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)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-CVS-D (03))
Program Officer
Adhikari, Bishow B
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
San Diego State University
Schools of Arts and Sciences
San Diego
United States
Zip Code
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
Siddiqi, Sailay; Sussman, Mark A (2014) The heart: mostly postmitotic or mostly premitotic? Myocyte cell cycle, senescence, and quiescence. Can J Cardiol 30:1270-8
McGregor, Michael; Hariharan, Nirmala; Joyo, Anya Y et al. (2014) CENP-A is essential for cardiac progenitor cell proliferation. Cell Cycle 13:739-48
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

Showing the most recent 10 out of 40 publications