心室肌细胞的钙循环建模与仿真

发布时间：2018-06-14 01:10

本文选题：心脏细胞 + 钙循环　；参考：《浙江大学》2011年博士论文

【摘要】：钙离子是心脏正常工作中极为重要、不可或缺的关键离子,深刻的影响着心脏的电兴奋、肌肉收缩、信号转导和基因表达等一系列生理过程,是心脏兴奋收缩耦联过程中连接电学和力学的关键桥梁和纽带。目前心脏钙循环的确切机制仍存在很多疑点和争议。应用数学的语言和方法对心脏钙循环进行建模仿真,对于探索心脏钙循环内在机制、研究分析心脏疾病中的钙循环相关病理机制具有重要的理论价值和应用价值。本文深入分析钙循环的内在规律和特征,建立了亚细胞水平上的微观钙循环模型和跨尺度复合钙循环模型,并在钙循环模型中引入新概念,为心脏疾病尤其是心力衰竭的机制研究提供了有力的模型支持和理论分析。本文涉及心肌细胞钙循环的生理学基础,钙循环建模仿真,病生理机制研究,主要研究内容和结论如下： (1)钙循环模型的研究进展和心脏钙循环的理论知识回顾了国际上钙循环领域相关数学模型的分类和最新研究进展,系统的介绍了钙循环所依赖的肌细胞解剖结构基础,心肌细胞电兴奋、肌肉收缩以及在兴奋收缩耦联中起桥梁作用的钙循环过程,着重介绍了钙循环的局部控制理论,以及钙离子通道特性和肌质网钙库释放和摄取,并详细描述了胞内钙释放事件(钙火花和钙波)的基本特征和内在机制。 (2)亚细胞水平的微观钙循环建模在胞内Ca2+反应-扩散系统的基础上,建立了更符合心室肌细胞微观解剖结构、并使用吸收边界条件的二维时空钙循环模型,用以模拟仿真亚细胞水平上的钙火花、钙波等基本钙信号,并对这些钙信号进行定量分析。此外,应用本模型研究分析心脏病理条件下心室肌细胞内钙信号异常和钙平衡紊乱现象,仿真结果显示RyR簇不稳定和/或静息[Ca2+]i升高将促进自发性钙波的形成,并加速其传播,而钙漏流和SR钙泵功能的影响较小,说明钙波的演变过程是由多重因素调控的。 (3) Rogue RyR对心衰钙循环的影响本文将"rogue RyR"通道整合进入二维时空微观钙循环数学模型,模拟仿真心衰时SR钙库部分卸载情况下的钙循环特点。仿真结果显示rogue RyR通道能够以钙夸克的形式增大静息期SR钙漏流；当SR钙库容量减小时,仍能增加自发性钙波的发生概率；并加速钙波的传播。说明rogue RyR对心衰时的钙平衡紊乱具有重要作用。在其他任何模型中通过调整RyR簇相关参数和其他离子通道都将无法模拟这种钙循环过程,因此我们的工作提出了一个全新的钙循环观点,有助于解释心衰时钙循环紊乱机制。 (4)跨尺度复合钙循环模型建立一个从亚细胞水平到细胞水平的跨尺度复合钙循环模型,同步仿真研究心室肌细胞内微观钙循环和全细胞钙循环以及电生理特性,以及它们之间的相互影响作用。利用该复合模型,我们仿真发现SR腔内钙离子浓度改变会对亚细胞和细胞水平上的钙信号以及细胞膜电位等细胞电生理特性产生影响,SR钙库过载则将诱发自发性钙波,并导致DAD。 (5) Rogue RyR对心衰细胞的致心律失常作用在跨尺度复合模型的基础上发展了整合rogue RyR通道的心衰心室肌细胞模型,对不同rogue RyR通道密度下的微观钙释放事件及所带来的细胞水平上的钙瞬变和电生理特性变化进行模拟仿真。研究发现心衰时,rogue RyR的存在会促使心室肌细胞发生DAD或触发性动作电位,这些触发活动的性质与rogue RyR分布密度有密切关系,说明rogue RyR对心衰细胞具有致心律失常作用。
[Abstract]:Ca ~ ( 2 + ) ion is an important and indispensable key ion in the normal operation of the heart . It is a key bridge and ligament connecting electricity and mechanics in the process of cardiac muscle contraction and coupling .

( 1 ) The research progress of calcium circulation model and the theoretical knowledge of calcium circulation in the heart

This paper reviews the classification and the latest development of relevant mathematical models in the field of calcium cycling in the world , systematically introduces the anatomical structure of muscle cells , the electric excitation , muscle contraction and the calcium circulation process of the bridge in the coupling of excitation and contraction . The local control theory of calcium circulation , the calcium ion channel characteristics and the release and uptake of calcium channel of the sarcoplasmic reticulum are emphatically introduced , and the basic characteristics and internal mechanisms of intracellular calcium release events ( calcium spark and calcium wave ) are described in detail .

( 2 ) Micro - calcium cycle modeling of sub - cell level

On the basis of intracellular Ca2 + reaction - diffusion system , a two - dimensional temporal and temporal calcium cycling model is established which is more consistent with the microscopic anatomical structure of ventricular myocytes and uses the absorption boundary conditions to simulate the basic calcium signals such as calcium sparks and calcium waves at simulated sub - cell levels .

( 3 ) The influence of RyR on Ca ~ ( 2 + ) circulation in heart failure

In this paper , a mathematical model of Ca ~ ( 2 + ) Ca ~ ( 2 + ) Ca ~ ( 2 + ) Ca ~ ( 2 + ) Ca ~ ( 2 + ) Ca ~ ( 2 + ) Ca ~ ( 2 + ) Ca ~ ( 2 + ) Ca ~ ( 2 + ) Ca ~ ( 2 + ) Ca ~ ( 2 + ) Ca ~ ( 2 + ) Ca ~ ( 2 + ) Ca ~ ( 2 + ) Ca ~ ( 2 + ) Ca ~ ( 2 + ) Ca ~ ( 2 + ) Ca ~ ( 2 + ) Ca ~ ( 2 + ) Ca ~ ( 2 + ) Ca ~ ( 2 + ) Ca ~ ( 2 + ) Ca ~ ( 2 + ) Ca ~ ( 2 + ) Ca ~ ( 2 + ) Ca ~ ( 2 + ) Ca ~ ( 2 + ) ~
The occurrence probability of spontaneous calcium wave can be increased when the capacity of SR Ca is decreased .
It is shown that the calcium balance in heart failure plays an important role in other models . In any other model , the calcium circulation can not be simulated by adjusting the related parameters of RyR cluster and other ion channels . Therefore , we have proposed a new viewpoint of calcium cycling , which can help explain the mechanism of calcium circulatory disturbance in heart failure .

( 4 ) Cross - scale composite calcium circulation model

A cross - scale composite calcium cycle model from sub - cell level to cell level was established , and the effects of calcium ion concentration in SR cavity on cellular electrophysiological properties such as calcium signal and cell membrane potential were studied .

( 5 ) Armogenic Effects on Heart Failure Cells Induced by rogue RyR

Based on the cross - scale composite model , the ventricular myocytes model of heart failure integrated with the RyR channel was developed . The microscopic calcium release events and the changes of calcium transient and electrophysiological properties were simulated under different densities of RyR channels .
【学位授予单位】：浙江大学
【学位级别】：博士
【学位授予年份】：2011
【分类号】：R331

【共引文献】