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（由申请人提供）：心脏钙动力学的多尺度建模； 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组织水平为新颖的治疗策略提供理论基础。我们最近展示了由于L型Ca电流的重新激活而引起的EADS如何导致组织中的耐火性梯度，从而产生重新进入的底物。 EADS也由自发的CA释放启动。爸爸通常是由自发的CA释放发起的。为了了解在ryanodine受体（RYR）水平上引起的EAD和DAD是如何在组织水平上诱发的活动，我们使用计算机模拟和数学分析CA循环的生理详细模型和动作电位（AP）。在这项研究中，我们考虑了五个量表1）单RYR 2）CA释放单元（多个通道）3）子细胞（CA释放单元的阵列）4）4）全细胞5）组织。这项研究的前半部分是建立单一RYR通道特性和亚细胞CA动力学的链接。最近，Zima等人表明，CA从SR释放可以通过CA火花或根据SR CA负载泄漏。我们将展示RYR通道的打开和关闭速率如何受到胞质和腔内CA的调节，它会改变形成CA火花或泄漏的概率。我们还知道，当CA被超载时，CA波更频繁地发生。我们将研究一个自发的CA火花如何招募附近的CA释放单元以启动CA波，CA的簇如何传播或终止。这项研究的后半部分是建立亚细胞CA动力学与组织AP动力学之间的联系。首先，我们将解决亚细胞CA波如何与AP相互作用以诱导父亲和EAD。然后，我们将解决父亲和EADS与组织特性相互作用以诱导活动的活动。我们将要解决的关键问题是1）在不同的生理条件和组织几何形状下，一组爸爸或EAD的细胞的批评大小是什么，以克服电源源 - 链接不匹配，成为一种触发的活动。 2）来自单个细胞的EAD或DAD如何使一组细胞同时产生EAD或DAD超过传播所需的临界大小。 3）如何从RYR特性估算组织中触发活性的敏感性。