Cardiomyocyte mitochondria and mtROS in cardiac aging, hypertrophy and failure

心肌细胞线粒体和 mtROS 在心脏衰老、肥大和衰竭中的作用

• 批准号: 8244481
• 负责人: PETER S RABINOVITCH
• 金额: $ 63.65万
• 依托单位: UNIVERSITY OF WASHINGTON
• 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/8244481
• 关键词: Affect; Aging; Antioxidants; Biochemical; Biogenesis; Bioinformatics; Biological; Biological Markers; Biology; Biometry; Cardiac; Cardiac Myocytes; Clinical; Data Set; Disease; Disease Resistance; Failure; Fiber; Health; Heart; Heart Hypertrophy; Heart failure; Hypertrophy; Intervention; Label; Measurement; Measures; Methodology; Mitochondria; Mitochondrial Proteins; Molecular; Mus; Myocardial; NMR Spectroscopy; Oxidative Stress; Pathology; Peptides; Performance; Pharmaceutical Preparations; Physiological; Physiology; Protective Agents; Protein Biosynthesis; Proteome; Proteomics; Reactive Oxygen Species; Regulation; Role; Signal Pathway; Structure; Technology; Testing; Translating; Translations; Work; abstracting; catalase; improved; in vivo; insight; mitochondrial dysfunction; multidisciplinary; novel; overexpression; prevent; protein degradation; respiratory; response

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)

描述（由申请人提供）： 这是一个多学科团队的一项建议，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，以共同提高对心肌性心脏功能障碍和心脏衰减和失败的心肌细胞功能的了解。这一建议是基于我们新颖的观察结果，即线粒体过氧化氢酶（MCAT）的过表达可以延迟心脏衰老并预防心脏肥大和失败，并且线粒体靶向的肽抗氧化剂可以受到心脏保护。我们将研究MCAT赋予心脏保护的机制，并将测试新开发的线粒体靶向抗氧化剂和保护性肽药物的翻译潜力。 AIM 1（机制）将确定此保护的机制，并将阐明线粒体蛋白质组的变化如何有助于心脏肥大和失败的功能和生化原因。为此，我们将结合最先进的无标记差差蛋白质组学，以测量心脏线粒体蛋白质组丰度的差异，并在体内重型标记中，以测量心脏线粒体蛋白质合成和转离速度的心脏蛋白质组差异。提出的蛋白质组学方法将为线粒体功能，生物学和蛋白质更新和丰度之间的关系提供独特的见解。 AIM 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有可能将线粒体保护转化为临床干预措施。这种全面的方法将对线粒体在心脏健康，疾病和抗病的作用中的作用进行综合评估。 （抽象的结尾）