Calcium Entrained Arrhythmias

描述（由申请人提供）：钙（Ca2+）依赖性心律失常已被确定为导致室性心动过速，纤颤和死亡的重大健康问题。这些心律失常产生的确切机制仍然是一个非常重要但令人烦恼的问题。我们假设这些Ca2+依赖性心律失常是通过一个过程发生的，在这个过程中，升高的钙传播波穿过心脏细胞，从而激活和携带电活动。建议pi （Lederer， Jafri和Winslow）将在多尺度方法中结合最先进的计算模型和新颖的实验室实验，以确定钙信号缺陷如何发展并严格测试假设。该系统生物学研究将在正常和病理条件下以高时间和空间分辨率检查心脏Ca2+信号的分子生理学。它将利用异常强大的方法，专门研究Ca2+依赖性心律失常的分子病理生理学，使用分子疾病，儿茶酚胺能多态性室性心动过速（CPVT），由一个非常明确的过程点突变引起的关键Ca2+调节蛋白。我们将研究钙释放通道（红嘌呤受体2型，RyR2）和Ca2+结合蛋白钙调蛋白（CASQ2）的突变如何促进Ca2+依赖性心律失常的发生。这两种心律失常的小鼠模型将用于高级细胞生物学研究。通过对小鼠和豚鼠Ca2+超载心律失常的检查，这项工作将变得更加普遍。计划中的研究将涵盖多个尺度：从分子缺陷到细胞Ca2+功能障碍，再到使用数学模型和生物实验的组织心律失常。该项目将解决以下四个具体目标：1)Ca2+火花如何触发和维持钙波？2) Ca2+波如何在细胞间传播？Ca2+波是如何引起电活动的？3) RyR2和CASQ2的特异性突变如何影响Ca2+火花、Ca2+波和Ca2+波在细胞间的传播？4)心脏的三维组织如何影响Ca2+夹带性心律失常？这项工作将为心脏和Ca2+在电功能障碍和心律失常中的作用提供新的认识，并为新的治疗方法奠定基础。

DESCRIPTION (provided by applicant): Calcium (Ca2+) dependent arrhythmias have been identified as a significant health problem leading to ventricular tachycardia, fibrillation and death. The exact mechanism by which these arrhythmias arise remains a critically important yet vexing problem. We hypothesize that these Ca2+ dependent arrhythmias occur through a process in which a propagating wave of elevated calcium travels through heart cells and thereby activates and entrains electrical activity. The proposals PIs (Lederer, Jafri, and Winslow) will combine state-of- the art computational modeling with novel laboratory experiments in a multi-scale approach to determine how the calcium signaling defect develops and critically test the hypothesis. This systems biology investigation will examine the molecular physiology of cardiac Ca2+ signaling at high temporal and spatial resolution under normal and pathological conditions. It will utilize the unusually powerful approach of specifically examining the molecular pathophysiology of the Ca2+ dependent arrhythmia using the molecular disease, catecholaminergic polymorphic ventricular tachycardia (CPVT) caused by an extremely well-defined process - point mutations of critical Ca2+ regulatory proteins. We will examine how mutations in the calcium release channel (ryanodine receptor type 2, RyR2) and the Ca2+ binding protein, calsequestrin (CASQ2) contribute to Ca2+ dependent arrhythmogenesis. Mouse models of these two arrhythmias will be used to enable advanced cell biology investigations. The work will be made more general by also including an examination of Ca2+ overload arrhythmias in mouse and guinea pig. The planned investigation will encompass multiple scales: from the molecular defect, to cellular Ca2+ dysfunction to tissue arrhythmia using both mathematical modeling and biological experiments. The project will address the following four specific aims: 1) How do Ca2+sparks trigger and sustain calcium waves? 2) How do Ca2+waves propagate from cell to cell? How do Ca2+waves entrain electrical activity? 3) How do specific mutations in RyR2 and CASQ2 affect Ca2+sparks, Ca2+waves and the propagation of Ca2+waves from cell to cell? 4) How does the 3D organization of the heart affect Ca2+ entrained arrhythmogenesis? This work should provide fundamental new understanding of the heart and the role of Ca2+ in electrical dysfunction and arrhythmia and lay the foundation for new therapeutic approaches. PUBLIC HEALTH RELEVANCE: Calcium dependent cardiac arrhythmias have been identified as a significant health problem and a major cause of cardiac death. The proposed work will provide new understanding of the molecular and cellular causes of these heart rhythm disturbances and enable new treatments.