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.

项目总结