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因素 AF促进性心房肌病变演变的分子机制是复杂的， 不太了解。天然炎症信号传导，包括“含NLR家族pyrin结构域3”（NLRP3） 炎性小体通路可调节心功能和心房颤动的发生。我们的初步研究 显示NLRP 3炎性小体活性在持续性AF的心房心脏成纤维细胞（CF）中增强 与窦性心律对照组比较。小鼠中NLRP 3的CF特异性激活促进了细胞内的细胞凋亡。 心房纤维化的发展，左心房增大，心房收缩力降低，异常冲动传导， 窦房结功能障碍，房颤易感性增加，与房颤相关的房性肌病表型 发展在这个建议中，我们将测试CF炎性小体激活增强心房肌细胞增殖的假设。 通过促进心房肌病变而引起心房肌病变。此外，增强免疫抑制剂的治疗潜力也是一个潜在的问题。 对抗心房肌病和心房肌纤维化的炎症消退值得评价。在这 建议，我们还将评估炎症消退诱导剂是否可以预防炎性小体， 诱发心房肌病变，从而减少心房肌的发生。该提案涉及几个 AF发病机制研究不足的领域。这项研究的结果将提供新的见解， 心房肌病变和窦房结功能障碍的发展，以及提供使用前 分辨率分子在预防房颤中的作用