Mechanisms of mitochondrial calcium exchange in heart failure

心力衰竭中线粒体钙交换的机制

• 批准号: 8754254
• 负责人: John William Elrod
• 金额: $ 39万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 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/8754254
• 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; 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; public health relevance; signal processing; theories

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）：未来 20 年，心力衰竭 (HF) 的发病率预计将增加 25%，预计费用将达到 697 亿美元，给美国带来巨大的健康和经济负担。一般来说，心力衰竭的特点是收缩力下降和心室重塑适应不良，最终导致体循环心输出量受损。巨大的科学努力一直集中在揭示导致心肌收缩力下降的分子和细胞机制上，虽然无疑有多种变化起作用，但人们普遍认为收缩力缺陷大部分是由于胞质钙 (Ca2+) 瞬变的减少和肌浆网 (SR) Ca2+ 含量的减少造成的。同样，最近的研究也支持这样的理论：尽管舒张期 Ca2+ 升高，但心力衰竭时线粒体 Ca2+ 含量实际上会减少。为了研究 mitoCa2+ 在 HF 发生和进展中的作用，我们开发了线粒体 Na+/Ca2+ 交换器 (mitoNCX) 的突变小鼠模型。 mitoCa2+ 微区因其对能量产生和细胞死亡的显着影响而受到密切研究，特别是 HF，其特点是显着的代谢功能障碍和逐渐的细胞脱落。该项目正在测试中心假设 减少 mitoCa2+ 外流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中的细胞逐渐脱落和不良重塑。我们将首次利用遗传功能获得和丧失的方法来表征这种新型交换器的生物物理特性，评估其对细胞生理学的贡献，并检查其在临床相关动物模型中的作用。这项研究的最终目标是确定 mitoCa2+ 信号在心力衰竭发生和进展中的作用并促进治疗应用。