Myocyte Repolarization and Cardiac Dysfunction with Age

随年龄增长的心肌细胞复极化和心脏功能障碍

基本信息

批准号：
9920638
负责人：
Marcello Rota
金额：
$ 40.41万
依托单位：
NEW YORK MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9920638
关键词：
Ablation Action Potentials Address Adoption Adrenergic Agents Adrenergic beta-Agonists Age Aging Animals Arrhythmia Cardiac Cardiac Myocytes Cardiac development Cardiovascular Diseases Cause of Death Cells Complex Congestive Heart Failure Coupled Coupling Data Defect Deterioration Development Drug Targeting Elderly Electrophysiology (science)Event Failure Feedback Frequencies Functional disorder Genetic Genetic Engineering Genetically Engineered Mouse Heart Homeostasis Human Impairment Incidence Intervention Kinetics Left Life Link Macromolecular Complexes Mechanics Mediating Modification Mus Muscle Muscle Cells Mutation Myocardial Myocardial dysfunction Myocardium Myopathy Organ Donor Performance Pharmacology Phenotype Phosphorylation Phosphorylation Site Population Preventive Process Property Recovery Relaxation Risk Factors Rodent Role Ryanodine Receptor Calcium Release Channel Ryanodine Receptors Sarcoplasmic Reticulum Secondary to Stress Structure Testing Therapeutic Tissues Transplantation Ventricular Ventricular Remodeling Work Workload age related aged attenuation calmodulin-dependent protein kinase II defined contribution direct application exercise intolerance heart function hemodynamics in vivo indexing loss of function novel strategies novel therapeutics older patient operation prevent receptor function response senescence therapeutic target voltage

项目摘要

7. Project Summary/Abstract Aging is the major independent risk factor of chronic heart failure and the leading cause of death in the elderly, which constitutes a significant segment of the US population predicted to increase in the next decades. Thus, identification of factors involved in the origin and progression of aging myopathy together with the development of preventive and therapeutic strategies for elderly patients are necessary to counteract the projected growing incidence of cardiovascular diseases. The central hypothesis of this proposal is that increased late Na+ current (INaL) with age is a major determinant of the electrophysiological and functional defects of senescent myocytes and ventricles. The increase in intracellular Na+ secondary to the enhancement of the late Na+ current in aged cardiomyocytes may influence Ca2+ cycling and provide inotropic support to the aged myocardium. However, imbalance of the process may result into a vicious positive feedback loop comprising the Ca2+/calmodulin-dependent protein kinase II (CaMKII) and phosphorylation and operation of Na+ channels and ryanodine receptors. Thus, aberrant Na+ and Ca2+ homeostasis are viewed as major components of the delayed electromechanical coupling and diastolic dysfunction in the senescent heart. To test these possibilities, initially we will establish whether INaL is enhanced in myocytes of aged human heart, employing donor organ declined for transplantation. Subsequently, we will use engineered genetic gain- and loss-of-function mouse lines to modulate INaL in cardiomyocytes. The effects of INaL increase or failure to enhance INaL on Ca2+ cycling, electromechanical coupling, and diastolic function in vivo will be established in mice at different age, to dissect the contribution of enhanced late Na+ currents on the manifestation of the aging myopathy. Moreover, modulation of CaMKII activity, intracellular Na+ load, and ryanodine receptor function will be induced experimentally to gain mechanistic information on the cascade of events linking INaL, incidence of arrhythmias, and diastolic dysfunction. Whether components of the vicious feedback loop are critically altered with aging will also be established. Collectively, our work will define the contributions of electrophysiological remodeling of ventricular myocytes on the defective performance of the aged myocardium. Also proposed studies have the potential to identify therapeutic targets of pharmacological intervention to prevent or delay the progressive functional deterioration of the aging heart.

7. 项目总结/摘要衰老是慢性心力衰竭的主要独立危险因素，也是老年人死亡的主要原因，这占美国人口的很大一部分，预计未来几十年将增加。因此，识别参与衰老肌病的起源和进展以及发展的因素老年患者的预防和治疗策略对于抵消预计的增长是必要的心血管疾病的发病率。该提案的中心假设是晚期Na+增加随着年龄的增长，电流（INaL）是电生理和功能缺陷的主要决定因素。衰老的肌细胞和心室。继发于细胞内Na+的增加老年心肌细胞中的晚Na+电流可能影响Ca2+循环并为老年人提供正性肌力支持心肌。然而，过程的不平衡可能会导致恶性正反馈循环包括 Ca2+/钙调蛋白依赖性蛋白激酶 II (CaMKII) 以及磷酸化和操作 Na+ 通道和兰尼碱受体。因此，异常的 Na+ 和 Ca2+ 稳态被视为主要的衰老心脏中延迟机电耦合和舒张功能障碍的组成部分。到测试这些可能性，首先我们将确定 INaL 在老年人心脏的肌细胞中是否增强，使用供体器官拒绝移植。随后，我们将使用工程遗传增益和功能丧失小鼠系调节心肌细胞中的 INaL。 INaL 增加或失败的影响增强 INaL 对 Ca2+ 循环、机电耦合和体内舒张功能的影响将在不同年龄的小鼠，剖析增强的晚期 Na+ 电流对表现的贡献衰老性肌病。此外，调节 CaMKII 活性、细胞内 Na+ 负荷和兰尼碱受体将通过实验诱导函数以获得连接 INaL 的级联事件的机械信息，心律失常和舒张功能障碍的发生率。恶性反馈循环的组成部分是否也将随着年龄的增长而发生严重改变。总的来说，我们的工作将定义以下人员的贡献：心室肌细胞的电生理重塑对老化心肌性能缺陷的影响。拟议的研究还有可能确定药物干预的治疗靶点预防或延缓衰老心脏功能的进行性恶化。