Metabolic signaling in atrial fibrillation and remodeling

项目摘要 房颤是一个重大的公共卫生问题，目前预防房颤的治疗方法有限。 代谢压力是易患房颤的常见疾病的标志，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 病理性心房重构仍不清楚。我们的中心假设是通过主机发出的信号 代谢调节剂AMPK是控制心房结构和电生理(EP)的关键中枢 在代谢性疾病中发生的AMPK途径失活是一种统一的机制 这两个触发因素和底物促进了房颤的发生和持续。此应用程序将利用 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 室性和心律失常机制，阐明驱动不良心房的新的上游机制 重塑和房颤。具体地说，我们将调查AMPK途径失活导致的假设 代谢应激致房颤。基于最近的实验和临床研究，以及我们的新 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 创新的遗传模型、细胞和分子生物学工具以及小分子的组合 药理AMPK激动剂。我们的实验设计结合了先进的电生理学研究 拥有最先进的心脏结构和功能成像，使用高分辨率光学动作电位 心电地形图和门控心脏显微CT成像，以全面评估生理和结构 体内和体外的心房重塑。目标1将揭示AMPK途径的机制 失活可促进早期心房异位和房颤的发生。目标2将阐明损失的机制 AMPK信号促进疾病进展，形成持续性房颤的底物。目标3将 确定AMPK激活剂治疗是否预防和/或逆转病理性心房重构和房颤 不会引起室性心律失常的倾向。此应用程序的总体目标是 促进我们对代谢信号、心房电和结构之间的接口的理解 为了最终开发针对房颤的创新治疗方法，我们将继续研究房颤患者的心脏重构和心律失常。 因此，拟议的实验结果有望阐明心房的基本机制。 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 检测AMPK激动剂在预防和治疗房颤中的作用。

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.