Metabolic signaling in atrial fibrillation and remodeling

心房颤动和重构中的代谢信号

• 批准号: 10393659
• 负责人: FADI GABRIEL AKAR
• 金额: $ 55.21万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10393659
• 关键词: Action Potentials; Acute; Aging; Angiotensin II; Arrhythmia; Atrial Fibrillation; Autophagocytosis; Biological; Biology; Biopsy; Cardiac; Clinical; Clinical Research; Connexins; Data; Development; Diabetes Mellitus; Disease Progression; Drug Targeting; EFRAC; Electrophysiology (science); Evolution; Exercise; Exhibits; Experimental Designs; Fibrosis; Foundations; Future; Gene Expression; Genetic; Genetic Models; Genetic Transcription; Goals; Heart Atrium; Heart failure; Hormones; Human; Hypertrophy; Image; Ion Channel; Ischemia; Left; Link; Mediating; Metabolic; Metabolic Diseases; Metabolic stress; Metabolism; Mitochondria; Molecular; Mus; Obesity; Optics; Oxidative Stress; Pathogenesis; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phosphorylation; Physiological; Prevention; Prevention approach; Property; Proteins; Public Health; Reperfusion Injury; Reporting; Research; Resolution; Role; STK11 gene; Sex Differences; Signal Transduction; Stress; Structure; Testing; Therapeutic; Transcriptional Regulation; Ventricular; Ventricular Remodeling; X-Ray Computed Tomography; autocrine; base; experience; experimental study; heart imaging; heart metabolism; in vivo; innovation; microCT; mouse model; novel; novel therapeutic intervention; paracrine; preclinical study; preservation; prevent; reconstitution; response; small molecule; tool; transcription factor

Project Summary Atrial fibrillation (AF) is a major public health problem and current therapies for its prevention are limited. Metabolic stress is a hallmark of common conditions that predispose to AF, including aging, diabetes and heart failure with preserved ejection fraction. Yet the origins of metabolic stress and its mechanistic link to pathological atrial remodeling remain unknown. Our central hypothesis is that signaling via the master metabolic regulator AMPK is a key hub in the control of atrial structural and electrophysiological (EP) properties, and that AMPK pathway inactivation, as occurs in metabolic diseases, is a unifying mechanism for both the triggers and substrate that promote the onset and perpetuation of AF. This application will leverage our extensive experience in studying AMPK-regulated cardiac metabolism and metabolic signaling in the ventricle and arrhythmia mechanisms, to elucidate novel upstream mechanisms that drive adverse atrial remodeling and AF. Specifically, we will investigate the hypothesis that AMPK pathway inactivation causes metabolic stress induced AF. Based on recent experimental and clinical studies, together with our new preliminary data, we hypothesize that AMPK modulates atrial electrophysiology via direct target phosphorylation and transcriptional regulation as well as via indirect mechanisms involving AMPK mediated metabolic/oxidative stress in the atria. We will systematically and rigorously uncover these mechanisms using a combination of innovative genetic models, cellular and molecular biological tools and small molecule pharmacological AMPK activators. Our experimental design integrates advanced electrophysiological studies with state-of–the-art cardiac imaging of structure and function, using high-resolution optical action potential mapping and gated cardiac micro-CT imaging, to comprehensively assess the physiological and structural remodeling of the atria both in vivo and ex vivo. Aim 1 will uncover mechanisms by which AMPK pathway inactivation promotes early atrial ectopy and the onset of AF. Aim 2 will elucidate mechanisms by which loss of AMPK signaling promotes disease progression forming the substrate for persistent AF. Aim 3 will determine whether AMPK activator therapy prevents and/or reverses pathological atrial remodeling and AF propensity without provoking ventricular pro-arrhythmia. The over-arching goal of this application is to advance our understanding of the interface between metabolic signaling, atrial electrical and structural remodeling, and arrhythmogenesis, in order to ultimately develop innovative therapeutic approaches for AF. Thus, the results of the proposed experiments are expected to elucidate the fundamental atrial mechanisms that underlie the pathogenesis of AF, and to provide the foundation for future pre-clinical and clinical studies to test the role of AMPK activators in both the prevention and treatment of AF.

项目摘要 心房颤动（AF）是一个主要的公共卫生问题，目前的治疗方法是有限的，其预防。 代谢应激是易患AF的常见疾病的标志，包括衰老、糖尿病和 射血分数正常的心力衰竭然而，代谢应激的起源及其与 病理性心房重构仍不清楚。我们的中心假设是通过主节点发出信号 代谢调节因子AMPK是控制心房结构和电生理（EP）的关键枢纽 AMPK通路失活，如发生在代谢性疾病中，是一种统一的机制， 触发器和底物，促进AF的发作和永久化。 我们在研究AMPK调节的心脏代谢和代谢信号方面的丰富经验， 心室和心律失常机制，以阐明新的上游机制，驱动不良心房 具体来说，我们将研究AMPK通路失活导致AF的假设， 代谢应激诱发房颤。根据最近的实验和临床研究，连同我们的新的 根据初步数据，我们假设AMPK通过直接靶点调节心房电生理 磷酸化和转录调控以及通过涉及AMPK介导的间接机制， 心房中的代谢/氧化应激。我们将系统地、严格地揭示这些机制， 结合创新的遗传模型，细胞和分子生物学工具和小分子 药理学AMPK激活剂。我们的实验设计整合了先进的电生理学研究 使用高分辨率光学动作电位， 标测和门控心脏微CT成像，以全面评估生理和结构 体内和离体心房重塑。目的1将揭示AMPK通路的机制， 失活促进早期心房异位和房颤的发生。目的2将阐明失活的机制， AMPK信号通路促进疾病进展，形成持续性AF的底物。 确定AMPK激活剂治疗是否预防和/或逆转病理性心房重构和AF 而不会引起室性心律失常。本应用程序的总体目标是 推进我们对代谢信号、心房电和结构之间接口的理解 重塑和血管生成，以便最终开发AF的创新治疗方法。 因此，所提出的实验结果有望阐明基本的心房机制 这是房颤发病机制的基础，并为未来的临床前和临床研究提供基础， 测试AMPK激活剂在预防和治疗AF中的作用。