Sigma-1 receptor and cardioprotection

项目概述：Sigma-1受体（Sigmar1）是一种在心脏中广泛表达的分子伴侣。我们发现Sigmar1的表达在人类心力衰竭和由于心肌细胞特异性表达突变型β - b -晶体蛋白（CryABR120G）而导致的蛋白质构象紊乱中都显著降低。尽管具有潜在的心脏保护功能，但Sigmar1在心脏中的作用仍然不清楚，对Sigmar1的亚细胞分布、功能、在心脏病中的作用及其在心脏隔室中的下游信号传导作用知之甚少。为了解决这些限制，我将使用心肌细胞特异性Sigmar1转基因（Tg）小鼠和全局敲除小鼠来探索Sigmar1在心脏中的功能。本研究的总体目标是揭示Sigmar1的新分子功能和机制，以保护心肌免受外部刺激和内部损伤。将采用两种损伤模型：缺血/再灌注损伤和蛋白质构象紊乱性心肌病。使用功能获得和功能丧失的方法，我将建立一个直接的因果关系，以确定心脏病理生理条件下Sigmar1的参与和潜在的保护作用。核心假设是Sigmar1激活可以保护心脏，通过调节钙离子从内质网流入线粒体并作为伴侣降解错误折叠的蛋白质来防止病理性心脏重塑。在强有力的初步数据的指导下，这一假设将通过追求3个具体目标来验证：1)确定Sigmar1在心脏基线和对心力衰竭诱导刺激的反应中的功能作用。2)为了验证Sigmar1的激活足以保护细胞的假设

DESCRIPTION (provided by applicant): Project Summary: Sigma-1 receptor (Sigmar1) is a molecular chaperone that is widely expressed in the heart. We showed that Sigmar1 expression is significantly decreased in both human heart failure and in a protein conformation disorder that occurs as a result of cardiomyocyte-specific expression of mutant �-B-crystallin (CryABR120G). Despite having potential cardioprotective functions, Sigmar1's role in the heart remains obscure and little is known about Sigmar1's subcellular distribution, functionality, role in heart disease and its downstream signaling effects in the cardiac compartment. To address these limitations, I will use cardiomyocyte-specific Sigmar1 transgenic (Tg) mice and global knockout mice to explore the functionality of Sigmar1 in the heart. The overall objective of this proposal is to uncover the novel molecular functions and mechanisms of Sigmar1 in order to protect the myocardium from both external stimuli and intrinsic insults. Two models of injury will be used: ischemia/reperfusion injury and protein conformation disorder-induced cardiomyopathy. Using both gain-of-function and loss-of-function approaches, I will establish a direct cause-effect relationship to define the involvement and potential protective role of Sigmar1 under pathophysiological conditions in the heart. The central hypothesis is that Sigmar1 activation can be cardioprotective, preventing pathological cardiac remodeling by regulating Ca2+ influx from ER into mitochondria and acting as a chaperone to degrade misfolded proteins. Guided by strong preliminary data, this hypothesis will be tested by pursuing 3 specific aims: 1) To determine the functional role of Sigmar1 in the heart at baseline and in response to heart failure-inducing stimuli. 2) To test the hypothesis that activation of Sigmar1 is sufficient to protect the heart against protein conformation disorder-induced adverse remodeling and heart failure. 3) To determine if the molecular mechanism underlying Sigmar1- dependent cardioprotection depends upon regulating the calcium influx from ER into mitochondria. These studies will uncover new mechanistic perspectives to therapeutically approach heart failure and will also provide candidates for pharmacologic and genetic targeting.