Cryopyrin/NLRP3 Signaling in Inflammation and Innate Immunity

Cryopyrin/NLRP3 信号在炎症和先天免疫中的作用

• 批准号: 10536627
• 负责人: Gabriel Nunez
• 金额: $ 39万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10536627
• 关键词: Actins; Alzheimer' s Disease; Atherosclerosis; Bacterial Toxins; Biochemical; CASP1 gene; Development; Diabetes Mellitus; Disease; Event; Gouty Arthritis; Grant; IL18 gene; In Vitro; Inflammasome; Inflammation; Inflammatory; Interleukin-1 beta; Link; Mediating; Molecular; Motor; Natural Immunity; Particulate Matter; Pathogenesis; Phosphorylation; Phosphotransferases; Proteins; Role; Signal Transduction; Silicosis; Stimulus; biological systems; in vivo; insight; novel therapeutic intervention; prevent; response

The NLRP3 inflammasome is a critical platform for the activation of caspase-1 and secretion of biologically active IL-1β and IL-18 in response to bacterial toxins, particulate matter and certain endogenous stimuli. Furthermore, aberrant activation of NLRP3 has been linked to the pathogenesis of several acquired inflammatory disorders including gouty arthritis, silicosis, atherosclerosis, diabetes and Alzheimer’s disease. Although much progress has been made about the stimuli and cellular events that activate the NLRP3 inflammasome, a major gap in the field is the identification of molecules that are required for NLRP3 activation and the mechanism of caspase-1 activation in response to NLRP3 activating stimuli. The Nek7 kinase was identified during the last cycle of the grant as a critical factor required for NLRP3 activation in response to a wide array of stimuli in vitro and in vivo. Nek7 was shown to act downstream of K+ efflux to activate NLRP3. However, the mechanism by which K+ efflux activates NLRP3 via Nek7 remains unknown. Furthermore, the molecular events by which NLRP3 activates caspase-1 via the adaptor ASC to induce ASC oligomerization and ASC speck formation are poorly understood. In this renewal application, we propose studies in three specific Aims to (i) determine how K+ efflux activates the NLRP3 inflammasome through the kinase Nek7 using biochemical and in vivo approaches; (ii) identify factors that regulate the phosphorylation of Nek7 to mediate the activation of NLRP3 and (iii) further characterize the role of actin-based motor proteins in the mechanism of ASC-mediated inflammasome activation. Understanding how NLRP3 is activated is expected to provide critical insight into the role of the inflammasomes in different biological systems which will aid the development of new therapeutic approaches to prevent and/or treat inflammasome-associated diseases.

NLRP3 炎症小体是激活 caspase-1 和分泌生物活性物质的关键平台。 活性 IL-1β 和 IL-18 对细菌毒素、颗粒物和某些内源性刺激作出反应。 此外，NLRP3 的异常激活与多种获得性遗传病的发病机制有关。 炎症性疾病，包括痛风性关节炎、矽肺、动脉粥样硬化、糖尿病和阿尔茨海默病 疾病。尽管在激活细胞的刺激和细胞事件方面已经取得了很大进展 NLRP3 炎症小体，该领域的一个主要空白是鉴定所需的分子 NLRP3 激活和 caspase-1 响应 NLRP3 激活刺激而激活的机制。这 Nek7 激酶在资助的最后一个周期中被确定为 NLRP3 所需的关键因素 响应体内和体外的各种刺激而激活。 Nek7被证明在下游发挥作用 K+ 流出以激活 NLRP3。然而，K+ 外排通过 Nek7 激活 NLRP3 的机制 仍然未知。此外，NLRP3 通过适配器激活 caspase-1 的分子事件 ASC 诱导 ASC 寡聚化和 ASC 斑点形成的作用尚不清楚。在这次更新中 应用中，我们提出了三个具体目标的研究，以 (i) 确定 K+ 外排如何激活 NLRP3 使用生化和体内方法通过激酶 Nek7 产生炎症小体； (ii) 确定因素 调节 Nek7 的磷酸化以介导 NLRP3 的激活，并且 (iii) 进一步表征 基于肌动蛋白的运动蛋白在 ASC 介导的炎症小体激活机制中的作用。 了解 NLRP3 的激活方式有望为了解 NLRP3 的作用提供重要见解。 不同生物系统中的炎症小体将有助于开发新的治疗方法 预防和/或治疗炎性体相关疾病的方法。