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: 10364296
• 负责人: JOSEPH Mark METZGER
• 金额: $ 55.14万
• 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 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10364296
• 关键词: Actins; Affect; Binding; Biosensor; Cardiac; Cardiac Myocytes; Cardiac Myosins; Cells; Complex; Contractile Proteins; Country; Disease; Fluorescence Resonance Energy Transfer; Foundations; Functional disorder; Genetic; Genetic Diseases; Genetic Models; Health; Heart; Heart Diseases; Heart failure; Human; Hypertrophic Cardiomyopathy; Inherited; Kinetics; Knockout Mice; Length; Ligands; Methodology; Microfilaments; Mission; Modification; Molecular; Molecular Conformation; Morbidity - disease rate; Muscle Cells; Muscle Contraction; Mutation; Myocardial Ischemia; Myocardium; Myosin ATPase; Pathogenesis; Performance; Persons; Physiological; Play; Proteins; Pump; Regulation; Role; Sarcomeres; Signal Transduction; System; Tertiary Protein Structure; Testing; Therapeutic; Thick; Thick Filament; Thin Filament; Thinness; Time; Tropomyosin; Troponin; Troponin I; United States National Institutes of Health; base; clinical translation; experimental study; heart function; innovation; insight; ischemic cardiomyopathy; mortality; myosin-binding protein C; novel therapeutics; public health relevance; small molecule

Abstract Ischemic cardiomyopathy and heart failure are the leading causes of combined morbidity and mortality in humans. Herein, sarcomere dysfunction has a central role in disease pathogenesis. The sarcomere is the essential functional unit of cardiac muscle, directly responsible for the pumping action of the heart. The cardiac sarcomere is a multimeric contractile apparatus consisting of a thin myofilament-based allosteric regulatory complex together with the myosin-based thick myofilament that generates force. Interlacing myofilaments operate in synchrony to regulate and generate the forces necessary for heart performance. Beat-to-beat control of cardiac sarcomere activation refers to the status of the thin filament regulatory system in controlling the degree to which contraction is turned on and off during a twitch. Disruption in sarcomere function underlies the basis for numerous forms of acquired and inherited heart diseases affecting millions of people in this country. Thus, focus here on mechanistic insights into sarcomere regulation underscores the major health relevance of this proposal. Recently, emerging results have come to the fore positing synergistic inter-myofilament regulatory signaling mechanisms, including a new role of myosin cross-bridge ON/OFF states in controlling muscle contraction. Building on our sarcomere activation innovations featuring single unloaded cardiac myocytes, we have made a breakthrough methodological advance, permitting real-time recordings of sarcomere activation in intact cardiac muscle under physiological load. This system is capable of detecting, by intramolecular FRET, multiple myofilament activating ligands during the physiological time course of a single twitch contraction in intact cardiac muscle under load. Guiding hypothesis: During physiologically relevant twitch contractions under load, thin filament activation is controlled dynamically by multiple synergistic inter-myofilament regulatory inputs, including TnC bound Ca2+, TnI switch domain-TnC interaction, OFF to ON state myosin cross-bridges, and MyBP-C in live cardiac muscle. This proposal aims to investigate inter-myofilament signaling by altering the TnI molecular switch mechanism during the physiological time-course of a single cardiac twitch in live cardiac muscles under load; to investigate the mechanism of inter-myofilament signaling during the cardiac twitch contraction in live intact cardiac muscles by modification in myosin cross-bridges; and to investigate the role MyBP-C in inter-myofilament signaling during physiological twitch contractions in intact cardiac muscles. Enabled by our innovative approach, the new insights into inter-myofilament signaling mechanisms gained here will significantly impact our understanding of cardiac function. In turn, this provides the essential foundation to guide new therapeutic discovery for the diseased heart by leveraging the sarcomere as an excellent target for developing new treatments and therapies for the diseased heart.

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。本文中，肌节功能障碍在疾病发病机理中具有核心作用。肌膜是 心肌的基本功能单位，直接负责心脏的抽水作用。心脏 Saromere是一种多聚体收缩设备，由薄的肌膜变构调节组成 复杂与产生力的基于肌球蛋白的厚肌膜。交织肌丝 通过同步操作，以调节和产生心脏表现所需的力量。跳动控制 心脏肌节的激活是指薄丝调节系统的状态 抽搐期间打开和关闭收缩。肌节功能的破坏是基础 多种形式的被收购和遗传的心脏病影响了这个国家的数百万人。因此，集中精力 关于肌节调节的机械洞察力强调了该提议的主要健康相关性。 最近，新兴的结果已经提出了协同膜间调节信号传导 机制，包括肌球蛋白杂交桥开/OFF状态在控制肌肉收缩中的新作用。 在我们的肌节激活创新的基础上，以单个卸载心肌细胞为特征，我们做了一个 突破性的方法学进步，允许在完整心脏中的肌膜激活的实时记录 肌肉在生理负荷下。该系统能够通过分子内fret检测多个 在完整心脏的单个抽搐收缩的生理时间过程中激活配体的肌丝激活配体 负载下的肌肉。指导假设：在负载下的生理相关的抽搐收缩期间，薄 丝激活受多种协同膜间调节输入动态控制，包括 TNC绑定的Ca2+，TNI开关域TNC相互作用，在状态肌球蛋白横桥和Live中的MYBP-C 心肌。该建议旨在通过改变TNI分子开关来研究胸膜间信号传导 在负载下活心肌肌肉中单个心脏抽搐的生理时间过程中的机制；到 研究在无效的心脏抽搐收缩期间胸膜间信号传导的机制 心肌通过肌球蛋白跨桥进行修饰；并研究MyBP-C在胸膜间中的作用 完整心肌的生理抽搐收缩期间的信号传导。通过我们的创新方法启用 对这里获取的胸膜间信号传导机制的新见解将极大地影响我们的 了解心脏功能。反过来，这为指导新的治疗提供了重要的基础 通过利用肌节作为开发新的目标的绝佳目标，可以发现患病心脏的发现 患病心脏的治疗和疗法。