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: 9964988
• 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/9964988
• 关键词: Actins; Alzheimer' s Disease; Atherosclerosis; Bacterial Toxins; Biochemical; Biological; CASP1 gene; Development; Diabetes Mellitus; Disease; Event; Gouty Arthritis; Grant; In Vitro; Inflammasome; Inflammation; Inflammatory; Interleukin-1 beta; Interleukin-18; Link; Mediating; Molecular; Motor; Natural Immunity; Particulate Matter; Pathogenesis; Phosphorylation; Phosphotransferases; Proteins; Role; Signal Transduction; Silicosis; Stimulus; base; 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炎症体是caspase-1激活和生物分泌的重要平台 激活IL-1β和IL-18，以应对细菌毒素、颗粒物和某些内源性刺激。 此外，NLRP3的异常激活与几种获得性疾病的发病机制有关 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氏症 疾病。尽管关于刺激和激活细胞事件的研究已经取得了很大进展 NLRP3炎症体，该领域的一个主要空白是识别 NLRP3激活及caspase-1对NLRP3激活的响应机制。这个 在授予的最后一个周期中，Nek7激酶被确定为NLRP3所需的关键因素 在体外和体内对各种刺激作出反应时的激活。Nek7被证明在下游起作用 K+外流激活NLRP3。然而，K+外流通过Nek7激活NLRP3的机制 仍然不为人知。此外，NLRP3通过适配器激活caspase-1的分子事件 ASC诱导ASC齐聚和ASC斑点形成的机制还知之甚少。在这次更新中 应用，我们提出了三个特定目标的研究：(I)确定K+外流如何激活NLRP3 使用生化和活体方法通过激酶Nek7产生炎症体；(Ii)确定 调节Nek7的磷酸化以介导NLRP3的激活和(Iii)进一步表征 基于肌动蛋白的运动蛋白在ASC介导的炎症体激活机制中的作用。 了解NLRP3是如何激活的，有望为了解NLRP3的作用提供关键的见解 不同生物系统中的炎性小体将有助于新疗法的开发 预防和/或治疗炎症性疾病的方法。