Defining the roles of Orai3 channel in cardiomyocytes and cardiomyopathy.

定义 Orai3 通道在心肌细胞和心肌病中的作用。

基本信息

批准号：
10238106
负责人：
Salvatore Mancarella
金额：
$ 38万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10238106
关键词：
Ablation Adult Affect Anatomy Architecture Attention Autophagocytosis Behavior Biochemical Bioenergetics Biogenesis Calcium Calmodulin Cardiac Cardiac Myocytes Cardiomyopathies Cause of Death Cell Death Cell Respiration Cells Cellular Structures Cessation of life Clinical Combination Medication Complex Congestive Heart Failure Data Deterioration Development Dilatation - action Dilated Cardiomyopathy Disease Down-Regulation Energy Metabolism Enzymes Equilibrium Exhibits Failure Functional disorder Genes Genetic Genetic Transcription Goals Heart Heart Diseases Heart Transplantation Heart failure Histone Deacetylase Homeostasis Human Individual Investigation Ion Channel Knock-out Link Maintenance Measures Mediating Mediator of activation protein Membrane Potentials Metabolic Metabolism Mitochondria Mitochondrial Proteins Modeling Molecular Mus Muscle function Myocardial Myocardium Outcome PPAR gamma Pathogenesis Pathway interactions Patients Peripheral Pharmacology Phenotype Phosphotransferases Production Prognosis Proteins Pulmonary Edema Regulatory Pathway Research Role Sarcomeres Secondary to Series Serum Response Factor Signal Pathway Signal Transduction Structure Tamoxifen Testing Ventricular Ventricular Function Work age related electrical property energy balance fatty acid oxidation genetic approach heart function implantable device in vivo insight member mitochondrial dysfunction mitochondrial membrane mitochondrial metabolism myocyte-specific enhancer-binding factor 2 novel postnatal postnatal development premature programs public health relevance respiratory uptake

项目摘要

Abstract Dilated cardiomyopathy (DCM) is a severe condition, often idiopathic, that results in ventricular enlargement and progressive systolic dysfunction. While usually treated with a combination of medications or using implantable devices, cardiac transplantation is typically the ultimate treatment for DCM. The precise mechanisms leading to ventricular dilatation and dysfunction are not well understood. However, during the last few years, attention has focused on abnormalities of contractile and structural myocardial proteins and disorders of cardiac energy metabolism. We identified Orai3, a Ca2+-selective ion channel and a member of the store-operated Ca2+ channels (SOCC), as a critical proactive factor required for maintenance of postnatal cardiac function. The goal of this proposal is to investigate the roles of Orai3-mediated Ca2+ entry and associated molecular mechanisms in cardiomyocytes. To pursue our goal, we have generated several lines of cardiomyocyte-specific Orai3 knockout (Orai3cKO) mice. While constitutive Orai3cKO mice are fertile and viable, they nevertheless develop DCM that closely resembles many of the anatomical, pathophysiological, and clinical features of human DCM culminating in heart failure (HF) and premature death. We discovered through our preliminary research that Orai3-deficient cardiomyocytes exhibited loss of myofiber integrity and ultrastructural abnormalities associated with severe dysregulation of mitochondrial proteins involved in oxidative metabolism and autophagy. Our preliminary data strongly indicate that the Orai3 channel is an essential regulator of cardiac muscle function, and the data provide evidence linking Orai3-mediated Ca2+ signaling to sarcomere cell integrity and bioenergetics balance. We hypothesize that Orai3-mediated Ca2+ entry activates genetic programs through Ca2+ sensitive pathways that promote survival of post-natal cardiomyocytes. We plan to test our hypothesis by pursuing the following Specific Aims: Aim 1: To characterize the DCM phenotype following loss of Orai3 expression in the adult myocardium; Aim 2: To elucidate mechanisms by which Orai3 loss leads to cardiac function deterioration and DCM by analyzing inducible Orai3cKO mice; and Aim 3: To test the hypothesis that Orai3-mediated Ca2+ entry regulates mitochondrial metabolism. This work will lead to discovery of the molecular mechanisms by which Orai3 regulates heart function; identification of Orai as a novel mediator of DCM; and potential identification of new strategies aimed at reversing or delaying the metabolic and functional derangements seen in HF.

抽象的扩张的心肌病（DCM）是一种严重的疾病，通常是特发性的，导致心室肿大和进行性收缩功能障碍。虽然通常用药物组合或使用可植入的装置，心脏移植通常是DCM的最终处理。精确的机制导致心室扩张和功能障碍尚不清楚。但是，在过去的几年中，注意力集中在收缩和结构心肌蛋白和心脏疾病的异常上能量代谢。我们确定了Orai3，Ca2+选择性离子通道和商店经营的CA2+的成员通道（SOCC），是维持产后心脏功能所需的关键主动因素。目标该建议是研究ORAI3介导的Ca2+进入和相关分子机制的作用在心肌细胞中。为了实现我们的目标，我们产生了几行心肌细胞特异性ORAI3 敲除（Orai3cko）小鼠。虽然构成型OAI3CKO小鼠肥沃且可行，但它们仍会发展为DCM 这与人类DCM的许多解剖学，病理生理和临床特征非常相似最终心力衰竭（HF）和过早死亡。我们通过初步研究发现了 ORAI3缺陷型心肌细胞表现出肌纤维完整性和与超微结构异常相关的丧失与氧化代谢和自噬有关的线粒体蛋白的严重失调。我们的初步数据强烈表明ORAI3通道是心肌功能的重要调节剂，并且数据提供了将ORAI3介导的Ca2+信号与肌节细胞完整性和生物能学连接的证据平衡。我们假设ORAI3介导的Ca2+进入可以通过CA2+激活遗传程序促进产后心肌细胞存活的敏感途径。我们计划通过追求以下特定目的：目标1：丢失ORAI3后表征DCM表型在成年心肌中表达；目标2：阐明ORAI3损失导致心脏的机制功能恶化和DCM通过分析诱导的ORAI3CKO小鼠；和目标3：检验以下假设 ORAI3介导的Ca2+进入调节线粒体代谢。这项工作将导致发现分子 ORAI3调节心脏功能的机制；将Orai识别为DCM的新调解人；和旨在逆转或延迟代谢和功能的新策略的潜在识别在HF中看到的危险。