MItochondrial Dysfunction in Cardiac Hypertrophy and Failure

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29.2万人死于与心力衰竭相关的并发症。虽然人们对心脏肥大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，对死亡率几乎没有总体影响。最近的研究为疾病进展中涉及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，而且还需要对基因和蛋白质水平的变化如何影响心脏细胞的电生理、钙处理和能量子系统之间的复杂相互作用的综合理解。这项建议汇集了兴奋-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先者，以研究离子转运途径和线粒体蛋白的重塑如何导致压力超负荷肥厚模型的不良适应反应，该肥厚模型会在几周内进展为心力衰竭。需要探索的中心假设是，钙离子动力学的改变不仅导致压力超负荷后能量供需匹配受损，而且显著损害了负责处理线粒体和细胞中的活性氧(ROS)和氮(RNS)物种的途径。这种失衡导致参与EC偶联和线粒体氧化磷酸化的关键蛋白的ROS/RNS依赖的修饰，并伴随着对功能的影响，从而导致细胞损伤或死亡。因此，这些复杂的有害相互作用的恶性循环可能会导致衰竭心脏的失代偿。 (摘要结束)

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)