Molecular mechanism of NLRP3 inflammasome activation

NLRP3炎症小体激活的分子机制

• 批准号: 10390480
• 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/10390480
• 关键词: ATP phosphohydrolase; Alzheimer' s Disease; Atherosclerosis; Binding; 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.

项目概要 含有 NAHT、LRR 和 PYD 结构域的蛋白 3 (NLRP3) 是 先天免疫系统形成 NLRP3 炎性体（一种细胞内分子平台） 驱动 caspase-1 激活以及具有生物活性的 IL-1β 和 IL-18 的分泌。 其在先天免疫中的保护作用，NLRP3 炎症小体的异常激活 导致多种遗传性和获得性炎症性疾病的发病机制，例如 如冷吡啶相关自身炎症综合征、痛风、克罗恩病、阿尔茨海默病 尽管进行了广泛的研究，但其分子机制仍然存在。 最近，蛋白激酶 Nek7 导致 NLRP3 炎症小体激活仍然难以捉摸。 已发现独立于其激酶活性来介导 NLRP3 炎性体激活。 然而，Nek7 与 NLRP3 炎症小体激活的机制尚不清楚。 我们最近的研究表明 Nek7 磷酸化在 NLRP3 炎症小体中发挥着关键作用 在此应用中，我们旨在阐明 Nek7 介导的分子机制。 NLRP3 炎症小体激活并确定新型调节剂在该途径中的作用。 研究结果有望为 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 驱动的新治疗策略 炎症性疾病。