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: 10672422
• 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 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10672422
• 关键词: Acceleration; Actins; Area; Atomic Force Microscopy; Binding; Biochemical; Biophysical Process; Biophysics; Blood; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiovascular system; Cell physiology; Cells; Circulation; 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; 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 心室进行工作的能力（即产生能力）对于整个过程中移动血液至关重要 循环系统。心室功率取决于肌膜的发电能力 在心肌细胞中。但是，调节肌丝功率的亚细胞过程是 不完全理解。该提案的总体目的是使用生化，生物物理和 转基因工具可辨别（i）细丝和（ii）调节功率和基于厚的细丝机制 （iii）将这些控制机制集成到一个计算模型中，该模型可以预测肌节级 修饰会影响血液动力学。两个机械假设是（AIM 1）功能的改变 细丝调节单元的刚性调节跨桥的合作募集，这反过来又 确定功率和（目标2）肌球蛋白结合蛋白C（MYBP-C）的磷酸化本身增加 三种不同的生物物理机制的肌原纤维功率输出。在（AIM 3）中，一种多状态动力学模型 将生成肉瘤的功率输出，从而可以使细丝动态属性是 对合作和权力的功能影响进行了操纵和评估。 AIM 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 撞击心室功能和血液动力学，将在假设驱动的实验测试 方式。多尺度建模将为询问生物物理修饰的新平台 最大的功能效应，因此阐明了高价值治疗靶标，以优化心室 患有遗传和适应性心肌病的患者的表现。

项目成果

Human skeletal myopathy myosin mutations disrupt myosin head sequestration.

• DOI: 10.1172/jci.insight.172322
• 发表时间: 2023-11-08
• 期刊: JCI INSIGHT
• 影响因子: 8
• 作者: Carrington, Glenn;Hau, Abbi;Kosta, Sarah;Dugdale, Hannah F.;Muntoni, Francesco;D'Amico, Adele;Van den Bergh, Peter;Romero, Norma B.;Malfatti, Edoardo;Vilchez, Juan Jesus;Oldfors, Anders;Pajusalu, Sander;Ounap, Katrin;Giralt-Pujol, Marta;Zanoteli, Edmar;Campbell, Kenneth S.;Iwamoto, Hiroyuki;Peckham, Michelle;Ochala, Julien
• 通讯作者: Ochala, Julien