Molecular modulation of the mitochondrial Na+/Ca2+ exchanger as a novel therapeutic target for heart failure.

线粒体 Na /Ca2 交换器的分子调节作为心力衰竭的新型治疗靶点。

• 批准号: 9909571
• 负责人: Joanne Frances Garbincius
• 金额: $ 6.53万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9909571
• 关键词: Acute; Address; Affect; Alternative Splicing; Alzheimer' s Disease; American; Artificial Heart; Attenuated; Automobile Driving; Biotin; Blood; Calcium; Cardiac; Cardiac Myocytes; Cardiovascular Pathology; Cell Death; Cells; Cessation of life; Chronic; Chronic stress; Conflict (Psychology); Congestive Heart Failure; Data; Deterioration; Development; Disease; Disease Progression; Economic Burden; Energy Metabolism; Ensure; Etiology; Exhibits; Failure; Fostering; Genetic; Genetic Transcription; Heart; Heart Diseases; Heart Hypertrophy; Heart Mitochondria; Heart failure; Homeostasis; Human; Hypertrophy; In Vitro; Knowledge; Lead; Ligase; Link; Measurement; Mediating; Mentorship; Mitochondria; Molecular; Mus; Myocardial; Myocardial Ischemia; Necrosis; Nerve Degeneration; Outcome; Oxygen; Pathogenicity; Pathologic; Pathology; Pathway interactions; Phosphorylation; Physiological; Post-Translational Protein Processing; Process; Proteins; Proteomics; RNA Splicing; Regulation; Reporting; Research Personnel; Resources; Role; Shapes; Sodium-Calcium Exchanger; Starvation; Stress; Structure; Surgical Models; Testing; Therapeutic; Time; Training; Transgenic Organisms; Treatment Efficacy; Treatment Failure; United States; Universities; Ventricular Remodeling; Work; base; cardiogenesis; cost; disability; effective therapy; genetic approach; heart function; insight; mouse model; new therapeutic target; novel; novel therapeutics; overexpression; protein protein interaction; release of sequestered calcium ion into cytoplasm; response; therapeutic development; therapeutic target; translational approach; translational medicine; uptake

PROJECT SUMMARY/ABSTRACT Heart failure (HF) is a leading cause of disability and death among Americans that currently affects 6 million people at an economic burden of ~$30 billion per year in the United States alone. The flow of calcium (Ca2+) into and out of the mitochondria is a key mechanism regulating cellular energy metabolism and cell death. Since both energetics and cardiomyocyte survival are compromised in the failing heart, altered mitochondrial Ca2+ (mCa2+) handling has been proposed as a contributing factor in HF. However, the specific changes that occur in mCa2+ exchange during the development and progression of HF, and the mechanisms that mediate these effects, remain poorly defined. Therefore, a necessary step before the development of HF therapies aimed at modulating mCa2+ exchange is to determine exactly how mCa2+ handling changes throughout the failure process and to understand the specific consequences of chronically-altered mCa2+ exchange on the function of the failing heart. Recent studies reveal that the mitochondrial sodium-calcium exchanger (NCLX), which mediates extrusion of mCa2+, is transcriptionally upregulated in human HF. NCLX structure and function are also controlled via mechanisms including phosphorylation and alternative splicing, and preliminary data indicate that cardiomyocytes regulate NCLX through these processes during physiological or pathological stress. Initial findings also suggest that transgenic overexpression of NCLX to enhance cardiomyocyte mCa2+ extrusion is sufficient to protect contractile function and attenuate pathological remodeling in mouse models of non-ischemic HF. Based on these data, we hypothesize that cardiomyocytes increase net NCLX activity as an adaptive mechanism to control mCa2+ homeostasis in HF. Here we will pursue Specific Aims employing genetic mouse models with net gain or reduction of cardiac NCLX function to examine the contribution of altered NCLX activity to the development and progression of chronic HF and assess the therapeutic potential of NCLX modulation for this disease. We will also combine robust proteomic and molecular approaches with direct in vitro assessments of NCLX function to determine the endogenous mechanisms that control NCLX activity within the heart. This project will be the first to causatively examine how alterations in NCLX activity protect or predispose the heart to failure when subjected to sustained pathological stress, and will generate fundamental knowledge that can be exploited for therapeutic control of NCLX activity. These findings will have broad translational relevance not only for cardiac disease, but also for other conditions characterized by altered mCa2+ homeostasis such as Alzheimer’s disease and neurodegeneration. A detailed training plan outlining the mentorship to be provided to the Applicant and the resources and technical support available at Temple University’s Center for Translational Medicine has been developed to ensure successful completion of the proposed work and foster the Applicant’s scientific maturation into an independent academic investigator.

项目总结/摘要 心力衰竭（HF）是美国人致残和死亡的主要原因，目前影响600万人 仅在美国，每年就有300亿美元的经济负担。钙（Ca 2+）的流动 进出线粒体是调节细胞能量代谢和细胞死亡的关键机制。 由于衰竭心脏的能量和心肌细胞存活都受到损害， Ca 2+（mCa 2+）处理已被认为是HF的一个影响因素。然而，具体的变化， 在HF的发展和进展过程中发生mCa 2+交换，以及介导mCa 2+交换的机制 这些影响的定义仍然不明确。因此，在开发HF疗法之前， 旨在调节mCa 2+交换的目的是准确确定mCa 2+处理在整个过程中的变化， 失败的过程，并了解慢性改变的mCa 2+交换的具体后果， 衰竭的心脏的功能。最近的研究表明，线粒体钠钙交换器（NCLX）， 其介导mCa 2+的排出，在人HF中转录上调。NCLX结构和功能 也通过磷酸化和选择性剪接等机制进行控制， 表明心肌细胞在生理或病理过程中通过这些过程调节NCLX， 应力初步研究结果还表明，转基因过表达NCLX，以提高心肌细胞mCa 2 + 挤压足以保护收缩功能并减弱小鼠模型中的病理性重塑。 非缺血性HF。基于这些数据，我们假设心肌细胞增加了NCLX的净活性， 适应机制控制mCa 2+稳态HF。在这里，我们将追求特定的目标，利用遗传 具有心脏NCLX功能的净增益或降低的小鼠模型，以检查改变的NCLX的贡献 对慢性心力衰竭的发生和进展的作用并评估NCLX的治疗潜力 调制这种疾病。我们还将结合联合收割机强大的蛋白质组学和分子方法， 体外评估NCLX功能，以确定控制NCLX活性的内源性机制 在心脏内。这个项目将是第一个因果关系研究如何改变NCLX活动保护或 当受到持续的病理性压力时，易使心脏衰竭，并将产生基本的 这些知识可用于NCLX活性的治疗控制。这些发现将具有广泛的 翻译相关性不仅与心脏疾病有关，而且与以mCa 2+改变为特征的其他疾病有关 如阿尔茨海默病和神经变性。详细的培训计划， 向申请人提供的指导，以及Temple提供的资源和技术支持 大学的转化医学中心已经开发，以确保成功完成 建议的工作，并促进申请人的科学成熟，成为一个独立的学术研究者。