The role of STIM1 in cardiac and skeletal muscle function

说明（申请人提供）：心肌和骨骼肌的收缩在很大程度上取决于从称为肌浆网（SR）的细胞内钙库中释放的钙的量。因此，SR钙的调节是心脏和肌肉性能的基础，钙释放的紊乱导致肌无力和心力衰竭。此外，钙信号参与基因表达的调节，使横纹肌适应需求或收缩压力的变化。虽然对钙是如何从SR中释放的有详细的了解，但对如何补充储存的了解甚少。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钙储备的消耗，并激活细胞外间隙的钙进入，以补充SR（钙储备操作的钙进入，SOCE）。我们的初步数据表明，最近确定的钙传感器基质相互作用分子1（STIM 1）的表达和功能在横纹肌。心脏中缺乏功能性STIM 1分子的小鼠表现出心脏功能受损。我们假设STIM 1是SOC电流的关键调节器，该电流对于细胞内储存的补充是必要的，并且对于横纹肌中的收缩性和钙依赖性基因表达是必需的。因此，我们提出了以下具体目标：具体目标1：确定在体外的作用，STIM 1介导的存储操作的钙离子进入横纹肌细胞;具体目标2：确定在体外的作用，STIM 1的钙依赖性基因表达;具体目标3：确定在体内的作用，STIM 1在调节存储操作的钙离子进入心肌。

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.