Metabolic signaling in atrial fibrillation and remodeling

心房颤动和重构中的代谢信号

• 批准号: 10593102
• 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/10593102
• 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 Modulation; 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; Ion Channel; Ischemia; Left; Link; Maps; Mediating; Metabolic; Metabolic Diseases; Metabolic stress; Metabolism; Mitochondria; Molecular; Mus; Obesity; Optics; Oxidative Stress; Pathogenesis; Pathologic; Pathway interactions; Patients; 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; experience; experimental study; heart imaging; heart metabolism; in vivo; innovation; microCT; mouse model; novel; novel therapeutic intervention; paracrine; pharmacologic; 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.

项目概要 心房颤动（AF）是一个主要的公共卫生问题，目前的预防疗法有限。 代谢应激是导致房颤的常见病症的标志，包括衰老、糖尿病和 射血分数保留的心力衰竭然而代谢应激的起源及其与射血分数的机制联系。 我们的中心假设是通过主信号传递病理性心房重塑。 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（如代谢疾病中发生的情况）是一种统一机制 该应用程序将利用促进 AF 发生和持续的触发因素和底物。 我们在研究 AMPK 调节的心脏代谢和代谢信号传导方面拥有丰富的经验 心室和心律失常机制，阐明驱动不良心房的新上游机制 具体来说，我们将研究 AMPK 通路失活导致的假设。 基于最近的实验和临床研究以及我们的新研究，代谢应激诱发了房颤。 根据初步数据，我们发现 AMPK 通过直接靶点调节心房电生理 磷酸化和转录调节以及通过涉及 AMPK 介导的间接机制 我们将系统地、严格地揭示心房的代谢/氧化应激机制。 创新遗传模型、细胞和分子生物学工具以及小分子的结合 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进行最先进的心脏结构和功能成像 测绘和门控心脏显微 CT 成像，全面评估生理和结构 体内和离体心房的重塑目标 1 将揭示 AMPK 通路的机制。 失活促进早期心房异位和 AF 的发生，目标 2 将阐明失活的机制。 AMPK 信号传导促进疾病进展，形成持续性 AF 的基础。 确定 AMPK 激活剂治疗是否可以预防和/或逆转病理性心房重构和 AF 该应用程序的首要目标是不引起室性心律失常。 我们对高级代谢信号、心房电和结构之间接口的理解 重塑和心律失常发生，以最终开发 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 AF 发病机制的基础，并为未来的临床前和临床研究奠定基础 测试 AMPK 激活剂在预防和治疗 AF 中的作用。