Leveraging Mechanical Control of Relaxation to Improve Diastolic Function

利用放松的机械控制来改善舒张功能

• 批准号: 10322185
• 负责人: Charles S Chung
• 金额: $ 38.63万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10322185
• 关键词: Actins; Acute; Address; Attention; Attenuated; Biochemical Process; Biophysics; Calcium; Cardiac; Catheterization; Clinical; Contracts; Data; Dependence; Diagnosis; Diagnostic; Disease; EFRAC; Excision; Failure; Fibrinogen; Filament; Fructose; Functional disorder; Goals; Head; Heart; Heart Diseases; Heart failure; Impairment; In Vitro; Individual; Isometric Exercise; Kinetics; Lead; Length; Link; Mechanics; Mediating; Mediator of activation protein; Methods; Modeling; Modification; Molecular; Motion; Myocardial; Myocardium; Myofibrils; Myosin ATPase; Outcome Study; Patients; Peripheral Resistance; Pharmaceutical Preparations; Pharmacology; Physiological; Positioning Attribute; Protein Isoforms; Rattus; Regulation; Relaxation; Research; Role; Sodium Chloride; Stretching; Techniques; Testing; Thick Filament; Thin Filament; Tissues; Translating; Translations; Validation; Work; X ray diffraction analysis; arm; attenuation; base; biomechanical test; biophysical properties; clinical practice; clinically relevant; connectin; experimental study; hemodynamics; imaging biomarker; improved; in vivo; indexing; new therapeutic target; novel; preservation; pressure; response; tau Proteins; ultrasound

7. PROJECT SUMMARY/ABSTRACT Impaired diastolic relaxation, an important component of diastolic dysfunction, is present in nearly all patients with heart failure-both with reduced and with preserved ejection fraction- and is present in nearly 25% of asymptomatic individuals. Unfortunately, no treatments for impaired relaxation exist. Recently, my lab identified and defined Mechanical Control of Relaxation as a faster relaxation rate in response to the rate of a lengthening strain. In other words, the relaxation rate is sensitive to the strain rate of the myocardium. Our data demonstrate that this mechanical regulation of relaxation can increase the relaxation rate two-fold beyond the biochemical processes that limit myosin detachment from actin, including calcium removal and thin filament deactivation. Thus, diastolic dysfunction might result from two factors: i) a loss of the sensitivity of relaxation to strain rate and ii) an attenuation in strain, restricting the strain rate. The molecular mechanism underlying strain-rate sensitivity remains unknown, but our preliminary studies indicate that myosin detachment kinetics are key. Strain-sensitive myosin detachment is a poorly characterized biophysical property, especially in intact cardiac tissues. Our preliminary data further demonstrates that in vivo hemodynamics can alter myocardial strain. The global hypothesis of this proposal is that myosin-detachment kinetics biophysically regulates Mechanical Control of Relaxation. The goals of this project are to confirm this mechanism and to identify molecular and hemodynamic factors that regulate Mechanical Control of Relaxation. Aim 1 will determine whether myosin detachment rate modifies the sensitivity of the relaxation rate to the strain rate. We hypothesize that both myosin isoforms and myosin activating drugs will modify the strain-sensitive detachment rate of myosin. Using myosin isoform altering treatments and myosin-specific activating drugs, we will evaluate Mechanical Control of Relaxation using intact cardiac trabeculae. Importantly, we will assess myosin head position using x-ray diffraction techniques. Aim 2 will determine the role of titin based stiffness on Mechanical Control of Relaxation. Our preliminary studies suggest that high titin compliance eliminates a length (preload)-dependent change in myosin detachment. We hypothesize that titin-mediated thick filament extensibility is a mediator of relaxation and will test this hypothesis in trabeculae expressing altered titin isoforms using the same techniques as in Aim 1. Aim 3 will determine how strain rate and/or the sensitivity of the relaxation rate to the strain rate is modified in vivo using i) the molecular modifications studied in Aims 1 and 2 and ii) a clinically relevant Fructose+High Salt model that replicates several markers of heart failure with preserved ejection fraction. The proposed methods uniquely consider how the myocardium moves (strains) throughout the cardiac cycle, an advance beyond standard methods (isolated myofibril, trabeculae) that are isometric. These studies will drive the discovery of novel targets to improve the treatment and diagnosis of impaired relaxation by isolating mechanisms underlying Mechanical Control of Relaxation.

7.项目总结/摘要 舒张功能障碍的一个重要组成部分，舒张期舒张功能受损， 心力衰竭患者-射血分数降低和保留-近25% 无症状的人。不幸的是，没有治疗放松受损的方法。最近，我的实验室 确定并定义松弛的机械控制为响应于松弛速率的更快松弛速率。 伸长应变换句话说，舒张率对心肌的应变率敏感。我们 数据表明，松弛的这种机械调节可以使松弛速率增加两倍， 限制肌球蛋白从肌动蛋白上脱离的生化过程，包括钙离子的去除和细丝的变细 去活化因此，舒张功能障碍可能由两个因素引起：i）舒张对舒张的敏感性丧失， 应变速率和ii）应变的衰减，限制应变速率。的分子机制 应变率敏感性仍然未知，但我们的初步研究表明，肌球蛋白脱离动力学 是关键。应变敏感性肌球蛋白脱离是一种特征性不强的生物物理特性，特别是在完整的肌球蛋白中。 心脏组织我们的初步数据进一步表明，在体内血流动力学可以改变心肌， 株这一提议的总体假设是肌球蛋白脱离动力学生物病理学调节 放松的机械控制。本项目的目标是确认这一机制， 分子和血液动力学因素，调节机械控制的放松。目标1将决定 肌球蛋白脱离率是否改变了松弛率对应变率的敏感性。我们 假设肌球蛋白亚型和肌球蛋白激活药物都会改变应变敏感性脱离 肌球蛋白率。使用肌球蛋白异构体改变治疗和肌球蛋白特异性激活药物，我们将 使用完整的心脏小梁评价舒张的机械控制。重要的是，我们将评估肌球蛋白 使用X射线衍射技术进行磁头定位。目标2将确定肌联蛋白的作用， 放松的机械控制。我们的初步研究表明，高titin顺应性消除了 肌球蛋白脱离长度（前负荷）依赖性变化。我们假设肌联蛋白介导的粗丝 伸展性是松弛的介质，并将在表达改变的肌联蛋白的小梁中检验这一假设。 使用与目的1中相同的技术制备同种型。目标3将确定如何应变率和/或敏感性 使用i）在目标1中研究的分子修饰， 和2和ii）临床相关的果糖+高盐模型，其复制心力衰竭的几种标志物， 射血分数正常所提出的方法独特地考虑了心肌如何移动（应变） 在整个心动周期中，超越标准方法（分离的肌原纤维，小梁）的进步， 等距的这些研究将推动新靶点的发现，以改善对糖尿病的治疗和诊断。 通过机械控制放松的隔离机制损害放松。