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）：心脏钙动态的多尺度建模； 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 (EAD) 由于肌浆网 (SR) 自发释放 Ca 所引发的分子和离子机制，触发活动，从而在组织水平上观察室颤（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 电流重新激活而导致的 EAD 如何导致组织中的大不应期梯度，从而为再入创造基质。 EAD 也是由自发的 Ca 释放引发的。 DAD 通常由自发的 Ca 释放引发。为了了解 EAD 和 DAD 如何在兰尼碱受体 (RyR) 水平引起并在组织水平诱导触发活动，我们使用 Ca 循环和动作电位 (AP) 生理详细模型的计算机模拟和数学分析。在本研究中，我们考虑五个尺度：1）单个 RyR 2）Ca 释放单元（多个通道）3）亚细胞（Ca 释放单元阵列）4）全细胞 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 Ca 负载，可以通过 Ca 火花或泄漏从 SR 中释放 Ca。我们将展示由胞质和管腔 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。我们还知道，当 Ca 超载时，Ca 波会更频繁地发生。我们将研究单个自发 Ca 火花如何招募邻近的 Ca 释放单元来引发 Ca 波，Ca 火花簇如何传播或终止。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 EAD。然后我们将讨论 DAD 和 EAD 如何与组织特性相互作用以诱发触发活动。我们要解决的关键问题是 1) 一组 DAD 或 EAD 细胞的临界尺寸是多少，以克服电紧张源库失配，成为不同生理条件和组织几何形状下的触发活动。 2) 来自单个细胞的EAD或DAD如何导致一组细胞同时生成超过传播所需的临界尺寸的EAD或DAD。 3) 如何根据 RyR 特性估计组织中触发活动的敏感性。