Atrial Remodeling and Susceptibility to Fibrillation

心房重塑和颤动的易感性

• 批准号: 10077580
• 负责人: Thao P. Nguyen
• 金额: $ 43.04万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10077580
• 关键词: Accounting; Action Potentials; Address; Aging; Animal Model; Arrhythmia; Atherosclerosis; Atrial Fibrillation; Behavior; Cardiac Myocytes; Cell Lineage; Cell Separation; Cells; Clinical; Clinical Research; Closure by clamp; Communication; Complex; Computational Biology; Coupling; Data; Dementia; Deposition; Development; Electrophysiology (science); Elements; Epidemic; Etiology; Evolution; Fibroblasts; Fibrosis; Functional disorder; Future; Gap Junctions; Gene Expression; Genetic Transcription; Genomics; Goals; Health Care Costs; Heart Atrium; Heart failure; High Prevalence; Human; Hypertension; Intervention; Knowledge; Laboratories; Link; Maintenance; Mathematics; Mission; Modeling; Morbidity - disease rate; Muscle Cells; Myofibroblast; Natural History; Obesity; Oryctolagus cuniculus; Pathway interactions; Patients; Pattern; Phase; Pre-Clinical Model; Predisposition; Prevalence; Prevention strategy; Preventive; Preventive therapy; Process; Public Health; Rattus; Reproducibility; RiboTag; Risk; Risk Factors; Role; Source; Stress; Stroke; Structure; Testing; Therapeutic; Tissues; United States National Institutes of Health; Work; base; clinically relevant; density; design; disability; epidemiology study; innovation; interdisciplinary approach; lifetime risk; mortality; myocardial injury; novel; patch clamp; pre-clinical; public health relevance; response; single-cell RNA sequencing; synergism; transcriptome; transcriptomics; virtual

PROJECT SUMMARY Long before the onset of permanent AF, AF risk factors promote fibrotic remodeling with ensuing progressive atriomyopathy. After the onset of permanent AF, electrical remodeling and transcriptional remodeling have occurred. Mechanisms underlying how these three remodeling processes relate to one another and to the evolution of AF from susceptibility in the clinical phase to permanence in the clinical phase are unknown. If the critical gap of knowledge regarding the cellular determinants of preclinical electrical remodeling is not elucidated, golden opportunities for intervention with risk-modifying and preventive therapies provided by the long preclinical phase of AF will remain missed. The long-term goal is to discover a novel preventive strategy for permanent AF. The overall objective in this application is to determine whether myocyte electrical remodeling is the final common pathway in preclinical atriomyopathy that increases the vulnerability of atrial myocytes to arrhythmia triggers and consequently of the fibrotic atrial tissue to AF. The central hypothesis is that whereas fibrosis initiates the preclinical phase of AF susceptibility, subsequent electrical remodeling is critical to transition from the preclinical to clinical phase of AF permanence. This hypothesis is formulated based on compelling preliminary data from the applicant's six novel robust and clinically relevant rat and rabbit models of AF susceptibility and permanence. An integrative multidisciplinary approach that incorporates technical innovations in electrophysiology, genomics, and computational biology will be used to test a novel, transformative mechanistic concept. Two aims are proposed to define how myofibroblast- and myocyte-centric mechanisms work independently and in synergy with stress to contribute to AF development and maintenance. Specifically, each aim is designed to determine whether preclinical electrical remodeling of atrial myocytes is caused by myocyte-myofibroblast electrical communication (Aim 1) and/or (2) remodeling of the gene expression of critical myocyte ionic currents (Aim 2). Both mechanisms will be investigated in the absence and presence with stress synergy. The proposal is significant because it will identify potential targets for early risk-modifying intervention in the preclinical phase. The study is conceptually innovative because we introduce six novel robust animal models of AF susceptibility and permanence and advance the novel mechanistic concept of atrial AP ventricularization as a driver for the transformation of AF from susceptibility to permanence. The study is also technically innovative because it will generate the first RiboTag rat model, the first single cell transcriptomic profiling using 10x Genomics for cardiomyocytes, and the first dynamic clamp application in atrial tissue.

项目概要 早在永久性房颤发生之前，房颤危险因素就促进纤维化重塑，并随之而来的进行性进展 心房肌病。永久性 AF 发生后，电重塑和转录重塑发生 发生。这三个重塑过程如何相互关联以及与 AF 从临床阶段的易感性到临床阶段的持久性的演变尚不清楚。如果 关于临床前电重塑的细胞决定因素的关键知识差距尚未阐明， 长期临床前研究提供了通过风险调整和预防性疗法进行干预的黄金机会 AF 阶段仍将被错过。长期目标是发现一种新的永久性房颤预防策略。 本申请的总体目标是确定肌细胞电重塑是否是最终的共同点 临床前心房肌病中增加心房肌细胞对心律失常触发的脆弱性的途径 心房组织纤维化最终导致房颤。中心假设是，纤维化引发 AF 易感性的临床前阶段，随后的电重塑对于从临床前阶段的过渡至关重要 到 AF 持久性的临床阶段。这一假设是根据令人信服的初步数据制定的 申请人的六种新型稳健且具有临床相关性的大鼠和兔房颤易感性和持久性模型。 一种综合的多学科方法，融合了电生理学、基因组学、 计算生物学将用于测试一种新颖的、变革性的机械概念。两个目标是 提议定义以肌成纤维细胞和肌细胞为中心的机制如何独立工作并与 强调为房颤的发展和维护做出贡献。具体来说，每个目标旨在确定 心房肌细胞的临床前电重构是否是由肌细胞-肌成纤维细胞电引起 通信（目标 1）和/或（2）重塑关键心肌细胞离子电流的基因表达（目标 2）。 这两种机制都将在压力协同作用不存在和存在的情况下进行研究。该提案是 意义重大，因为它将确定临床前阶段早期风险干预干预的潜在目标。 这项研究在概念上具有创新性，因为我们引入了六种新型稳健的 AF 易感性动物模型 和持久性并推进心房 AP 心室化的新机制概念作为驱动因素 房颤从易感性转变为永久性。这项研究在技术上也具有创新性，因为它将 生成第一个 RiboTag 大鼠模型，这是第一个使用 10x Genomics 进行单细胞转录组分析的模型 心肌细胞，以及心房组织中的第一个动态钳应用。