Myofilaments as regulators of heart function in disease

肌丝作为疾病中心脏功能的调节剂

• 批准号: 9311335
• 负责人: JOSEPH Mark METZGER
• 金额: $ 38万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9311335
• 关键词: Acidosis; Adult; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cells; Clinical Management; Complex; Contractile Proteins; Detection; Disease; Familial Hypertrophic Cardiomyopathy; Fluorescence Resonance Energy Transfer; Gene Proteins; Genetic; Genetic Models; Goals; Health; Heart; Heart Diseases; Heart failure; Human; Hydrophobicity; Inherited; Investigational Therapies; Ischemia; Lead; Ligands; Methodology; Microfilaments; Mind; Mission; Modeling; Molecular; Monitor; Morbidity - disease rate; Muscle Cells; Mutation; Myocardial Contraction; Myocardial Ischemia; Myocardial dysfunction; Myocardium; Myosin ATPase; N-terminal; Pathway interactions; Patients; Performance; Physiological; Positioning Attribute; Property; Proteins; Regulation; Role; Sarcomeres; Sodium Chloride; System; Testing; Therapeutic; Time; Troponin; Troponin I; United States National Institutes of Health; base; disease-causing mutation; heart function; innovation; insight; ischemic cardiomyopathy; membrane excitation; mortality; mutant; novel; novel strategies; novel therapeutics; public health relevance; small molecule; therapeutic target; tool

Abstract Ischemic cardiomyopathy and heart failure are the leading causes of combined morbidity and mortality in humans. Clinical management of patients with inherited and acquired forms of cardiomyopathy is challenging and limited by the scarcity of new therapies in the pipeline. This proposal's immediate focus is on mechanistic insights into sarcomere regulation and heart performance with the long-term goal to ultimately advance novel approaches to redress heart disease. This effort underscores the significant health relevance of this proposal. The cardiac sarcomere is a complex allosteric regulatory system that drives heart contraction, but has been significantly under studied as a therapeutic target for cardiac disorders. For decades, the cardiac field has considered intracellular Ca2+ handling as the key pathway regulating heart performance in health and disease. By contrast, less emphasis has been placed on the role of the sarcomere in governing heart performance, representing a significant gap and missed opportunity. Until now, a major limitation in the field has been the inability to directly monitor sarcomere activation in live cardiac myocytes. Sarcomere performance has been a "black box" in terms of detecting, in real time, myofilament activation in live intact myocytes. We leverage here a methodological breakthrough enabling real-time detection of sarcomere activation in live cardiac myocytes. This innovation will lead our mechanistically-driven studies on the function of the sarcomere in health and disease, including elucidating the roles of sarcomeric activating ligands. Using this FRET-based sarcomere activation platform, we are uniquely poised to define the physiological significance of the regulatory role of the sarcomere in live cells. In illuminating fundamental properties of cardiac sarcomere regulation using live cell recordings, we are in a unique position to test the hypothesis that sarcomere function is uncoupled from Ca2+ handling in models of inherited and acquired cardiomyopathy, pointing to the sarcomere as a key target for experimental therapeutic discoveries. By the integration of three complementary Aims, we will determine the molecular mechanism underlying sarcomere-based excitation-contraction uncoupling and investigate the effects on live cell sarcomere activation due to disease causing mutations in myosin, troponin and small molecules in cardiac muscle. This proposal will advance a new understanding of heart performance regulation and open the door to potential breakthroughs in sarcomere modulating genes, proteins and small molecules to positively impact heart performance in health and disease.

抽象的 缺血性心肌病和心力衰竭是综合发病率和死亡率的主要原因 人类。遗传和获得形式的心肌病的患者的临床管理具有挑战性 并受到管道中新疗法的稀缺的限制。该提议的直接重点是机械 对肌节调节和心脏表现的见解，并以长期目标最终推进小说 补救心脏病的方法。这项工作强调了该提案的重要健康相关性。 心脏肌膜是一个复杂的变构调节系统，可动drage心脏收缩，但一直是 大幅度地研究了心脏疾病的治疗靶点。几十年来，心脏领域有 被认为是细胞内Ca2+处理是调节健康和疾病心脏表现的关键途径。 相比之下，较少的重点是肉体在管理心脏表现中的作用， 代表一个很大的差距和错过的机会。到目前为止，该领域的主要限制是 无法直接监测活心肌细胞中的肌节激活。萨马尔的表现一直是 从实时检测现场完整的心肌细胞中的肌丝激活方面，“黑匣子”。我们在这里利用 一种方法上的突破，可以实时检测活心肌细胞中的肌膜激活。 这项创新将领导我们关于肉体健康功能的机械驱动的研究， 疾病，包括阐明棒球激活配体的作用。使用这个基于FRET的肌膜 激活平台，我们唯一准备定义调节作用的生理意义 活细胞中的肌膜。在阐明使用活细胞的心脏肌瘤调节的基本特性中 记录，我们处于一个独特的位置，可以测试肉体函数与Ca2+取消偶联的假设 在遗传和获得的心肌病模型中处理，以肉体为关键目标 实验性治疗发现。通过整合三个互补目标，我们将确定 基于肌节的基于肌节的激发反偶联的分子机制并研究了效果 在活细胞肌节激活中，由于疾病引起的肌球蛋白，肌钙蛋白和小分子的突变引起的激活 心肌。该提议将提出对心脏绩效调节的新理解，并打开 肌节中潜在突破的大门调节基因，蛋白质和小分子以积极 影响健康和疾病的心脏表现。