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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.

摘要