Modeling of Cardiac Calcium Dynamics; Ryanodine Receptor induced Arrhythmias

心脏钙动态建模；

• 批准号: 8225446
• 负责人: Daisuke Sato
• 金额: $ 9.71万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-21 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8225446
• 关键词: Action Potentials; Address; Anti-Arrhythmia Agents; Arrhythmia; Biological; Calcium; Calcium Oscillations; Cardiac; Cause of Death; Cell model; Cells; Characteristics; Computer Simulation; Coupled; Coupling; Gap Junctions; Goals; Heterogeneity; Individual; Ion Channel; L-Type Calcium Channels; Lead; Link; Membrane Potentials; Microscopic; Modeling; Molecular; Muscle Cells; Mutation; Performance; Pharmaceutical Preparations; Physiological; Predisposition; Probability; Process; Property; Randomized; Recovery; Recruitment Activity; Regulation; Research; Ryanodine Receptor Calcium Release Channel; Ryanodine Receptors; Sarcoplasmic Reticulum; Simulate; Sodium-Calcium Exchanger; Source; Techniques; Technology; Therapeutic; Time; Tissue Model; Tissues; United States; Ventricular Fibrillation; base; drug development; insight; mathematical model; multi-scale modeling; novel; novel therapeutics; reuptake; sudden cardiac death; theories

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.

描述(申请人提供)：心脏钙动力学的多尺度建模；Ryanodine受体如何诱发心律失常项目摘要：将研究心脏钙(Ca)动力学，以阐明延迟后除极(DAD)、早期后除极(EADS)的分子和离子机制，这些机制是由于肌浆网(SR)自发释放钙、触发活动，从而在组织水平上发生室颤(VF)，从而为新的治疗策略提供理论基础。我们最近展示了由于L型钙电流的重新激活而导致的EADS如何在组织中导致大的耐火度梯度，从而为再入创造了一个底物。EADS也是由自发的钙释放引起的。爸爸通常是通过自发的钙释放来启动的。为了了解EADS和DADS是如何在Ryanodine受体(RyR)水平上引起的，并在组织水平上引发触发活动，我们使用计算机模拟和数学分析钙循环和动作电位(AP)的详细生理模型。在这项研究中，我们考虑了五个尺度：1)单个RyR2；2)钙释放单元(多通道)；3)亚细胞(钙释放单元阵列)；4)整个细胞；5)组织。本研究的前半部分是建立单个RyR通道特性与亚细胞钙动力学之间的联系。最近，Zima等人发现，SR的钙释放可以通过钙火花或泄漏来实现，这取决于SR的钙负荷。我们将展示RyR通道的开启和关闭速率是如何改变形成钙火花或泄漏的概率的，这是由胞浆和腔内钙调节的。我们还知道，当钙超载时，钙波发生的频率更高。我们将研究单个自发的钙火花如何招募邻近的钙释放单位来启动钙波，钙火花簇是如何传播或终止的。本研究的后半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，我们将讨论亚细胞钙波如何与AP相互作用来诱发DAD和EADS。然后，我们将讨论DADS和EADS如何与组织属性相互作用以诱导触发的活动。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，一组DADS或EAD细胞克服电渗源-汇失配而成为触发活动的临界大小是多少。2)单个小区的EAD或DAD如何导致一组小区同时生成EAD或DAD超过传播所需的临界大小。3)如何从RyR特性估计组织中触发活动的敏感性。