Sigma-1 receptor and cardioprotection

描述(申请人提供)：项目摘要：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Sigmar1在人类心力衰竭和因心肌细胞特异性表达突变型B晶体蛋白(CryABR120G)引起的蛋白质构象紊乱中的表达显著降低。尽管Sigmar1具有潜在的心脏保护功能，但Sigmar1的S在心脏中的作用仍然不清楚，对Sigmar1的S在心脏各室的亚细胞分布、功能、在心脏病中的作用及其下游信号作用也知之甚少。为了解决这些局限性，我将使用心肌细胞特异的Sigmar1转基因(TG)小鼠和全球基因敲除小鼠来探索Sigmar1在心脏中的功能。这项建议的总体目标是揭示Sigmar1的新分子功能和机制，以保护心肌免受外部刺激和内在损伤的影响。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两种方法，我将建立一个直接的因果关系，以确定Sigmar1在心脏病理生理条件下的参与和潜在的保护作用。中心假设是，Sigmar1的激活可以保护心脏，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的心脏重塑。在强大的初步数据的指导下，这一假设将通过追求3个具体目标来检验：1)确定Sigmar1在基线和对心力衰竭诱发刺激的反应中在心脏中的功能作用。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构和心力衰竭。3)确定Sigmar1依赖的心肌保护的分子机制是否依赖于调节钙离子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。

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.