Sigma-1 receptor and cardioprotection

Sigma-1受体与心脏保护

基本信息

批准号：
9131784
负责人：
Md. Shenuarin Bhuiyan
金额：
$ 24.9万
依托单位：
LOUISIANA STATE UNIV HSC SHREVEPORT
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9131784
关键词：
Address Amyloid Animal Organ Binding Biochemical Biochemical Genetics Bioenergetics Biological Assay Calcium Cardiac Cardiac Myocytes Cardiomyopathies Cessation of life Complex Crystallins Data Disease Disease model Endoplasmic Reticulum Genetic Genetic Models Heart Heart Diseases Heart Hypertrophy Heart failure Human Infection Injury Inositol Ion Channel Ischemia Ischemic Brain Injury Knock-out Knockout Mice Length Ligand Binding Ligands Mediating Membrane Mitochondria Modeling Molecular Molecular Chaperones Mus Mutate Mutation Myocardial Ischemia Myocardial dysfunction Myocardium Neonatal Pathology Physiological Protein Conformation Proteins RNA Rattus Reperfusion Injury Reperfusion Therapy Reporting Research Personnel Role Signal Transduction Stimulus Testing Transgenic Mice Transgenic Organisms adenoviral-mediated gain of function genetic approach loss of function mitochondrial dysfunction mortality mouse model mutant novel overexpression premature prevent protein aggregate protein misfolding receptor response sigma-1 receptor therapeutic target tripolyphosphate

项目摘要

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.

描述（由申请人提供）：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 表达在人类心力衰竭和发生的蛋白质构象紊乱中均显着降低。尽管 Sigmar1 具有潜在的心脏保护功能，但其在心脏中的作用仍不清楚。对于 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其功能。该提案的总体目标是揭示 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。使用：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的方法，建立直接的因果关系来定义 Sigmar1 在病理生理学下的参与和潜在的保护作用。核心假设是 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，该假设将通过追求 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 激活的假设。 Sigmar1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 心脏依赖性保护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。还将提供药理学和基因靶向的候选药物。