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：
8443468
负责人：
JOSEPH A DUNCAN
金额：
$ 6.07万
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 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8443468
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-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 computerized data processing 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 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. PUBLIC HEALTH RELEVANCE: We have found that several virulence factors from Methicillin Resistant S. aureus (MRSA) activate an innate immune signaling complex known as the inflammasome. We propose to carry out studies to understand how activation of host inflammation by the inflammasome affects the pathogenesis of MRSA infections. We also propose detailed studies into the mechanism that underlies activation of the inflammasome, which may identify targets for the development of pharmacologic agents that could improve the treatment of these deadly infections.

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依赖于先天免疫系统信号传导。最近发现的病原体感应信号通路之一涉及炎症小体的激活，炎症小体是一种大分子复合物，负责几种未成熟细胞因子（特别是 IL-12 和 IL-18）的蛋白水解加工。 ATP 结合蛋白 NLRP3 在炎性体组装过程中充当中心支架。除了细胞因子加工之外，我们最近发现通过 NLRP3 的信号传导激活了一种具有坏死形态和生化特征的新型细胞死亡程序。 NLRP3 炎症小体可以被多种已知诱导 IL-12 分泌的刺激激活，这表明 NLRP3 的生理作用是将反应整合到一系列促炎症触发因素。 NLRP3 核苷酸结合域的突变可导致遗传性周期性发热综合征。我们最近还发现金黄色葡萄球菌的一些关键毒力因子也会激活 NLRP3 炎症小体。表达这些毒力因子的金黄色葡萄球菌可引起严重的坏死性肺炎，其特征是全身炎症反应和组织坏死。我们认为，突变和病原体衍生的毒力因子对 NLRP3 的激活代表了导致与这些刺激相关的炎症失调和疾病进展的病理事件。我们现在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发病机制中的作用。这些研究将为理解涉及大量人类疾病发病机制的炎症信号传导过程提供重要信息。公共健康相关性：我们发现，耐甲氧西林金黄色葡萄球菌 (MRSA) 的几种毒力因子会激活一种称为炎症小体的先天免疫信号复合物。我们建议开展研究以了解炎症小体激活宿主炎症如何影响 MRSA 感染的发病机制。我们还建议对炎症小体激活的机制进行详细研究，这可能会确定开发药物的靶标，从而改善这些致命感染的治疗。