Healthy myocardium responds to pathologic stress with alteration of cardiac structure and hemodynamic performance associated with increases in proteins primarily associated with embryonic and fetal development. While such chronic changes may be considered compensatory, they are not directed at repairing underlying acute damage or targeting cellular wound healing upon focal sites of trauma. Induction and/or potentiation of myocardial healing represent novel approaches to treatment of pathological insults. In turn, enhancement of reparative and/or regenerative mechanisms depends upon delineation of processes that regulate cellular and molecular responses. The long term goal of this study is to understand molecular mechanism(s) responsible for reparative and regenerative signaling in the myocardium. The goal of this proposal is to demonstrate that myocardial regeneration and repair depends upon two stem cell-associated signaling pathways expressed in injured myocardium that are critical regulators of cellular proliferation and survival: Notch and nucleostemin. Specifically, experiments are designed to optimize myocardial repair and regeneration. The hypothesis is that activation of regenerative signals promotes a combination of enhanced survival and/or proliferation as well as enabling communication between cardiac stem cells and the myocardium.
Specific aims will demonstrate that: 1) injury or stress stimuli in the heart promote increased expression and activation of regenerative signaling, 2) survival and proliferation of myocardial lineage cells in the damaged myocardium are enhanced by regenerative signaling activity, 3) survival and proliferative signaling effectors in myocardial lineage cells are regulated by regenerative signaling cascades, and 4) cellular commitment and myocardial repair are facilitated by regenerative signaling cascades. The innovative approach employed will involve molecular, biochemical, and microscopic analyses of cultured cardiomyocytes and mouse models manipulated to optimize Notch and nucleostemin activity via cardioprotective stimuli, recombinant adenoviruses, and genetically engineered transgenic mouse lines. The significance of these studies is to establish mechanism(s) of regenerative signaling that occur in pathologically challenged cardiomyocytes, to understand the role of these canonical regenerative signaling pathways in the context of the myocardium, to establish relevance of these regenerative cascades for potentiation of cardiomyocyte proliferation and survival, and to delineate the basis for how cardiomyocyte-autonomous stem cell signaling facilitates communication with local stem cell populations.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (ZRG1-CVS-D (03))
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Adhikari, Bishow B
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San Diego State University
Schools of Arts and Sciences
San Diego
United States
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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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