Mechanisms of mitochondrial calcium exchange in heart failure

心力衰竭中线粒体钙交换的机制

基本信息

批准号：
8898914
负责人：
John William Elrod
金额：
$ 38.42万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8898914
关键词：
Adult Animal Model Automobile Driving Blood Circulation Calcium Cardiac Cardiac Myocytes Cardiac Output Cell Death Cell Line Cell physiology Cells Complex Coupled Coupling Development Disease Progression Dropout Economic Burden Electron Transport Ensure Event Fostering Functional disorder Future Genes Genetic Genetic Models Goals Health Heart Diseases Heart failure In Vitro Incidence Investigation Ions Lead Link Measures Metabolic Metabolism Mitochondria Mitochondrial Matrix Modeling Molecular Mus Muscle Cells Mutant Strains Mice Myocardial Infarction Operative Surgical Procedures Oxidation-Reduction Oxidative Phosphorylation Oxidoreductase Pathology Patients Permeability Physiological Processes Physiology Play Process Production Regulation Reporter Reporting Research Research Project Grants Role Sarcoplasmic Reticulum Signal Transduction Sodium Testing Therapeutic Time Uncertainty Ventricular Remodeling Workload biophysical properties calcium uniporter cell type clinically relevant cost feeding flexibility health economics heart cell in vivo indexing indium arsenide loss of function meetings mutant mutant mouse model novel overexpression pressure signal processing theories

项目摘要

DESCRIPTION (provided by applicant): The incidence of heart failure (HF) is projected to increase by 25% over the next 20 years with a projected cost of $69.7 billion representing a substantial health and economic burden on the US. In general, HF is characterized by a decrease in contractility and maladaptive ventricular remodeling ultimately leading to impaired cardiac output to the systemic circulation. Immense scientific effort has been focused on unraveling the molecular and cellular mechanisms driving decreased cardiac contractility and while a multitude of changes no doubt contribute, it is generally agreed that much of the contractile deficit is due to a reduction in cytosolic calcium (Ca2+) transients and a decrease in sarcoplasmic reticulum (SR) Ca2+ content. Similarly, recent studies have supported the theory that mitoCa2+ content is actually diminished in HF despite elevations in diastolic Ca2+. To examine the role of mitoCa2+ in the development and progression of HF we have developed mutant mouse models of a proposed mitochondrial Na+/Ca2+ exchanger (mitoNCX). The mitoCa2+ microdomain has been under intense investigation due to its significant influence on energy production and cell death and HF in particular, is characterized by both significant metabolic dysfunction and gradual cell dropout. This project is testing the central hypothesis that reducing mitoCa2+ efflux protects against gradual cell dropout and adverse remodeling in heart failure by enhancing cardiomyocyte metabolic and redox capacity. For the first time, utilizing genetic gain- and loss-of-function approaches we will characterize the biophysical properties of this novel exchanger, assess its contribution to cellular physiology and examine its role in clinically relevant animal models. The ultimate goal of this research endeavor is to define the role of mitoCa2+ signaling in the development and progression of HF and foster therapeutic application.

描述（由申请人提供）：预计在未来20年内，心力衰竭的发生率（HF）将增加25％，预计成本为697亿美元，代表着美国的健康和经济负担。通常，HF的特征是收缩性和不良心室的降低最终导致心脏循环的心脏输出受损。巨大的科学努力一直集中在阐明驱动心脏收缩性的分子和细胞机制上，虽然毫无疑问，但毫无疑问，众所周知，由于胞质钙（CA2+）瞬变的减少和肌乳肿瘤的降低，因此，很多收缩的赤字都是造成的。同样，最近的研究支持了以下理论：尽管舒张期Ca2+升高，但在HF中，MitoCA2+含量实际上降低了。为了检查MitoCa2+在HF的发展和进展中的作用，我们开发了提出的线粒体Na+/Ca2+交换器（Mitoncx）的突变小鼠模型。 Mitoca2+微域因其对能量产生和细胞死亡而尤其是细胞死亡的重要影响，其特征在于明显的代谢功能障碍和逐渐的细胞辍学，这是由于其对能量产生和细胞死亡的重大影响。该项目正在检验一个中心假设，即减少Mitoca2+外排，可通过增强心肌细胞代谢和氧化还原能力来防止心力衰竭逐渐脱落和不良心脏重塑。我们将首次使用遗传增益和功能丧失方法来表征这种新型交换器的生物物理特性，评估其对细胞生理的贡献，并检查其在临床相关的动物模型中的作用。这项研究努力的最终目标是定义MitoCA2+信号在HF和寄养治疗应用的发展和发展中的作用。