MItochondrial Dysfunction in Cardiac Hypertrophy and Failure

心脏肥大和衰竭中的线粒体功能障碍

• 批准号: 7847834
• 负责人: LOTHAR A BLATTER
• 金额: $ 70.1万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 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/7847834
• 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; Energy Supply; 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; 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

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）： 美国估计有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。虽然对心脏肥大性生长和随后的失代偿导致衰竭的机制了解很多，但可用的治疗策略很少，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，对死亡率的总体影响很小。最近的研究提供了新的见解的分子信号通路参与疾病的进展，然而，心力衰竭仍然是一个复杂的多因素的问题。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修饰的靶点/途径，还需要综合理解基因和蛋白质水平的改变如何影响心脏细胞的电生理、Ca 2+处理和能量子系统之间的复杂相互作用。该提案汇集了兴奋-收缩偶联，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，以研究离子转运途径和线粒体蛋白质的重塑如何在压力超负荷模型中导致适应不良反应肥大，在几周内进展为心力衰竭。要探讨的中心假设是，Ca 2 +m动态的改变不仅有助于受损的能量供应和需求匹配后的压力过载，但也显着妥协的途径负责处理活性氧（ROS）和氮（RNS）的物种在线粒体和细胞。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质的ROS/RNS依赖性修饰，伴随着对功能的影响，导致细胞损伤或死亡。这些复杂的有害相互作用的恶性循环因此可以介导衰竭心脏的失代偿。 (End摘要）