Modeling of Cardiac Calcium Dynamics; Ryanodine Receptor induced Arrhythmias

描述（申请人提供）：心脏钙动力学的多尺度建模;兰尼碱受体如何诱导心律失常项目摘要：将研究心脏钙（Ca）动力学，以阐明延迟后除极（DAD）、由肌浆网（SR）自发Ca释放引起的早期后除极（埃兹）、触发活动，从而在组织水平上研究心室颤动（VF），为新的治疗策略提供理论依据。我们最近展示了由于L型钙电流的重新激活导致的埃兹如何导致组织中的大梯度不应性，从而为折返创造了基底。埃兹也由自发的Ca释放引发。DAD通常由自发的Ca释放引发。为了了解埃兹和DAD是如何在兰尼碱受体（RyR）水平上引起的，并在组织水平上诱导触发活动，我们使用计算机模拟和数学分析的生理详细模型的钙循环和动作电位（AP）。在这项研究中，我们考虑了五个尺度：1）单个RyR 2）Ca释放单位（多通道）3）亚细胞（Ca释放单位阵列）4）全细胞5）组织。本研究的前半部分是建立单一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 Ca负载，SR中的Ca释放可能是通过Ca火花或泄漏。我们将展示如何RyR通道开放和关闭率，这是由胞质和管腔钙调节，改变的概率，形成一个钙火花或泄漏。我们也知道钙波在钙超载时更容易发生。我们将研究单个自发钙火花如何招募邻近的钙释放单位来启动钙波，钙火花簇如何传播或终止。本研究的后半部分是建立亚细胞Ca动力学和组织AP动力学之间的联系。首先，我们将讨论亚细胞Ca波如何与AP相互作用，以诱导DAD和埃兹。然后，我们将讨论DAD和埃兹如何与组织特性相互作用以诱导触发活动。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，DAD或埃兹的一组细胞克服电紧张性源-汇失配成为触发活动的临界大小是多少。2)来自单个小区的EAD或DAD如何能够导致一组小区同时生成超过传播所需的临界大小的埃兹或DAD。3)如何从RyR特性估计组织中触发活动的敏感性。

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.