Dual filament control of myocardial power and hemodynamics

摘要 脑室做功(即发电)的能力对于血液的运输是必不可少的。 循环系统。脑室功率由肌丝的发电能力决定。 在心肌细胞内。然而，调节肌丝力量的亚细胞过程是 不完全理解。这项提案的总体目标是使用生化、生物物理和 用于识别(I)细丝和(Ii)基于粗丝的机制的转基因工具 (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水平如何 修饰会影响血流动力学。这两个机械假说是(目标1)泛函中的变化 细丝调节单位的刚性调节交叉桥的合作招募，这反过来， 决定功率和(目标2)肌球蛋白结合蛋白C(MyBP-C)本身的磷酸化增加 三种不同的生物物理机制产生的肌原纤维能量输出。在(Aim 3)中，一个多状态动力学模型 肌节的功率输出将由此产生细丝和粗丝的动态特性 操纵和评估对协作性和能力的功能影响。《目标3》超越了 并使用多尺度建模来预测对肌丝目标的战略性操纵将如何 对心功能和血流动力学的影响，这将在假设驱动的实验中进行测试 举止。多尺度建模将提供一个新的平台来询问产生 最大的功能效应，从而照亮高价值的治疗目标，以优化心脏 遗传性和适应性心肌病患者的表现。

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.