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：
8451323
负责人：
LOTHAR A BLATTER
金额：
$ 65.03万
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 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8451323
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）：美国估计有570万人患有心力衰竭，每年与心力衰竭相关的并发症死亡，超过292,000人死亡。尽管对心脏肥大生长的机制有很多了解和随后导致失败的失代偿机理，但很少有治疗策略可用，这些策略主要是针对缓解症状，防止住院和改善患者的生活质量，对死亡率总体影响很小。最近的研究为疾病发展所涉及的分子信号通路提供了新的见解。但是，心力衰竭仍然是一个复杂的多因素问题。对心力衰竭的全面理解不仅需要阐明疾病进展过程中修改的目标/途径，而且还需要对基因和蛋白质水平的变化如何影响电生理学，CA2+处理和心脏细胞能量子系统之间的复杂相互作用的综合理解。该提议将领导者汇集到激发控制耦合，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，以研究离子传输途径的重塑和线粒体蛋白的重塑如何在超压力越过的超压力范围内导致不良量的超压力量导致超高量的超肥力，从而导致多个多周多的心脏失败。要探讨的中心假设是，CA2+M动力学的改变不仅有助于压力越过压力后的能量供应和需求匹配受损，而且还显着损害了负责处理活性氧（ROS）和氮气（RNS）物种的途径。这种不平衡导致ROS/RNS依赖性修饰与EC偶联和线粒体氧化磷酸化有关的关键蛋白质，对功能的伴随作用，对功能的影响有助于细胞损伤或死亡。因此，这些复杂的有害相互作用的恶性循环可以介导失败的心脏的代偿作用。（抽象的结尾）