Regulation of the physiologic and pathologic activation of the NLRP3-inflammasome

NLRP3 炎症小体生理和病理激活的调节

基本信息

批准号：
8646852
负责人：
JOSEPH A DUNCAN
金额：
$ 42.7万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8646852
关键词：
ATP Hydrolysis ATP phosphohydrolase Affect Antibiotics Apoptosis Apoptotic Binding Binding Proteins Biochemical Caspase-1 Cathepsins B Cell-Free System Cells Complex Cultured Cells Cysteine Protease Development Disease Progression Event Fever G-substrate GTP-Binding Proteins Gene Components Genes Hemolysin Human Immune Immune response Immune system Immunologics In Vitro Infection Inflammation Inflammatory Inflammatory Response Inherited Injury Interleukin-1 Interleukin-12 Interleukin-18 Lead Life Macromolecular Complexes Mediating Molecular Morbidity - disease rate Mus Mutation Necrosis Nucleotides Panton-Valentine leukocidin Pathogenesis Pathologic Peptide Hydrolases Physiological Pneumonia Process Proteins Proteolytic Processing Recombinants Regulation Role Signal Pathway Signal Transduction Staphylococcus aureus Stimulus Syndrome System Tissues Toxin Virulence Factors cytokine guanine nucleotide binding protein human disease improved inhibitor/antagonist knock-down lung injury methicillin resistant Staphylococcus aureus mortality mouse model novel pathogen prevent public health relevance reconstitution response scaffold signal processing small hairpin RNA

项目摘要

DESCRIPTION (provided by applicant): The ability to recognize pathogens and initiate inflammatory and immunologic processes to control their spread relies on innate immune system signaling. One of the most recently identified pathogen-sensing signaling pathways involves the activation of the inflammasome, a macromolecular complex responsible for proteolytic processing of several immature cytokines (IL- 12 and IL-18 in particular). The ATP-binding protein NLRP3 acts as a central scaffold during in the assembly of the inflammasome. In addition to cytokine processing, we have recently found that signaling through NLRP3 activates a novel cell death program with morphologic and biochemical features of necrosis. The NLRP3-inflammasome can be activated by numerous stimuli known to induce IL-12 secretion, suggesting that the physiologic role of NLRP3 is to integrate the response to a range of pro-inflammatory triggers. Mutations in the nucleotide-binding domain of NLRP3 can cause inherited periodic fever syndromes. We have also recently discovered that some critical virulence factors from Staphylococcus aureus activate the NLRP3 inflammasome as well. S. aureus that express these virulence factors can cause with severe necrotizing pneumonias that are characterized by systemic inflammatory response and tissue necrosis. We believe activation of NLRP3 by mutation and pathogen-dervived virulence factors represent pathologic events that lead to dysregulated inflammation and progression diseases associated with these stimuli. We now propose to further investigate both the molecular mechanisms regulating NLRP3 activation and its role in the pathogenesis of S. aureus infections. These studies will provide crucial information in understanding inflammatory signaling processes involved in the pathogenesis of a huge array of human diseases.

描述（由申请人提供）：识别病原体并启动炎症和免疫过程以控制其传播的能力取决于先天免疫系统信号。最近确定的病原体传感信号通路之一涉及炎性体的激活，炎症体是一种大分子复合物，负责多种未成熟细胞因子（尤其是IL-12和IL-18）的蛋白水解加工。在炎性体组装过程中，ATP结合蛋白NLRP3充当中央支架。除了细胞因子加工之外，我们最近发现，通过NLRP3信号传导通过形态学和生化特征激活了新的细胞死亡程序。 NLRP3-炎症体可以通过已知诱导IL-12分泌的众多刺激激活，这表明NLRP3的生理作用是整合对一系列促炎性触发因素的反应。 NLRP3的核苷酸结合结构域中的突变会引起遗传周期性发烧综合征。我们最近还发现，金黄色葡萄球菌的一些关键毒力因子也激活了NLRP3炎症体。表达这些毒力因子的金黄色葡萄球菌可能导致严重的坏死性肺炎，其特征是全身性炎症反应和组织坏死。我们认为，通过突变和病原体衍生的毒力因子激活NLRP3代表病理事件，导致与这些刺激相关的炎症和进展疾病失调。现在，我们建议进一步研究调节NLRP3激活的分子机制及其在金黄色葡萄球菌感染的发病机理中的作用。这些研究将为理解大量人类疾病发病机理涉及的炎症信号传导过程提供至关重要的信息。