Calcium Entrained Arrhythmias

说明(申请人提供)：钙(Ca~(2+))依赖型心律失常已被认为是导致室性心动过速、纤颤和死亡的重要健康问题。这些心律失常的确切发生机制仍然是一个极其重要但令人头疼的问题。我们假设，这些钙依赖的心律失常发生在一个过程中，在这个过程中，钙升高的传播波穿过心肌细胞，从而激活和携带电活动。建议的PI(Leander、Jafri和Winlow)将以多尺度的方法将最先进的计算建模与新颖的实验室实验相结合，以确定钙信号缺陷是如何发展的，并对假说进行关键检验。这项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测心脏钙信号的分子生理学。它将利用异常强大的方法，利用关键钙调节蛋白的突变点突变引起的分子疾病-儿茶酚胺能多形性室性心动过速(CPVT)，特异性地检测钙依赖性心律失常的分子病理生理学。我们将研究钙释放通道(Ryanodine Receptor 2，RyR2)和钙结合蛋白Calequestrin(CASQ2)突变是如何导致钙依赖性心律失常的。这两种心律失常的小鼠模型将被用来进行高级细胞生物学研究。这项工作还将包括对小鼠和豚鼠的钙超负荷心律失常的检查，从而使这项工作变得更加普遍。计划中的调查将包括多个范围：从分子缺陷，到细胞钙离子功能障碍，再到组织心律失常，使用数学建模和生物实验。该项目将解决以下四个具体目标：1)钙火花如何触发和维持钙波？2)钙波如何在细胞间传播？钙波如何传导电活动？3)RyR2和CASQ2的特定突变如何影响钙火花、钙波和钙波在细胞间的传播？4)心脏的三维结构如何影响钙离子诱导的心律失常的发生？这项工作将提供对心脏和钙离子在电功能障碍和心律失常中的作用的根本新的理解，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.