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.

项目总结