The role of STIM1 in cardiac and skeletal muscle function

STIM1 在心脏和骨骼肌功能中的作用

基本信息

批准号：
8733230
负责人：
PAUL B ROSENBERG
金额：
$ 15.7万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8733230
关键词：
Address Adenoviruses Adult Calcineurin Calcium Calcium Channel Calcium Signaling Cardiac Cardiac Muscle Contraction Cardiac Myocytes Cardiomyopathies Cell membrane Cell physiology Cells Data Disease Endoplasmic Reticulum Extracellular Space Gene Expression Gene Expression Regulation Genes Growth Health Heart Heart Hypertrophy Heart failure Hypertrophy Image In Vitro Inherited Lead Link Mediating Membrane Mitochondria Molecular Mus Muscle Muscle Cells Muscle Fibers Muscle Weakness Muscle function Mutant Strains Mice Myocardium Oryctolagus cuniculus Performance Phenotype Phospholipase C Phosphoproteins Play Regulation Reporting Role Sarcoplasmic Reticulum Signal Pathway Signal Transduction Site Skeletal Muscle Stimulus Stress Striated Muscles Testing Work human STIM1 protein in vivo mutant novel novel therapeutics patch clamp pressure response sensor

项目摘要

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.

描述（由申请人提供）：心脏和骨骼肌肉的收缩很大程度上取决于细胞内钙商店中释放的钙量，称为肌浆网（SR）。因此，该SR钙的调节是对心脏和肌肉表现的基本，以及这种钙的释放导致肌肉弱和心脏失效的障碍。此外，钙信号传导与基因表达的调节有关，该基因表达使肌肉肌肉适应需求或收缩应激的变化。虽然对从SR释放钙的存在的详细理解，但几乎没有理解商店的补充。来自包括我们自己的几个小组的报告表明，心脏和骨骼肌肉都能够感知存储耗竭并激活细胞外空间的钙进入，以补充SR（商店操作的钙输入，SOCE）。我们的初步数据表明，最近鉴定出的钙传感器基质相互作用分子1（STIM1）表达并在条纹肌肉中起作用。缺乏功能性STIM1分子的小鼠表现出心脏功能受损。我们假设STIM1是对细胞内存储所必需的SOC电流的关键调节剂，并且需要收缩力和钙依赖性基因表达在横纹肌中。因此，我们提出以下特定目的：特定目标1：在体外确定STIM1在介导储存储存中的作用，在横纹肌肉细胞中运行的钙进入；特定目的2：确定体外STIM1在钙依赖基因表达中的作用；特定目标3：确定体内STIM1在调节心脏肌肉中钙进入的钙进入中的作用。