Cardiac fibroblast inflammasome and atrial myopathy

心脏成纤维细胞炎症小体与心房肌病

• 批准号: 10597243
• 负责人: Na Li
• 金额: $ 69.97万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-25 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10597243
• 关键词: Action Potentials; Address; Affect; Anti-Inflammatory Agents; Area; Arrhythmia; Atrial Fibrillation; Attenuated; Automobile Driving; Cardiac; Cardiac Myocytes; Cells; Chronic; Complex; Contractile Proteins; Coupling; Data; Development; Evaluation; Evolution; Exhibits; Family; Fibroblasts; Fibrosis; Functional disorder; Genetic Transcription; Glucocorticoid Receptor; HCN4 gene; Heart Atrium; Histology; Impairment; Infarction; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Interleukins; Knock-in Mouse; Left; Left atrial structure; Macrophage; Maintenance; Maps; Mediating; Messenger RNA; Modeling; Molecular; Morbidity - disease rate; Mus; Myocardium; Myopathy; NCOA3 gene; Nuclear; Optics; Outcome Study; Pacemakers; Pathogenesis; Pathology; Pathway interactions; Patients; Peroxisome Proliferator-Activated Receptors; Phase; Phenocopy; Phenotype; Pilot Projects; Predisposition; Prevalence; Prevention; Profibrotic signal; Proteins; Public Health; Recombinant Interleukins; Resolution; Role; Signal Transduction; Sinoatrial Node; Sinus; Testing; Therapeutic; Work; combat; efficacy evaluation; heart function; imaging study; improved; insight; knock-down; marenostrin; mortality; neutralizing antibody; novel; paracrine; patch clamp; prevent; response; transcription factor

PROJECT SUMMARY Atrial fibrillation (AF) is the most frequent arrhythmia. Atrial myopathy is a key determinant of the development of AF. The molecular mechanisms underlying the evolution of AF-promoting atrial myopathy are complex and poorly understood. Innate inflammatory signaling including the ‘NLR family pyrin domain containing 3’ (NLRP3) inflammasome pathway can modulate cardiac function and atrial arrhythmogenesis. Our preliminary study revealed that NLRP3 inflammasome activity is enhanced in atrial cardiac fibroblasts (CFs) of persistent AF patients compared with sinus rhythm controls. The CF-specific activation of NLRP3 in mice promotes the development of atrial fibrosis, enlarged left atrium, reduced atrial contractility, abnormal impulse conduction, sinus node dysfunction, and increased AF susceptibility, phenocopying atrial myopathy associated with AF development. In this proposal, we will test the hypothesis that activation of CF inflammasomes enhances atrial arrhythmogenesis by promoting atrial myopathy. Additionally, the therapeutic potential of enhancing the resolution of inflammation to combat atrial myopathy and atrial arrhythmogenesis deserves evaluation. In this proposal, we will also evaluate whether an inducer of inflammation resolution can prevent the inflammasome- induced atrial myopathy, thereby reducing atrial arrhythmogenesis. This proposal addresses several understudied areas in AF pathogenesis. The outcome of this study will provide novel insights into the development of atrial myopathy and sinus node dysfunction, as well as provide rationale for using the pro- resolution molecule in AF prevention.

项目摘要 心房颤动（AF）是最常见的心律失常。心房肌病是发展的关键决定者 AF。促进AF的心房肌病演变的基础的分子机制是复杂的，并且 理解不佳。先天炎症信号传导，包括“ NLR家族pyrin结构域，含有3'（NLRP3） 炎性途径可以调节心脏功能和心律失常发生。我们的初步研究 揭示了NLRP3炎性体活性在持久性AF的心房成纤维细胞（CFS）中增强了 患者与鼻窦节律对照相比。小鼠NLRP3的CF特异性激活促进了 心房纤维化的发展，左心房增加，心房收缩性降低，脉冲传导异常， 鼻窦淋巴结功能障碍和AF敏感性增加，表观复制与AF相关的心房肌病 发展。在此提案中，我们将检验以下假设：CF炎症的激活增强了心房 心律失常通过促进心房肌病。另外，增强的治疗潜力 炎症的分辨率应对房屋肌病和心律失常的作用应得到评估。在这个 提案，我们还将评估炎症诱导者是否可以防止炎症体 - 诱导心房肌病，从而减少心律失常。该提议解决了几个 AF发病机理的研究区域。这项研究的结果将为您提供新的见解 心房肌病和鼻窦节点功能障碍的发展，并提供了使用促进的理由 在预防AF中的分辨率分子。