Modeling of Cardiac Calcium Dynamics; Ryanodine Receptor induced Arrhythmias

项目名称： 心脏钙动力学的多尺度模型;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，以阐明分子和离子 延迟后去极化（DAD）、早期后去极化（埃兹）的机制， 肌浆网（SR）自发性钙释放，触发活动，从而 目的：在组织水平研究室颤（VF），为新型治疗方法提供理论依据 战略布局我们最近展示了由于L型钙电流的再激活引起的埃兹如何能够 导致组织中的大梯度的不应性，从而产生用于折返的基底。埃兹是 也由自发的Ca释放引发。DAD通常由自发性Ca 释放。了解埃兹和DAD是如何在ryanodine受体（RyR）水平引起的 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 Ca循环和动作电位（AP）的生理学详细模型的分析。在这 研究中我们考虑了5个尺度：1）单个RyR 2）Ca释放单位（多通道）3）亚细胞 （Ca释放单元阵列）4）全细胞5）组织。这项研究的前半部分是建立 单RyR通道特性和亚细胞Ca动力学之间的联系。最近，Zima等人 表明Ca从SR的释放可以是通过Ca火花或泄漏，这取决于SR Ca负载。我们 将显示RyR通道的开放和关闭速率，这是由胞质和 管腔Ca，改变形成Ca火花或泄漏的概率。我们也知道Ca波会发生在 当Ca过载时更频繁。我们将研究一个自发的钙火花 招募邻近的钙释放单位启动钙波，钙火花簇如何传播 或者终止本研究的第二部分是建立亚细胞钙离子与细胞外基质之间的联系。 动力学和组织AP动力学。首先，我们将讨论亚细胞钙波如何与 AP诱导DAD和埃兹。然后我们将讨论DAD和埃兹如何与组织相互作用 引发触发活动的属性。我们将解决的关键问题是：1） DAD或埃兹的一组单元的大小以克服电紧张源-汇失配， 在不同的生理条件和组织几何形状下成为触发活动。（二） 来自单个细胞的EAD或DAD如何导致一组细胞同时产生 埃兹或DAD超过传播所需的临界大小。3)如何易感性 组织中的触发活性可以从RyR特性估计。

Project Title: 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) at 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 between 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 critical 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.