Cardiomyocyte mitochondria and mtROS in cardiac aging, hypertrophy and failure

描述（由申请人提供）： 这是一个多学科团队的建议，他们在心脏生理学，线粒体生物学，先进的蛋白质组学技术，生物统计学和生物信息学方面具有专业知识，共同努力，以提高对心肌细胞线粒体功能障碍和适应在心脏衰老和衰竭中的作用的理解。这一提议建立在我们的新观察基础上，即线粒体过氧化氢酶（mCAT）的过表达可以延缓心脏衰老并预防心脏肥大和衰竭，并且线粒体靶向肽抗氧化剂可以具有心脏保护作用。我们将研究mCAT赋予的心脏保护机制，并测试新开发的脑靶向抗氧化剂和保护肽药物的翻译潜力。目的1（机制）将确定这种保护的机制，并阐明线粒体蛋白质组的变化如何有助于心脏肥大和衰竭的功能和生化原因。为此，我们将结合联合收割机最先进的定量无标记差异蛋白质组学来测量心脏线粒体蛋白质组丰度的差异，并在体内重标记来测量心脏线粒体蛋白质合成和周转率的蛋白质组范围差异。拟议的蛋白质组学方法将提供一个独特的洞察线粒体功能，生物学和蛋白质周转，和丰度之间的关系。目标2（翻译）将测试新开发的神经靶向抗氧化剂和保护药物是否以及如何将线粒体保护转化为临床干预。这种全面的方法将提供线粒体在心脏健康，疾病和抗病性中的作用的综合评估。 (End摘要）

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)