Frequency-dependent modulation of cardiac myofilament function in health/disease

健康/疾病中心肌丝功能的频率依赖性调节

• 批准号: 9754855
• 负责人: PAULUS ML JANSSEN
• 金额: $ 38.5万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-15 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9754855
• 关键词: Acceleration; Animal Model; Behavior; Calcium; Calcium Binding; Canis familiaris; Cardiac; Cardiovascular system; Cells; Confocal Microscopy; Data; Dilated Cardiomyopathy; Disease; Engineering; Etiology; Frequencies; Functional disorder; Health; Heart; Heart Rate; Heart failure; Human; Human Pathology; Impairment; In Vitro; Investigation; Kinetics; Knowledge; Literature; Microfilaments; Modification; Mus; Mutation; Myocardial tissue; Myocardium; Oryctolagus cuniculus; Outcome; Penetration; Peptides; Phase; Physiological; Play; Preparation; Process; Property; Protein Engineering; Proteins; Regulation; Regulatory Pathway; Relaxation; Research; Role; Speed; Thin Filament; Time; Tissues; Troponin C; Vacuum; base; desensitization; experience; experimental study; improved; ischemic cardiomyopathy; kinetic theory; public health relevance; response; success; theories

In a healthy human heart, an increase in heart rate results in an increase in force of contractions (positive force-frequency relationship, or FFR), and an acceleration of contractile kinetics (frequency-dependent acceleration of relaxation, or FDAR). In human heart failure, the FFR flattens or even becomes negative, while FDAR greatly diminishes; these two phenomena are classic hallmarks of heart failure. Despite its critical role in health and disease, frequency- dependent modulation of contraction and kinetics is poorly understood. The magnitude in contractile response to frequency response in mice is >10 times smaller than in humans, and most often even completely absent. This necessitates the investigation of frequency-dependent processes of contraction and kinetics in a large animal model, or better yet, in human myocardium. Guided by the literature, our own data, and the last 5 years of preliminary data from experiments on human heart tissue and its frequency-dependent regulation, we recently wrote a very extensive review that postulates the hypothesis that the kinetics of relaxation are governed by three interdependent processes: intracellular calcium decline, myofilament calcium binding kinetics, and cross-bridge cycling kinetics. Currently, there is a vast vacuum of data regarding the kinetic rate and regulation in human myocardium, which is critical, since data from the 10-times faster murine myocardium are nearly impossible to interpret in the context of the prevailing rates in the human. We have constructed aims that 1) first establish the kinetic rates for the three processes that govern relaxation in failing and non-failing human myocardium, and then proceed to 2) modify this kinetic rate by engineering a different myofilament calcium sensitivity in human failing and non-failing myocardium. In the first aim, we will assess the kinetic rates of calcium transient decline, myofilament responsiveness, and cross-bridge cycling kinetics in non-failing and failing human myocardium, in the second aim, we will assess whether modification of the kinetic rate governing myofilament calcium responsiveness can restore the FDAR in failing human myocardium by employing engineered TroponinC proteins. The above aims will be carried out in n>50 failing and n>50 non-failing human hearts. This will allow us to eventually perform a differential analysis based on disease etiology. Based on our experience in working with human hearts we will have sufficient statistical power to distinguish outcomes between hearts classified as ischemic-cardiomyopathy, dilated-cardiomyopathy, and those with a primary diastolic dysfunction.

在健康的人心脏中，心率的增加导致收缩力增加 （积极的力量关系或FFR），并加速收缩动力学 （频率依赖于松弛的加速度或FDAR）。在人类心力衰竭中，FFR 平坦甚至变平，而FDAR大大减少；这两个现象是 心力衰竭的经典标志。尽管在健康和疾病中起着至关重要的作用，但频率 - 对收缩和动力学的依赖调节知之甚少。大小为IN 收缩对小鼠频率反应的反应比人小> 10倍，并且 最常见的是完全不存在。这需要研究频率依赖性 大型动物模型中收缩和动力学的过程，或者在人类中更好 心肌。在文献，我们自己的数据和初步数据的最后5年的指导下 从人类心脏组织的实验及其频率依赖性调节，我们最近 写了一篇非常广泛的评论，假设放松动力学是 受三个相互依存过程的约束：细胞内钙下降，肌膜钙 结合动力学和跨桥循环动力学。目前，有大量的数据真空 关于人心肌的动力学率和调节，这很关键，因为来自 几乎不可能在 人类的盛行率。我们已经构建了目标，即1）首先建立动力学率 对于控制失败和未能失败的人类心肌的三个过程，以及 然后继续进行2）通过工程化的肌丝钙来修改这种动力学速率 对人类失败和非击败心肌的敏感性。在第一个目标中，我们将评估 钙短暂下降，肌丝反应性和跨桥循环的动力学速率 在第二个目的中，我们将评估是否在非释放和失败的人类心肌中进行动力学 修改控制肌丝钙反应性的动力学速率可以恢复 FDAR通过使用工程的troponinc蛋白来使人体心肌失败。以上 目标将在n> 50失败和n> 50的非失败的人类心脏中进行。这将使我们能够 最终基于疾病病因进行差异分析。根据我们的经验 在与人类心脏合作时，我们将拥有足够的统计能力来区分结果 在分类为缺血性心脏病，扩张性肌病的心脏之间以及患有 主要的舒张功能障碍。