Dual filament control of myocardial power and hemodynamics

摘要 心室做功的能力（即，发电）对于将血液 循环系统。心室功率由肌丝的发电能力决定 在心肌细胞内。然而，调节肌丝功率的亚细胞过程是 不完全理解。该提案的总体目标是利用生物化学、生物物理和 转基因工具，以辨别（i）细丝和（ii）厚的基于免疫调节的机制， (iii)将这些控制机制整合到一个计算模型中， 修改影响血流动力学。这两个机制假设是（目的1）功能的改变， 细丝调节单位的刚性调节跨桥的协同募集，反过来， 决定功率和（目的2）磷酸化肌球蛋白结合蛋白- C（MyBP-C）本身增加 肌原纤维功率输出由三种不同的生物物理机制。在（目标3）中， 将产生肌节功率输出，由此可以 操纵和评估对合作性和权力的功能影响。目标3超越了 肌节，并使用多尺度建模来预测肌丝靶点的策略操作将如何 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实验测试。 方式多尺度建模将提供一个新的平台，以询问生物物理修改， 最大的功能效应，从而阐明高价值的治疗靶点，以优化心室 在遗传性和适应性心肌病患者中的表现。

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.