Dual filament control of myocardial power and hemodynamics

心肌功率和血流动力学的双丝控制

基本信息

批准号：
10245290
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
项目类别：
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/10245290
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

项目摘要

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）基于粗丝的机制，以调节功率和 (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。