLRP3 炎性体生物学及其对 ALD 肝脏病理学的贡献可能导致为患有这种疾病的患者提供新的诊断和治疗策略。