Sigma-1 receptor and cardioprotection

Sigma-1受体与心脏保护

基本信息

批准号：
9327036
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/9327036
关键词：
Address Amyloid Animals 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 Organ Pathologic Pathology Pharmacology Physiological Protein Conformation Proteins RNA Rattus Receptor Activation Reperfusion Injury Reperfusion Therapy Reporting Research Personnel Role Signal Transduction Stimulus Testing Therapeutic Transgenic Mice Transgenic Organisms adenoviral-mediated gain of function genetic approach loss of function misfolded protein mitochondrial dysfunction mortality mouse model mutant novel overexpression premature prevent protein aggregate receptor receptor expression 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（由适用提供）：项目摘要：Sigma-1受体（Sigmar1）是一种分子链酮，在心脏中广泛表达。我们表明，在人体心力衰竭和蛋白质会议障碍中，SIGMAR1的表达显着降低，这是由于心肌细胞特异性表达突变体-B-晶状体蛋白（CryABR120G）而发生的。尽管具有潜在的心脏保护功能，但SIGMAR1在心脏中的作用仍然晦涩难懂，对SIGMAR1的亚细胞分布，功能，心脏病中的作用及其下游信号传导在心脏隔室中的作用知之甚少。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）小鼠和全球敲除小鼠探索心脏中Sigmar1的功能。该提案的总体目的是揭示Sigmar1的新分子功能和机制，以保护心肌免受外部刺激和内在感染的影响。将使用两种损伤模型：缺血/再灌注损伤和蛋白质会议障碍诱导的心肌病。使用功能获得和功能丧失方法，我将建立直接的因果关系，以定义SIGMAR1在心脏病生理条件下SIGMAR1的参与和潜在的保护作用。中心假设是SIGMAR1激活可以是心脏保护性的，可以通过调节从ER到线粒体的Ca2+影响来防止病理心脏重塑，并充当伴侣降解错误折叠蛋白的伴侣。在强大的初步数据的指导下，将通过追求3个特定目的来检验该假设：1）确定SIGMAR1在基线时心脏中的功能作用，并响应心力衰竭诱导刺激。 2）检验了sigmar1激活足以保护的假设反对蛋白质会议障碍引起的不良反应和心力衰竭的心脏。 3）确定sigmar1-依赖性心脏保护基础的分子机制是否取决于调节钙从ER到线粒体的影响。这些研究将发现新的机械观点，以治疗心力衰竭，还将为药物和遗传靶向提供候选。