Cardiac fibroblast inflammasome and atrial myopathy

心脏成纤维细胞炎症小体与心房肌病

基本信息

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
项目类别：
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

项目摘要

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.

项目概要心房颤动（AF）是最常见的心律失常，是心房肌病发生的关键决定因素。 AF 促进性心房肌病演变的分子机制非常复杂。对先天炎症信号传导知之甚少，包括“NLR家族pyrin结构域3”（NLRP3）。我们的初步研究表明，炎症小体通路可以调节心脏功能和房性心律失常的发生。揭示持续性 AF 的心房心脏成纤维细胞 (CF) 中 NLRP3 炎性体活性增强与窦性心律对照相比，患者中 NLRP3 的 CF 特异性激活促进了心房纤维化、左心房扩大、心房收缩力降低、冲动传导异常、窦房结功能障碍、房颤易感性增加、与房颤相关的表型心房肌病在本提案中，我们将测试 CF 炎症小体的激活增强心房的假设。此外，通过促进心房肌病的治疗潜力。消除炎症以对抗心房肌病和房性心律失常的作用值得评估。建议，我们还将评估炎症消退的诱导剂是否可以预防炎症小体- 诱发心房肌病，从而减少房性心律失常的发生。该提案解决了几个问题。这项研究的结果将为 AF 发病机制的研究提供新的见解。心房肌病和窦房结功能障碍的发展，并为使用亲 AF 预防中的解决分子。