The role of STIM1 in cardiac and skeletal muscle function

描述（由申请人提供）：心脏和骨骼肌的收缩在很大程度上取决于细胞内钙储存（称为肌浆网（SR））释放的钙量。因此，SR钙的调节对心脏和肌肉的表现至关重要，而这种钙释放的紊乱会导致肌肉无力和心力衰竭。此外，钙信号还参与调控基因表达，使横纹肌能够适应需求或收缩压力的变化。虽然人们对钙是如何从SR中释放出来有了详细的了解，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小组的报告已经证明，心肌和骨骼肌都能够感知储存耗尽，并激活钙从细胞外空间进入，以补充SR（储存操作钙进入，SOCE）。我们的初步数据表明，最近发现的钙传感器基质相互作用分子1 （STIM1）在横纹肌中表达和发挥功能。心脏中缺乏功能性STIM1分子的小鼠表现出心功能受损。我们假设STIM1是横纹肌中细胞内储存量的补充和收缩性和钙依赖基因表达所必需的SOC电流的关键调节剂。因此，我们提出以下具体目的：特异性目的1：在体外确定STIM1在介导横纹肌细胞储存操作钙进入中的作用；特异性目的2：在体外确定STIM1在钙依赖基因表达中的作用；特异性目的3：确定体内STIM1在调节心肌储存操作钙进入中的作用。

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.