MItochondrial Dysfunction in Cardiac Hypertrophy and Failure

心脏肥大和衰竭中的线粒体功能障碍

基本信息

批准号：
8319979
负责人：
LOTHAR A BLATTER
金额：
$ 3.99万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8319979
关键词：
Adult Affect Animals Antioxidants Area Arginine Arrhythmia Behavior Bioenergetics Biological Assay Biology Blood Pressure Buffers Cardiac Cardiac Glycosides Cardiac Myocytes Cardiovascular Diseases Catecholamines Cause of Death Cavia Cell Death Cells Cessation of life Complex Computational Biology Computer Simulation Coupling Data Disease Progression Drug Metabolic Detoxication Equilibrium Experimental Models Failure Fatty Acids Foundations Fura-2 Gel Gene Proteins Generations Giant Cells Glucose Growth Heart Heart Hypertrophy Heart failure Homeostasis Hospitalization Hypertrophy Incidence Ion Channel Ion Transport Ions Kinetics Lead Measurement Measures Mediating Metabolic Metabolic stress Methods Mitochondria Mitochondrial Proteins Modeling Modification Molecular Muscle Cells NADH NADP Nitrogen Nitrosation Normal Cell Oryctolagus cuniculus Oxidation-Reduction Oxidative Phosphorylation Oxidative Stress Oxidoreductase Oxygen Pathway interactions Patients Pattern Phosphorylation Post-Translational Protein Processing Process Production Protein Dephosphorylation Proteins Proteome Proteomics Quality of life Rattus Regulation Research Resources Respiratory Chain Role Sarcolemma Severity of illness Signal Pathway Signal Transduction Solid Stress Supplementation Symptoms System Testing Therapeutic Tissues Toxic effect United States abstracting acute stress base cell injury heart cell improved insight mitochondrial dysfunction mitochondrial permeability transition pore model development mortality multi-scale modeling oxidation pressure prevent response sensor tetrahydrobiopterin

项目摘要

DESCRIPTION (provided by applicant): An estimated 5.7 million people in the U.S. have heart failure and more than 292,000 die from heart failure-related complications each year. While much is known about the mechanisms of cardiac hypertrophic growth and subsequent decompensation leading to failure, few therapeutic strategies are available, and these are aimed primarily at relieving symptoms, preventing hospitalization, and improving the quality of life of patients, with little overall effect on mortality. Recent research has provided new insights into the molecular signaling pathways involved in the progression of the disease; however, heart failure remains a complex multifactorial problem. A comprehensive mechanistic understanding of heart failure requires not just elucidation of targets/pathways modified during the progression of the disease, but an integrative understanding of how alterations at the level of genes and proteins affect the sophisticated interplay between the electrophysiological, Ca2+ handling, and energetic subsystems of the cardiac cell. This proposal brings together leaders in the areas of excitation-contraction coupling, mitochondrial biology, redox modulation, proteomics, and computational biology to investigate how the remodeling of ion transport pathways and mitochondrial proteins contribute to maladaptive responses in a pressure-overload model of hypertrophy, which progresses to heart failure over several weeks. The central hypothesis to be explored is that alterations in Ca2+m dynamics not only contribute to impaired energy supply and demand matching following pressure-overload, but also significantly compromise the pathways responsible for handling reactive oxygen (ROS) and nitrogen (RNS) species in the mitochondria and the cell. This imbalance results in ROS/RNS-dependent modifications of key proteins involved in EC coupling and mitochondrial oxidative phosphorylation, with concomitant effects on function that contribute to cellular injury or death. A vicious circle of these complex deleterious interactions could thus mediate decompensation of the failing heart. (End of Abstract)

描述（由申请人提供）：据估计，美国有 570 万人患有心力衰竭，每年有超过 292,000 人死于心力衰竭相关并发症。虽然人们对心脏肥大性生长和随后导致衰竭的代偿失调的机制了解很多，但可用的治疗策略很少，而且这些策略主要旨在缓解症状、防止住院和改善患者的生活质量，对心脏的总体效果甚微。死亡。最近的研究为参与疾病进展的分子信号通路提供了新的见解；然而，心力衰竭仍然是一个复杂的多因素问题。对心力衰竭的全面机制理解不仅需要阐明疾病进展过程中改变的靶点/途径，还需要综合理解基因和蛋白质水平的改变如何影响电生理、Ca2+处理和能量之间复杂的相互作用。心肌细胞的子系统。该提案汇集了兴奋-收缩耦合、线粒体生物学、氧化还原调节、蛋白质组学和计算生物学领域的领导者，研究离子转运途径和线粒体蛋白质的重塑如何导致肥大压力超负荷模型中的适应不良反应，几周后会发展为心力衰竭。要探索的中心假设是，Ca2+m 动力学的改变不仅会导致压力过载后能量供应和需求匹配受损，而且还会严重损害负责处理活性氧 (ROS) 和氮 (RNS) 物质的途径。线粒体和细胞。这种不平衡导致参与 EC 偶联和线粒体氧化磷酸化的关键蛋白发生 ROS/RNS 依赖性修饰，同时对导致细胞损伤或死亡的功能产生影响。因此，这些复杂的有害相互作用的恶性循环可能会介导衰竭心脏的代偿失调。（摘要完）