The Role of Gasdermin-D/Interleukin-1 Nexus in Atrial Arrhythmogenesis

Gasdermin-D/IL-1 Nexus 在房性心律失常发生中的作用

• 批准号: 10363449
• 负责人: Na Li
• 金额: $ 67.89万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10363449
• 关键词: Acute; Address; Antibodies; Arrhythmia; Atrial Fibrillation; Attenuated; Biological Process; CASP1 gene; Cardiac Myocytes; Cell Death; Cell membrane; Cells; Chronic; Data; Development; Event; Exhibits; Frequencies; Goals; Heart Atrium; Human; Immune; In Vitro; Inflammasome; Inflammatory; Interleukin-1; Interleukin-1 Receptors; Interleukins; Lytic; Mediating; Modeling; Molecular; Mus; Mutate; N-terminal; Obesity; Outcome Study; Pathogenesis; Patients; Phenotype; Pilot Projects; Play; Postoperative Period; Predisposition; Prevalence; Proteins; Public Health; Refractory; Research Project Grants; Role; Signal Transduction; System; Testing; Viral; Work; anakinra; cytokine; gain of function; knock-down; mouse model; neutralizing antibody; novel; outcome prediction; overexpression; prevent; receptor

PROJECT SUMMARY Atrial fibrillation (AF) is the most frequent arrhythmia. Enhanced activation of ‘NACHT, LRR and PYD domains- containing protein 3’ (NLRP3) inflammasome plays a causal role in promoting proarrhythmic events associated with AF development. Activation of NLRP3 inflammasome produces two major effectors: interleukin (IL)-1b and cleaved (active) N-terminal gasdermin-D (GSDMDNT). The precise functions of IL-1b and GSDMDNT in cardiomyocytes and atrial arrhythmogenesis are largely unknown. Our preliminary data revealed that cardiomyocyte-specific knockdown of IL-1b receptor type-1 (IL-1R1) attenuates susceptibility to AF of mice with cardiomyocyte NLRP3 gain-of-function. Meanwhile, atrial specific overexpression of GSDMDNT in mice (aGSDMDNT) also creates an arrhythmic substrate for AF development. Because the main function of GSDMDNT is to form plasma membrane pores allowing the cell release of IL-1b and IL-1b protein is upregulated in aGSDMDNT mice, we hypothesized that this GSDMDNT/IL-1b nexus creates a substrate for AF by promoting a feedforward loop of NLRP3-inflammasome activation. Using mouse and human atrial systems we propose to 1) elucidate the role of IL-1b signaling in cardiomyocytes and atrial arrhythmogenesis, 2) establish the causative role and the functions of cardiomyocyte GSDMDNT in atrial arrhythmogenesis, and 3) establish and validate GSDMDNT/IL-1b nexus as the driver of a feedforward loop of NLRP3-inflammasome activation in atrial arrhythmogenesis. The outcome of these studies will provide a proof-of-concept for atrial specific targeting of IL- 1b signaling in AF patients and uncover novel and unique functions of IL-1b and GSDMDNT in atrial cardiomyocytes and their specific contributions to AF development.

项目摘要 心房颤动（AF）是最常见的心律失常。增强了'NACHT，LRR和PYD结构域的激活 含有蛋白质3'（nlrp3）炎性体在促进促伴有的事件中起因果作用 与自动房屋的开发。 NLRP3炎性体的激活产生两个主要影响：白介素（IL）-1b和 裂解（活跃的）N末端Gasdermin-D（GSDMDNT）。 IL-1B和GSDMDNT的精确函数 心肌细胞和心律失常的发生在很大程度上未知。我们的初步数据表明 IL-1B受体类型1B受体（IL-1R1）的心肌细胞特异性敲低可减弱对小鼠对AF的敏感性 心肌细胞NLRP3功能获得。同时，小鼠GSDMDNT的心房特异性过表达 （AGSDMDNT）还为AF开发创造了心律不齐的底物。因为GSDMDNT的主要功能 在形成允许IL-1B和IL-1B蛋白的细胞释放的质膜孔的形成质膜孔。 AGSDMDNT小鼠，我们假设该GSDMDNT/IL-1B Nexus通过促进A为AF创造了AF的底物 NLRP3-炎症体激活的前馈环。使用鼠标和人类心房系统，我们建议1） 阐明IL-1B信号传导在心肌细胞中的作用和心律失常发生，2）建立病因 心肌心律发生中心肌细胞GSDMDNT的作用和功能，3）建立和验证 GSDMDNT/IL-1B Nexus作为心房中NLRP3-炎症的前进环的驱动器 心律失常。这些研究的结果将为心房特异性靶向IL-提供概念概念。 AF患者的1B信号传导，并发现心房中IL-1B和GSDMD的新颖和独特功能 心肌细胞及其对AF发育的具体贡献。