Cardiomyocyte mitochondria and mtROS in cardiac aging, hypertrophy and failure

描述(由申请人提供)： 这是一个拥有心脏生理学、线粒体生物学、先进蛋白质组学技术、生物统计学和生物信息学专业知识的多学科团队提出的建议，旨在提高对心肌细胞线粒体功能障碍和适应在心脏老化和衰竭中的作用的理解。这一建议建立在我们新的观察结果的基础上，即线粒体过氧化氢酶(MCAT)的过表达可以延缓心脏衰老，防止心肌肥大和衰竭，并且线粒体靶向多肽抗氧化剂可以保护心脏。我们将研究MCAT赋予心脏保护的机制，并测试新开发的线粒体靶向抗氧化剂和保护性多肽药物的翻译潜力。目的1(机制)将确定这种保护的机制(S)，并将阐明线粒体蛋白质组的变化如何参与心肌肥厚和衰竭的功能和生化原因。为了做到这一点，我们将结合最先进的无标记差异蛋白质组学来测量心肌线粒体蛋白质组丰度的差异，并结合体内大量标记来测量心肌线粒体蛋白质合成和周转率的蛋白质组范围的差异。建议的蛋白质组学方法将为线粒体功能、生物学和蛋白质周转以及丰度之间的关系提供独特的见解。目标2(翻译)将测试新开发的线粒体靶向抗氧化剂和保护性药物是否以及如何有可能将线粒体保护转化为临床干预。这一综合方法将对线粒体在心脏健康、疾病和抗病能力中的作用进行综合评估。 (摘要结束)

DESCRIPTION (provided by applicant): This is a proposal from a multidisciplinary team with expertise in cardiac physiology, mitochondrial biology, advanced proteomics technologies, biostatistics and bioinformatics to work together to improve understanding of the role of cardiomyocyte mitochondrial dysfunction and adaptation in cardiac aging and failure. This proposal builds upon our novel observations that overexpression of mitochondrial catalase (mCAT) can delay cardiac aging and prevent cardiac hypertrophy and failure and that mitochondrial targeted peptide antioxidants can be cardioprotective. We will study the mechanisms responsible for cardioprotection conferred by mCAT and we will test the translational potential of newly developed mitochondrially targeted antioxidant and protective peptide drugs. Aim 1 (Mechanism) will determine the mechanism(s) of this protection and will elucidate how the changes in the mitochondrial proteome contribute to the functional and biochemical causes of cardiac hypertrophy and failure. To do this we will combine state-of-the art quantitative label-free differential proteomics to measure differences in abundance of the cardiac mitochondrial proteome with in vivo heavy labeling to measure proteome-wide differences in cardiac mitochondrial protein syntheses and turnover rates. The proposed proteomic approach will provide a unique insight into the relationship between mitochondrial function, biology and protein turnover, and abundance. Aim 2 (Translation) will test whether and how newly developed mitochondrially targeted antioxidant and protective drugs have the potential to translate mitochondrial protection into a clinical intervention. This comprehensive approach will provide an integrated assessment of the role of mitochondria in cardiac health, disease and disease-resistance. (End of Abstract)