Sarcoplasmic reticulum calcium leak and calcium instability in cardiac myocytes

描述（申请人提供）：每次心跳时，少量钙通过膜通道进入细胞，触发细胞内储存的大量钙释放。细胞内钙的增加具有双重作用：1）使收缩和2）影响形成动作电位的离子电流。因此，心肌细胞中钙的不适当转运可导致心室功能受损和心力衰竭等疾病状态下的致死性心律失常。研究表明，不稳定的钙调节和心律失常与从细胞内储存到细胞质的“泄漏”增加有关。特别是，遗传性疾病儿茶酚胺能多形性室性心动过速（CPVT）导致渗漏增加和由钙自发释放触发的危险室性心律失常。因此，这种疾病代表了心脏细胞中离子转运和电信号之间密切联系的一个明显例子。然而，钙连接增加心律失常风险的机制仍不清楚。我们假设，由于心肌细胞内钙信号传导和竞争效应的固有复杂性，泄漏仅在某些条件下是有害的。创新实验和计算建模的结合将定量确定控制钙泄漏的因素，并确定泄漏何时是危险的，何时是保护性的边界。这些研究将有助于深入了解影响CPVT和心力衰竭患者心律失常风险的因素。该项目可以细分为以下具体目标：目标1：确定健康细胞中控制钙泄漏的因素。目的2：确定心力衰竭中渗漏增加的潜在机制。目标3：确定尽管肌浆网钙含量降低，但兰尼碱受体门控改变可增加心律失常风险的机制。这项工作将提供有关健康心脏细胞中Ca2+正常调节和病理学中发生的缺陷的基本新信息。通过建立一个定量的框架来了解正常和有缺陷的钙释放，这些研究可以帮助确定心脏治疗的深思熟虑的目标 公共卫生相关性：心脏细胞中钙的不适当调节已被确定为导致不稳定和潜在致命心律的重要因素。该项目旨在定量了解钙调节的变化如何导致心脏功能改善和更大的稳定性，或潜在的危险不稳定性。这些研究将为可能有效预防不稳定和危险心律的治疗提供新的见解。

DESCRIPTION (provided by applicant): With each heartbeat, a small amount of calcium entering the cell through membrane channels triggers the release of a larger amount of calcium from intracellular stores. The resulting increase in intracellular calcium has the dual effects of both: 1) enabling contraction and 2) influencing the ionic currents that shape of the action potential. Improper transport of calcium in cardiac myocytes can therefore contribute to both impaired ventricular function and lethal cardiac arrhythmias in disease states such as heart failure. Studies suggest that unstable calcium regulation and arrhythmias are associated with increased "leak" from intracellular stores to the cytosol. In particular, the inherited disorder catecholaminergic polymorphic ventricular tachycardia (CPVT) results in both increased leak and dangerous ventricular arrhythmias triggered by spontaneous release of calcium. This disease therefore represents an obvious example of the close links between ion transport and electrical signaling in heart cells. However, the mechanisms by which calcium link can increase arrhythmia risk remain unclear. We hypothesize that, because of the inherent complexity of calcium signaling and competing effects within cardiac myocytes, leak is only deleterious under certain conditions. A combination of innovative experiments and computational modeling will quantitatively determine the factors that control calcium leak and define the boundaries of when leak is dangerous and when it is protective. Together the studies proposed will yield significant insight into the factors that influence arrhythmia risk in CPVT and in heart failure. The project can be sub-divided into the following Specific Aims: Aim 1: Determine, in healthy cells, the factors that control calcium leak. Aim 2: Determine the mechanisms underlying increased leak in heart failure. Aim 3: Determine the mechanisms by which altered gating of ryanodine receptors can increase the risk of arrhythmia despite reduced sarcoplasmic reticulum calcium content. The work will provide fundamental new information concerning both the normal regulation of Ca2+ in healthy heart cells and the defects that occur in pathology. By developing a quantitative framework for understanding normal and defective calcium release, these studies can help identify thoughtful targets for cardiac therapies PUBLIC HEALTH RELEVANCE: Improper regulation of calcium in heart cells has been identified as an important factor contributing to instability and potentially lethal heart rhythms. This project is aimed at developing a quantitative understanding of how changes in calcium regulation can lead to either improved heart function and greater stability, or to potentially dangerous instability. The studies will provide new insight into therapies that are likely to be effective at preventing instability and dangerous heart rhythms.