Systems Modeling of Cardiac Excitation-Contraction-Metabolism Coupling

描述（由申请人提供）：心脏功能需要紧密的兴奋-收缩-代谢（ECM）偶联。改变这些过程及其相互作用可能导致心脏疾病。在临床环境中，这些过程之一的异常可能没有症状，但两个或两个以上的组合可能协同相互作用，触发致命事件。例如，先天性心力衰竭或长QT患者发生心律失常的倾向甚至在中等代谢应激下也可能大大增加。然而，兴奋，钙（Ca）循环，代谢和收缩之间的相互作用是非常复杂的，动态是时空和不规则的。通过实验来系统地探索其动力学和潜在机制是昂贵且有限的。该项目旨在使用系统生物学方法，将多尺度建模与非线性动力学和统计物理，计算机模拟和心室肌细胞实验相结合，以研究这个复杂的问题。我们首先开发了一个空间分布的ECM偶联模型，该模型是偶联的Ca释放单元、线粒体和肌丝的三维网络，其中L型Ca通道、兰尼碱受体和线粒体离子通道使用马尔可夫模型随机建模。不同尺度的复杂性模型也被开发用于机械的理解和有效的计算。然后，我们使用ECM模型来研究代谢应激下心室肌细胞的钙循环和动作电位动力学。我们假设，代谢应激，其影响是非常复杂的，可能会协同与其他变化相互作用，导致钙交替和波和振荡，这可以通过我们的理论统一的3R的（随机性，招聘，和Refractoriness）和自组织临界性。我们还研究了改变肌丝钙敏感性的影响，并协同钙循环动力学。我们假设这些变化可能通过以下情况引起Ca交替和波：1）通过3R理论和临界性改变Ca缓冲以引起Ca交替和波; 2）改变Ca-肌丝结合动力学以引起机械交替，这反过来又引起Ca交替和波。后一种情况建立了机械交替和心律失常之间的机械联系。将在心室肌细胞实验中验证模型的预测，并根据实验信息进一步完善模型。该项目的研究结果将带来对ECM偶联在心脏疾病发展中的整体理解。

DESCRIPTION (provided by applicant): The heart function requires a tight excitation-contraction-metabolism (ECM) coupling. Altering these processes and their interactions may cause cardiac diseases. In clinical settings, an aberration of one of these processes may not be symptomatic, but a combination of two or more may interact synergistically to trigger lethal events. For example, the propensity of a congenital heart failure or long QT patient to arrhythmias may be greatly increased under even moderate metabolic stress. However, the interactions between excitation, calcium (Ca) cycling, metabolism, and contraction are extremely complex, and the dynamics are spatiotemporal and irregular. To systematically explore the dynamics and the underlying mechanisms by experiments is costly and limited. This project aims to use a systems biological approach by combining multi-scale modeling with nonlinear dynamics and statistical physics, computer simulations, and ventricular myocyte experiments to study this complex problem. We first develop a spatially-distributed ECM coupling model that is a three- dimensional network of coupled Ca release units, mitochondria, and myofilaments, in which the L-type Ca channels, the ryanodine receptors, and the mitochondrial ion channels are modeled stochastically using Markov models. Models at different scales of complexity are also developed for mechanistic understanding and effective computation. We then use the ECM models to study the Ca cycling and action potential dynamics in ventricular myocytes under metabolic stresses. We hypothesize that metabolic stress, whose effects are extremely complex, may synergistically interact with other changes to cause Ca alternans and waves and oscillations, which can be unified by our theories of 3R's (Randomness, Recruitment, and Refractoriness) and self-organized criticality. We also investigate the effects of altered myofilament Ca sensitivity and cooperatively on Ca cycling dynamics. We hypothesize that these changes may cause Ca alternans and waves via the following scenarios: 1) altering Ca buffering to cause Ca alternans and waves via the 3R theory and criticality; 2) altering Ca-myofilament binding kinetics to cause mechanical alternans, which in turn causes Ca alternans and waves. The later scenario establishes a mechanistic link between mechanical alternans and arrhythmias. The predictions from the models will be validated in ventricular myocyte experiments and the models will be further refined based the on the experimental information. The findings in this project will bring in a holistic understanding o ECM coupling in the development of cardiac diseases.