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: 10544739
• 负责人: Charles S Chung
• 金额: $ 39.22万
• 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/10544739
• 关键词: Acceleration; Actins; Acute; Address; Attention; Attenuated; Biochemical Process; Biophysics; Calcium; Cardiac; Catheterization; Clinical; Contracts; Data; Dependence; Diagnosis; Diagnostic; Disease; EFRAC; Excision; Filament; Fructose; Functional disorder; Goals; Head; Heart; Heart Diseases; Heart failure; Impairment; In Vitro; Individual; Isometric Exercise; Kinetics; Length; Link; Mechanics; Mediating; Mediator; Methods; Modeling; Modification; Molecular; Motion; Myocardial; Myocardium; Myofibrils; Myosin ATPase; Outcome Study; Patients; Peripheral Resistance; Pharmaceutical Preparations; Physiological; Positioning Attribute; Property; 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; biomechanical test; biophysical properties; clinical practice; clinically relevant; connectin; experimental study; hemodynamics; imaging biomarker; improved; in vivo; indexing; new therapeutic target; novel; pharmacologic; 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。项目摘要/摘要 舒张压放松受损，这是舒张功能障碍的重要组成部分，几乎所有 心力衰竭的患者减少且保留的射血分数 - 近25％ 无症状的个体。不幸的是，没有治疗放松受损的治疗方法。最近，我的实验室 响应于A 延长应变。换句话说，放松率对心肌的应变率很敏感。我们的 数据表明，这种放松的机械调节可以提高放松率，超出两倍 限制肌动蛋白脱离肌动蛋白的生化过程，包括去除钙和细丝 停用。因此，舒张功能障碍可能是两个因素引起的：i）放松对 应变速率和II）应变衰减，限制应变率。底层分子机制 应变率敏感性仍然未知，但是我们的初步研究表明肌球蛋白脱离动力学 是关键。菌株敏感的肌球蛋白脱离是一种表征不佳的生物物理特性，尤其是完整的 心脏组织。我们的初步数据进一步表明，体内血液动力学可以改变心肌 拉紧。该提议的全球假设是肌球蛋白详细动力学对生物物理进行调节 放松的机械控制。该项目的目标是确认这种机制并确定 调节弛豫的机械控制的分子和血液动力学因素。 AIM 1将确定 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 假设肌球蛋白同工型和肌球蛋白激活药物都会改变应变敏感的脱离 肌球蛋白的速率。使用肌球蛋白同工型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来评估放松的机械控制。重要的是，我们将评估肌球蛋白 使用X射线衍射技术的头部位置。 AIM 2将确定基于Titin的刚度在 放松的机械控制。我们的初步研究表明，高滴定依从性消除了 肌球蛋白脱离的长度（预加载）依赖性变化。我们假设Titin介导的厚细丝 可扩展性是放松的中介者，将在表达替丁的小梁中检验这一假设 使用与AIM 1中相同技术的同工型。AIM3将决定应变率和/或如何敏感性 使用i）在AIMS 1中研究的分子修饰在体内修饰应变率的松弛率。 2和II）一种临床相关的果糖+高盐模型，该模型复制了多种心力衰竭标记 保留的射血分数。所提出的方法独特地考虑心肌如何移动（菌株） 在整个心脏周期中，超出标准方法（孤立的肌原纤维，小梁）的进步是 等距。这些研究将推动发现新目标以改善治疗和诊断 通过隔离松弛机械控制的机制来损害松弛。