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

• 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
• 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' 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

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.

酗酒是全世界发病率和死亡率的主要原因。的有害 酒精滥用对肝脏的影响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。NLRP 3炎性小体是一种多蛋白质 作为模式识别受体的细胞质复合物， 炎症介质和细胞死亡。NLRP 3炎性小体感知损伤- 相关的分子模式，并诱导分泌IL-1β和IL-18， 破坏组织。我们和其他人最近发现，肝半胱天冬酶1的激活 发生在ASH和非酒精性脂肪性肝炎（NASH）的发展过程中， 活化似乎通过NLRP 3炎性体介导。这些研究 表明半胱天冬酶1在ASH期间的炎症和纤维化中起重要作用， 和NASH的发展，而IL-1受体拮抗剂改善小鼠中的ASH。的作用 NLRP 3炎性小体功能获得性突变最初在一组罕见的 自身炎性单基因病症。随后，多个基因多态性 已经被描述过，有些与常见的慢性炎症有关 包括克罗恩病和类风湿性关节炎。特别是，两种常见的多态性 影响15-20%的普通人群，已显示可导致功能获得 表型与IL-1β水平中度升高相关。 基于这些初步数据，我们提出了中心假设：1）NLRP 3是 小鼠中乙醇诱导的脂肪肝进展为ASH和纤维化所需; 2） NLRP 3-炎性体表达的遗传变异可预测疾病进展和/或严重程度 ALD和对基于IL-1的治疗的反应。为了研究这一假设， 提案有以下具体目标。第一：确定NLRP 3炎性体的作用 激活对ALD从脂肪肝进展为脂肪性肝炎和纤维化的影响。第二个： 确定导致功能获得性的NLRP 3炎性体的遗传变异的作用 ALD患者对ALD的易感性和对IL-1治疗的反应。 为了解决这些核心问题，我们组建了一个多PI调查小组，包括 炎症体生物学的先驱科学家，细胞死亡，纤维化和 酒精性肝病病理学。这些研究的结果将揭示 NLRP 3炎性体生物学及其对ALD肝脏病理学的贡献， 对患有这种疾病的患者的新的诊断和治疗策略。