Myocrdial biology has been transformed by recognition of the role played by cardiac progenitor cells (CPC) in repair and regeneration following pathological injury as well as their participation in normal cardiac homoestsis, remodeling, and aging. The initial period of this MERIT award focused upon two key regulatory proteins that our group identified as key players in CPC biology: Notch and nucleostemin. Since our initial descriptions of these signaling proteins in the myocardial context both have been studied and integrated into the fabric of cardiovascular literature. This MERIT award extension period will take our understanding of Notch and nucleostemin to a higher level by defining connections between these molecules, canonical pathways in myocardial regulatory signaling, and involvement in the biology of CPC. The significance of this proposal is novel information that can be applied directly toward the manipulation of CPC to enhance myocardial repair and regeneration as well as understanding pathological mechanisms resulting from CPC dysfunction. Innovative aspects of this proposal include the use of unique reagents to manipulate Notch and nucleostemin activity through use of inducible constructs, silencing vectors, and observation of activity through genetically engineered reporters both in cultured cells and transgenic mice.
Specific aims are 1) Notch signaling potentiates cardiac progenitor differentiation into cardiac lineages in vitro and in vivo, 2) Notch signaling facilitates repair and regeneration of damaged mouse myocardium in vivo, S) Pim-1 mediated c-Myc stabilization induces nucleostemin that enhances regenerative potential and survival of cardiac progenitor cells, 4) nucleostemin regulates stem and progenitor cell pluripotency, and 5) elevated nucleostemin expression triggers hypertrophic signaling and enhances regenerative potential in the heart. The impact of the proposal will be advancing the use, manipulation, and control of CPC biology to facilitate myocardial reparative processes as well as explaining the underlying biology of myocardial responses to injury, adaptive remodeling, and aging. As cardiovascular stem cell biology enters the clinical arena it is essential to acquire mechanistic understanding to achieve optimal results.

Public Health Relevance

Cardiovascular disease remains a major cause of morbidity and mortality in the United States and places a substantial economic burden upon society. This proposal seeks to understand mechanisms responsible for repair and regeneration of the damaged heart that are by nature not designed to replace acute injuries. Successful completion of the proposed aims will provide significant insight for how reparative and regenerative processes will successfully be implemented as clinically-relevant treatments for heart disease.

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 (NSS)
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
Broughton, Kathleen M; Wang, Bingyan J; Firouzi, Fareheh et al. (2018) Mechanisms of Cardiac Repair and Regeneration. Circ Res 122:1151-1163
Broughton, Kathleen M; Sussman, Mark A (2018) Enhancement Strategies for Cardiac Regenerative Cell Therapy: Focus on Adult Stem Cells. Circ Res 123:177-187
Gude, Natalie A; Sussman, Mark A (2018) Chasing c-Kit through the heart: Taking a broader view. Pharmacol Res 127:110-115
Gude, Natalie A; Firouzi, Fareheh; Broughton, Kathleen M et al. (2018) Cardiac c-Kit Biology Revealed by Inducible Transgenesis. Circ Res 123:57-72
Kubli, Dieter A; Sussman, Mark A (2018) Editorial commentary: Mitochondrial autophagy in cardiac aging is all fluxed up. Trends Cardiovasc Med 28:261-262
Matsumoto, Collin; Jiang, Yan; Emathinger, Jacqueline et al. (2018) Short Telomeres Induce p53 and Autophagy and Modulate Age-Associated Changes in Cardiac Progenitor Cell Fate. Stem Cells 36:868-880
Eschenhagen, Thomas; Bolli, Roberto; Braun, Thomas et al. (2017) Cardiomyocyte Regeneration: A Consensus Statement. Circulation 136:680-686
Monsanto, Megan M; Wang, Bingyan J; Sussman, Mark A (2017) Synthetic MSC? Nothing Beats the Real Thing. Circ Res 120:1694-1695
Khalafalla, Farid G; Greene, Steven; Khan, Hashim et al. (2017) P2Y2 Nucleotide Receptor Prompts Human Cardiac Progenitor Cell Activation by Modulating Hippo Signaling. Circ Res 121:1224-1236
Fernández-Avilés, Francisco; Sanz-Ruiz, Ricardo; Climent, Andreu M et al. (2017) Global position paper on cardiovascular regenerative medicine. Eur Heart J 38:2532-2546

Showing the most recent 10 out of 81 publications