The role of STIM1 in cardiac and skeletal muscle function

描述(申请人提供)：心肌和骨骼肌的收缩在很大程度上取决于细胞内称为肌浆网(SR)的钙库释放的钙量。因此，肌浆网钙的调节对心脏和肌肉的性能是基本的，这种钙的释放障碍会导致肌肉无力和心力衰竭。此外，钙信号参与了基因表达的调节，使横纹肌能够适应需求或收缩压力的变化。虽然对钙是如何从SR中释放出来的有详细的了解，但对钙是如何补充的却知之甚少。包括我们自己在内的几个研究小组的报告表明，心肌和骨骼肌都能够感觉到细胞外钙的耗竭，并激活细胞外空间的钙内流，以补充SR(Store Operated Calcial Entry，存储操作钙进入，SOCE)。我们的初步数据表明，最近发现的钙传感器间质相互作用分子1(STIM1)在横纹肌中表达并具有功能。心脏中缺乏功能STIM1分子的小鼠表现出心脏功能受损。我们假设STIM1是SOC电流的关键调节者，SOC电流是细胞内储存物补充所必需的，也是横纹肌收缩和钙依赖基因表达所必需的。因此，我们提出以下特异性目标：特异性目的1：在体外确定STIM1在调节横纹肌细胞钙离子内流中的作用；特异性目标2：体外确定STIM1在钙依赖基因表达中的作用；特异性目标3：在体内确定STIM1在调节心肌细胞钙离子内流中的作用。

DESCRIPTION (provided by applicant): Contraction of cardiac and skeletal muscle depends in large part on the amount of calcium released from the intracellular calcium store called the sarcoplasmic reticulum (SR).The regulation of this SR calcium is therefore fundamental to heart and muscle performance, and disturbances in the release of this calcium lead to muscle weakness and heart failure. In addition, calcium signaling is involved in the regulation of gene expression that allows striated muscle to adapt to changes in demand or contractile stress. While a detailed understanding of how calcium is released from the SR exists, little is understood about how the stores are replenished. Reports from several groups, including our own, have demonstrated that both cardiac and skeletal muscles are able to sense store depletion and activate calcium entry from the extracellular space in order to replenish the SR (Store operated calcium entry, SOCE). Our preliminary data demonstrate that the recently identified calcium sensor stromal interaction molecule 1 (STIM1) is expressed and functional in striated muscle. Mice lacking a functional STIM1 molecule in the heart demonstrate impaired cardiac function. We hypothesize that STIM1 is critical regulator of the SOC current necessary for repletion of the intracellular stores and required for contractility and calcium dependent gene expression in striated muscle. We therefore propose the following specific aims: Specific Aim1: To determine in vitro the role of STIM1 in mediating store operated calcium entry in striated muscle cells; Specific Aim 2: To determine in vitro the role of STIM1 in calcium dependent gene expression; Specific Aim 3: To determine in vivo the role of STIM1 in regulating store operated calcium entry in cardiac muscle.