Control of Local Calcium Signaling in the Heart

描述（由申请人提供）：每次心跳需要每个心脏细胞的电兴奋和机械收缩的协调，这一过程需要相对少量的钙（Ca）进入细胞，以触发从肌浆网（SR）释放更大的钙。在健康的心脏中，钙诱导的钙释放（CICR）过程令人惊讶地稳定，尽管它依赖于正反馈。然而，CICR的错误调控最近被证明在诸如心力衰竭等疾病状态中起着核心作用。尽管对于钙释放的基本单位钙火花是如何被触发已经有了相当多的了解，但对于这些事件是如何终止的，或者是否有缺陷的终止在疾病中起作用，我们知之甚少。本研究的目的是研究Ca火花终止的基本分子机制，以及这些事件的终止如何影响CICR的调控。本提案的目的是进行关键的实验测试，以解决有关Ca火花如何触发和如何终止的几个基本未解问题。

DESCRIPTION (provided by applicant): Each heartbeat requires the coordination of electrical excitation and mechanical contraction in every heart cell, a process that requires a relatively small amount of calcium (Ca) entering the cell to trigger a much larger release of Ca from the sarcoplasmic reticulum (SR). In healthy hearts, this process of Ca-induced Ca release (CICR) is surprisingly stable despite the fact that it relies on positive feedback. However, mis-regulation of CICR has recently been shown to play a central role in disease states such as heart failure. Although a considerable amount has been learned about how the elementary units of Ca release, Ca sparks, are triggered, very little is known about how these events terminate or whether defective termination plays a role in disease. The goal of this proposal is to investigate fundamental molecular mechanisms by which Ca sparks terminate and how the termination of these events affects the regulation of CICR. The aims of this proposal will be to perform critical experimental tests that address several fundamental unanswered questions regarding how Ca sparks are triggered and how they terminate. To accomplish the Specific Aims of this proposal, experiments will be performed on single ventricular myocytes isolated from rat and rabbit hearts. Sub-cellular changes in Ca concentration in these cells will be tracked with a fluorescent indicator and a confocal microscope. Computer modeling, based on the Pi's previous work, will be used to interpret data and develop hypotheses. This work will provide fundamental new information about how Ca is regulated in normal hearts. This can provide a foundation for better understanding how Ca can be mis-regulated in disease. This work therefore fits in with the Pi's long term objective of understanding electrical and chemical signaling in healthy and diseased hearts.