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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL105759-01
Application #
8024238
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Liang, Isabella Y
Project Start
2011-01-01
Project End
2015-12-31
Budget Start
2011-01-01
Budget End
2011-12-31
Support Year
1
Fiscal Year
2011
Total Cost
$373,750
Indirect Cost
Name
San Diego State University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
073371346
City
San Diego
State
CA
Country
United States
Zip Code
92182
Samse, Kaitlen; Hariharan, Nirmala; Sussman, Mark A (2016) Personalizing cardiac regenerative therapy: At the heart of Pim1 kinase. Pharmacol Res 103:13-6
Broughton, Kathleen M; Sussman, Mark A (2016) Empowering Adult Stem Cells for Myocardial Regeneration V2.0: Success in Small Steps. Circ Res 118:867-80
Orogo, Amabel M; Gonzalez, Eileen R; Kubli, Dieter A et al. (2015) Accumulation of Mitochondrial DNA Mutations Disrupts Cardiac Progenitor Cell Function and Reduces Survival. J Biol Chem 290:22061-75
Hariharan, Nirmala; Sussman, Mark A (2015) Cardiac aging - Getting to the stem of the problem. J Mol Cell Cardiol 83:32-6
Nguyen, Nathalie; Sussman, Mark A (2015) Rejuvenating the senescent heart. Curr Opin Cardiol 30:235-9
Hariharan, Nirmala; Quijada, Pearl; Mohsin, Sadia et al. (2015) Nucleostemin rejuvenates cardiac progenitor cells and antagonizes myocardial aging. J Am Coll Cardiol 65:133-47
Quijada, Pearl; Sussman, Mark A (2015) Circulating around the tissue: hematopoietic cell-based fusion versus transdifferentiation. Circ Res 116:563-5
Quijada, Pearl; Hariharan, Nirmala; Cubillo, Jonathan D et al. (2015) Nuclear Calcium/Calmodulin-dependent Protein Kinase II Signaling Enhances Cardiac Progenitor Cell Survival and Cardiac Lineage Commitment. J Biol Chem 290:25411-26
Samse, Kaitlen; Emathinger, Jacqueline; Hariharan, Nirmala et al. (2015) Functional Effect of Pim1 Depends upon Intracellular Localization in Human Cardiac Progenitor Cells. J Biol Chem 290:13935-47
Gude, Natalie; Joyo, Eri; Toko, Haruhiro et al. (2015) Notch activation enhances lineage commitment and protective signaling in cardiac progenitor cells. Basic Res Cardiol 110:29

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