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.
This multidisciplinary proposal combines molecular, physiologic and proteomics approaches with biostatistical and bioinformatic analyses to provide an integrated assessment of in vivo cardiac function, mitochondrial energetics and changes in the mitochondrial proteome. Important insights will be gained from study of the mechanisms of cardioprotection conferred by mitochondrial targeted catalase and the ability of mitochondrially targeted antioxidant and protective drugs to provide similar cardioprotective effects.
|Chiao, Ying Ann; Rabinovitch, Peter S (2015) The Aging Heart. Cold Spring Harb Perspect Med 5:a025148|
|Karunadharma, Pabalu P; Basisty, Nathan; Chiao, Ying Ann et al. (2015) Respiratory chain protein turnover rates in mice are highly heterogeneous but strikingly conserved across tissues, ages, and treatments. FASEB J 29:3582-92|
|Karunadharma, Pabalu P; Basisty, Nathan; Dai, Dao-Fu et al. (2015) Subacute calorie restriction and rapamycin discordantly alter mouse liver proteome homeostasis and reverse aging effects. Aging Cell 14:547-57|
|Stefanska, Ania; Eng, Diana; Kaverina, Natalya et al. (2015) Interstitial pericytes decrease in aged mouse kidneys. Aging (Albany NY) 7:370-82|
|Roeder, Sebastian S; Stefanska, Ania; Eng, Diana G et al. (2015) Changes in glomerular parietal epithelial cells in mouse kidneys with advanced age. Am J Physiol Renal Physiol 309:F164-78|
|Ping, Peipei; Gustafsson, Åsa B; Bers, Don M et al. (2015) Harnessing the Power of Integrated Mitochondrial Biology and Physiology: A Special Report on the NHLBI Mitochondria in Heart Diseases Initiative. Circ Res 117:234-8|
|Szeto, H H; Birk, A V (2014) Serendipity and the discovery of novel compounds that restore mitochondrial plasticity. Clin Pharmacol Ther 96:672-83|
|Dai, Dao-Fu; Karunadharma, Pabalu P; Chiao, Ying A et al. (2014) Altered proteome turnover and remodeling by short-term caloric restriction or rapamycin rejuvenate the aging heart. Aging Cell 13:529-39|
|Wang, Ying; Wang, Gary Z; Rabinovitch, Peter S et al. (2014) Macrophage mitochondrial oxidative stress promotes atherosclerosis and nuclear factor-?B-mediated inflammation in macrophages. Circ Res 114:421-33|
|Dai, Dao-Fu; Hsieh, Edward J; Chen, Tony et al. (2013) Global proteomics and pathway analysis of pressure-overload-induced heart failure and its attenuation by mitochondrial-targeted peptides. Circ Heart Fail 6:1067-76|
Showing the most recent 10 out of 21 publications