Molecular mechanism of NLRP3 inflammasome activation

NLRP3炎症小体激活的分子机制

• 批准号: 10158435
• 负责人: Yuan He
• 金额: $ 38.01万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-04 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10158435
• 关键词: ATP phosphohydrolase; Alzheimer' s Disease; Atherosclerosis; Binding; Biological; CASP1 gene; Crohn' s disease; Data; Development; Diabetes Mellitus; Disease; Event; Goals; Gout; In Vitro; Inflammasome; Inflammatory; Inherited; Innate Immune System; Interleukin-1 beta; Interleukin-18; Investigation; Link; Mediating; Molecular; Natural Immunity; Pathogenesis; Pathway interactions; Peptides; Periodicity; Phosphorylation; Phosphotransferases; Potassium; Protein Kinase; Proteins; Regulation; Role; Signal Transduction; Stimulus; Surface; Syndrome; Testing; Therapeutic Intervention; autoinflammatory; base; human disease; in vivo; innovation; insight; macrophage; molecular targeted therapies; novel; novel therapeutic intervention

Project Summary NACHT, LRR and PYD domains-containing protein 3 (NLRP3) is a critical component of the innate immune system that forms the NLRP3 inflammasome, an intracellular molecular platform that drives caspase-1 activation and the secretion of biologically active IL-1β and IL-18. In addition to its protective role in innate immunity, aberrant activation of the NLRP3 inflammasome contributes to the pathogenesis of several inherited and acquired inflammatory disorders, such as Cryopyrin-associated autoinflammatory syndrome, gout, Crohn's disease, Alzheimer's disease, diabetes and atherosclerosis. Despite extensive investigation, the molecular mechanism leading to NLRP3 inflammasome activation remains elusive. Recently, the protein kinase Nek7 has been found to mediate NLRP3 inflammasome activation independently of its kinase activity. However, it is unknown how Nek7 is mechanistically linked to NLRP3 inflammasome activation. Our recent studies implicate a critical role for Nek7 phosphorylation in NLRP3 inflammasome activation. In this application we aim to elucidate the molecular mechanism of Nek7-mediated NLRP3 inflammasome activation and determine the role of a novel regulator in this pathway. Our results are expected to provide new mechanistic insights into NLRP3 inflammasome activation and might guide the development of novel therapeutic strategies for treating NLRP3-driven inflammatory diseases.

项目摘要 Nacht、LRR和PYD结构域包含蛋白3(NLRP3)是NACHT、LRR和PYD结构域的重要组成部分 形成NLRP3炎症体的天然免疫系统，这是细胞内的分子平台 这推动了caspase-1的激活以及生物活性IL-1β和IL-18的分泌。此外 NLRP3炎症体的异常激活对先天免疫的保护作用 与几种遗传性和获得性炎症性疾病的发病机制有关，如 如低温蛋白相关性自炎综合征、痛风、克罗恩病、阿尔茨海默氏症 疾病、糖尿病和动脉粥样硬化。尽管进行了广泛的研究，但其分子机制 导致NLRP3炎症的小体激活仍然难以捉摸。最近，蛋白激酶Nek7 已被发现介导NLRP3炎症体激活不依赖于其激酶活性。 然而，目前尚不清楚Nek7与NLRP3炎性小体激活之间的机制联系。 我们最近的研究表明，Nek7的磷酸化在NLRP3炎症体中起着关键作用 激活。在这一应用中，我们旨在阐明Nek7介导的分子机制 NLRP3炎症体激活，并确定一个新的调节因子在这一途径中的作用。我们的 这一结果有望为NLRP3炎症小体激活提供新的机制见解 并可能指导开发治疗NLRP3驱动的新的治疗策略 炎症性疾病。