Modeling of Cardiac Calcium Dynamics; Ryanodine Receptor induced Arrhythmias

描述（由申请人提供）：心脏钙动力学的多尺度建模；项目摘要：研究心脏钙（Ca）动力学，以阐明延迟后去极化（DADs）、早期后去极化（EADs）的分子和离子机制，这些机制是由肌浆网（SR）自发钙释放引起的，触发活动，从而在组织水平上引起心室颤动（VF），为新的治疗策略提供理论基础。我们最近展示了由于l型Ca电流的再激活而导致的EADs如何在组织中产生大的耐火度梯度，从而为再入创造基底。ead也是由自发Ca释放引起的。DADs通常由自发的Ca释放引起。为了了解EADs和DADs是如何在ryanodine受体（RyR）水平上引起的，并在组织水平上诱导触发活动，我们对Ca循环和动作电位（AP）的生理详细模型进行了计算机模拟和数学分析。在这项研究中，我们考虑了五个尺度：1)单个RyR 2) Ca释放单元（多通道）3)亚细胞（Ca释放单元阵列）4)整个细胞5)组织。本研究的前半部分是建立单RyR通道特性与亚细胞Ca动力学之间的联系。最近，Zima等人表明，根据SR的Ca负载，Ca可以通过Ca火花或泄漏从SR中释放。我们将展示由细胞质和腔内Ca调节的RyR通道打开和关闭速率如何改变形成Ca火花或泄漏的概率。我们也知道当Ca过载时，Ca波会更频繁地出现。我们将研究单个自发Ca火花如何招募相邻的Ca释放单元来启动Ca波，以及Ca火花簇如何传播或终止。本研究的第二部分是建立亚细胞钙动力学和组织AP动力学之间的联系。首先，我们将探讨亚细胞Ca波如何与AP相互作用以诱导dad和EADs。然后，我们将讨论DADs和EADs如何与组织特性相互作用以诱导触发活性。我们将解决的关键问题是：1)在不同的生理条件和组织几何形状下，一组dad或EADs细胞克服电紧张源-汇错配成为触发活动的临界大小是多少？2)来自单个细胞的EAD或DAD如何导致一组细胞同时产生超过繁殖所需的临界尺寸的EAD或DAD。3)如何通过RyR特性来估计组织中触发活性的易感性。

DESCRIPTION (provided by applicant): Multiscale Modeling of Cardiac Calcium Dynamics; How Ryanodine Receptors can induce Arrhythmias Project Summary: Cardiac calcium (Ca) dynamics will be investigated to elucidate molecular and ionic mechanisms of delayed afterdepolarizations (DADs), early afterdepolarizations (EADs) due to spontaneous Ca releases from the sarcoplasmic reticulum (SR), triggered activities, and thus ventricular fibrillation (VF) t the tissue level to provide theoretical bases for novel therapeutic strategies. We recently showed how EADs due to reactivation of the L-type Ca current can result in large gradients of refractoriness in tissue, creating a substrate for reentry. EADs are also initiated by spontaneous Ca releases. DADs are normally initiated by spontaneous Ca releases. To understand how EADs and DADs are caused at the ryanodine receptor (RyR) level and induce triggered activities at the tissue level, we use computer simulation and mathematical analysis of physiologically detailed models of Ca cycling and the action potential (AP). In this study we consider five scales 1) single RyR 2) Ca release unit (multiple channels) 3) subcell (array of Ca release units) 4) whole cell 5) tissue. The first half of this research is to establish link betwee single RyR channel properties and subcellular Ca dynamics. Recently, Zima et al showed that Ca release from the SR can be via Ca spark or leak depending on SR Ca load. We will show how RyR channel opening and closing rates, which are regulated by cytosolic and luminal Ca, change the probability to form a Ca spark or leak. We also know Ca waves occur more often when the Ca is overloaded. We will investigate how a single spontaneous Ca spark recruits neighboring Ca release units to initiate a Ca wave, how clusters of Ca sparks propagate or terminate. The second half of this research is to establish the link between subcellular Ca dynamics and tissue AP dynamics. First, we will address how subcellular Ca waves interact with AP to induce DADs and EADs. Then we will address how DADs and EADs interact with tissue properties to induce a triggered activity. Key questions we will address are 1) what is the critica size of a group of cells of DADs or EADs to overcome electrotonic source-sink mismatch to become a triggered activity under different physiological conditions and tissue geometry. 2) how an EAD or DAD from a single cell can cause a group of cells to simultaneously generate EADs or DADs to exceed the critical size required for propagation. 3) how susceptibility of triggered activity in tissue can be estimated from the RyR properties.