The realization that the heart is a regenerative organ has spurred renewed interest in the possibilities for antagonizing the aging of the myocardium through enhanced repair. However, deterioration of myocardial function over our lifespan stems from combinatorial effects of diminished regenerative capabilities together with increasing accumulation of senescent cells with marginal functional performance. Thus, the optimal interventional strategy to antagonize aging of the heart would need to promote maintenance of youthful characteristics typified by a robust stem cell population and minimal accrual of senescent cells. This proposal will antagonize the aging phenotype through a molecular strategy involving Pim-1, a survival and proliferative kinase recently identified in the myocardium. Judicious enhancement of Pim-1 activity will antagonize senescence of stem cell and cardiomyocyte populations, conferring upon the heart a more youthful phenotype capable of greater hemodynamic function and resistance to cardiomyopathic injury including the degenerative consequences of aging. Accomplishing the stated aims of the proposal will provide a comprehensive mechanistic understanding of improvements mediated by myocardial Pim-1 activity. The innovation of this proposal rests with the unique nature of Pim-1 kinase as a targeted strategy to antagonize the aging phenotype and prolong the functional lifespan of cardiomyocytes as well as cardiac progenitor cells responsible for repair and regeneration. The short term goal is to delineate the aging-associated targets influenced by Pim-1 and demonstrate the efficacy of Pim-1 interventional approaches to retard the aging process.
Specific aims are: 1) Myocardial senescence is antagonized by Pim-1 mediated signaling, 2) Loss of Pim-1 activity leads to premature aging of the myocardium and associated decline in hemodynamic performance, and 3) the proliferative phase of cardiac progenitor cell and young cardiomyocyte expansion is extended by Pim-1 kinase. The significance of these studies is the inhibition of myocardial aging and maintenance of youthful characteristics for a longer period of lifespan. Collectively, these studies will set the stage for interventional approaches to regulate Pim-1 kinase activity in service of antagonizing senescence and promoting stem cell-mediated regeneration.
Heart disease remains a major cause or morbidity and mortality in the United States, with long term care and hospitalization of patients a significant burden on the national health care system. Despite advances over the last several decades we are still not truly capable of addressing the fundamental issue in heart failure: the progressive loss of contractile function and viable tissue. This proposal focuses upon a novel fundamental molecular mechanism involving antagonizing the aging phenotype to maintain cardiac structure and function resulting in extended quality of life and decreased medical cost.
|Mohsin, Sadia; Wu, Joseph C; Sussman, Mark A (2014) Predicting the future with stem cells. Circulation 129:136-8|
|Hariharan, Nirmala; Sussman, Mark A (2014) Stressing on the nucleolus in cardiovascular disease. Biochim Biophys Acta 1842:798-801|
|Völkers, Mirko; Doroudgar, Shirin; Nguyen, Nathalie et al. (2014) PRAS40 prevents development of diabetic cardiomyopathy and improves hepatic insulin sensitivity in obesity. EMBO Mol Med 6:57-65|
|Anderson, Mark E; Goldhaber, Joshua; Houser, Steven R et al. (2014) Embryonic stem cell-derived cardiac myocytes are not ready for human trials. Circ Res 115:335-8|
|Quijada, Pearl; Sussman, Mark A (2014) Making it stick: chasing the optimal stem cells for cardiac regeneration. Expert Rev Cardiovasc Ther 12:1275-88|
|Din, Shabana; Konstandin, Mathias H; Johnson, Bevan et al. (2014) Metabolic dysfunction consistent with premature aging results from deletion of Pim kinases. Circ Res 115:376-87|
|Hariharan, Nirmala; Sussman, Mark A (2014) Pin1: a molecular orchestrator in the heart. Trends Cardiovasc Med 24:256-62|
|Gaetani, Roberto; Feyen, Dries A M; Doevendans, Pieter A et al. (2014) Different types of cultured human adult cardiac progenitor cells have a high degree of transcriptome similarity. J Cell Mol Med 18:2147-51|
|Toko, Haruhiro; Hariharan, Nirmala; Konstandin, Mathias H et al. (2014) Differential regulation of cellular senescence and differentiation by prolyl isomerase Pin1 in cardiac progenitor cells. J Biol Chem 289:5348-56|
|Khan, Mohsin; Mohsin, Sadia; Toko, Haruhiro et al. (2014) Cardiac progenitor cells engineered with *ARKct have enhanced *-adrenergic tolerance. Mol Ther 22:178-85|
Showing the most recent 10 out of 25 publications