Dual filament control of myocardial power and hemodynamics

心肌功率和血流动力学的双丝控制

• 批准号: 10472655
• 负责人: Kenneth S Campbell
• 金额: $ 46.71万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-25 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10472655
• 关键词: Actins; Area; Atomic Force Microscopy; Binding; Biochemical; Biophysical Process; Biophysics; Blood; Blood Circulation; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiovascular system; Cell physiology; Cells; Clinical; Computer Models; Coupled; Coupling; Cyclic AMP-Dependent Protein Kinases; Data; Filament; Generations; Genetic; Heart; Heart failure; Human; Intervention; Link; Measures; Mechanics; Mediating; Microfilaments; Modeling; Modification; Molecular; Mus; Mutation; Myocardial; Myosin ATPase; Organ; Output; Patients; Performance; Phosphorylation; Physiology; Property; Pump; Regulation; Research; Sarcomeres; Signal Pathway; Speed; System; Testing; Thick; Thick Filament; Thin Filament; Thinness; Time; Transcend; Transgenic Mice; Transgenic Organisms; Translating; Translations; Ventricular; Ventricular Function; Work; base; blood pump; combinatorial; experimental study; heart function; hemodynamics; innovation; kinetic model; multi-scale modeling; myosin-binding protein C; novel; predictive modeling; pressure; recruit; simulation; therapeutic target; tool

Abstract The capacity of the ventricles to perform work (i.e., generate power) is essential for moving blood throughout the circulatory systems. Ventricular power is determined by the power generating capacity of the myofilaments within the cardiac myocyte. However, the sub-cellular processes that regulate myofilament power are incompletely understood. The overall objective of this proposal is to use biochemical, biophysical, and transgenic tools to discern (i) thin filament and (ii) thick filament-based mechanisms that regulate power and (iii) integrate these control mechanisms into a computational model that can predict how sarcomere-level modifications impact hemodynamics. The two mechanistic hypotheses are (Aim 1) alterations in the functional rigidity of thin filament regulatory units modulate cooperative recruitment of cross-bridges, which, in turn, determines power and (Aim 2) phosphorylation of myosin binding protein- C (MyBP-C) per se increases myofibrillar power output by three distinct biophysical mechanisms. In (Aim 3), a multi-state kinetic model of sarcomeric power output will be generated whereby thin and thick filament dynamic properties can be manipulated and evaluated for functional impacts to cooperativity and power. Aim 3 goes beyond the sarcomere and uses multiscale modeling to predict how strategic manipulation of myofilament targets will impact ventricular function and hemodynamics, which will be experimentally tested in a hypothesis-driven manner. Multi-scale modeling will provide a new platform to interrogate biophysical modifications that produce the largest functional effects and, thus, illuminate high-value therapeutic targets to optimize ventricular performance in patients with genetic and adaptive cardiomyopathies.

抽象的 心室做功（即发电）的能力对于血液在整个过程中的流动至关重要 循环系统。心室功率由肌丝的发电能力决定 心肌细胞内。然而，调节肌丝能量的亚细胞过程是 不完全理解。该提案的总体目标是利用生物化学、生物物理和 转基因工具可识别（i）细丝和（ii）基于粗丝的调节功率和能量的机制 (iii) 将这些控制机制整合到一个计算模型中，该模型可以预测肌节水平如何 修改影响血流动力学。这两个机制假设是（目标 1）功能的改变 细丝调节单元的刚性调节跨桥的合作招募，反过来， 确定功率和（目标 2）肌球蛋白结合蛋白-C (MyBP-C) 本身的磷酸化增加 通过三种不同的生物物理机制输出肌原纤维功率。在（目标 3）中，多态动力学模型 将产生肌节功率输出，从而可以调节细丝和粗丝的动态特性 操纵和评估对合作性和权力的功能影响。目标 3 超出了 肌节并使用多尺度建模来预测肌丝目标的战略操纵将如何 影响心室功能和血流动力学，这将在假设驱动的实验中进行测试 方式。多尺度建模将提供一个新的平台来询问产生的生物物理修饰 最大的功能效应，从而阐明高价值的治疗目标，以优化心室 遗传性和适应性心肌病患者的表现。