Sigma-1 receptor and cardioprotection

描述（由申请人提供）：项目概述：Sigma-1受体（Sigmar 1）是一种在心脏中广泛表达的分子伴侣。我们发现，Sigmar 1的表达在人类心力衰竭和由于突变型β-B-晶体蛋白（CryABR 120 G）的心肌细胞特异性表达而发生的蛋白质构象紊乱中均显著降低。尽管具有潜在的心脏保护功能，但Sigmar 1在心脏中的作用仍然不清楚，关于Sigmar 1的亚细胞分布，功能，在心脏疾病中的作用及其在心脏室中的下游信号传导作用知之甚少。为了解决这些局限性，我将使用心肌细胞特异性Sigmar 1转基因（Tg）小鼠和整体敲除小鼠来探索Sigmar 1在心脏中的功能。本研究的总体目标是揭示Sigmar 1的新的分子功能和机制，以保护心肌免受外部刺激和内在损伤。将使用两种损伤模型：缺血/再灌注损伤和蛋白质构象紊乱诱导的心肌病。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，以确定在心脏病理生理条件下Sigmar 1的参与和潜在的保护作用。核心假设是Sigmar 1激活可以是心脏保护性的，通过调节从ER到线粒体的Ca 2+内流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，该假设将通过追求3个具体目标来检验：1）确定Sigmar 1在基线时和响应心力衰竭诱导刺激时在心脏中的功能作用。2)为了验证Sigmar 1的激活足以保护细胞的假设， 心脏对抗蛋白质构象紊乱引起的不良重构和心力衰竭。3)确定Sigmar 1依赖性心脏保护作用的分子机制是否依赖于调节钙从ER流入线粒体。这些研究将揭示治疗心力衰竭的新机制观点，也将为药理学和遗传靶向提供候选人。

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.