Sigma-1 receptor and cardioprotection

描述（申请人提供）： 项目概要：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，在人类心力衰竭和蛋白质构象紊乱中，Sigmar1 表达显着降低，而蛋白质构象紊乱是由于心肌细胞特异性表达突变体 ¿-B-晶状体蛋白 (CryABR120G) 所致。尽管具有潜在的心脏保护功能，但 Sigmar1 在心脏中的作用仍然模糊，并且人们对 Sigmar1 的亚细胞分布、功能、在心脏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 Sigmar1 转基因 (Tg) 小鼠和全局基因敲除小鼠来探索 Sigmar1 在心脏中的功能。该提案的总体目标是揭示 Sigmar1 的新颖分子功能和机制，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发的心肌病。我将使用功能获得和功能丧失方法建立直接因果关系，以定义 Sigmar1 在心脏病理生理条件下的参与和潜在保护作用。中心假设是 Sigmar1 激活可以起到心脏保护作用，通过调节 Ca2 从 ER 流入线粒体并充当伴侣来降解错误折叠的蛋白质，从而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 个具体目标进行检验：1) 确定 Sigmar1 在基线时在心脏中的功能作用以及对心力衰竭诱发刺激的反应。 2) 检验 Sigmar1 的激活足以保护 心脏对抗蛋白质构象紊乱引起的不良重塑和心力衰竭。 3) 确定Sigmar1依赖性心脏保护作用的分子机制是否依赖于调节钙从内质网流入线粒体。这些研究将揭示治疗心力衰竭的新机制观点，并将为药理学和基因靶向提供候选药物。

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.