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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37HL091102-03
Application #
7872974
Study Section
Special Emphasis Panel (ZRG1-CVS-D (03))
Program Officer
Adhikari, Bishow B
Project Start
2008-06-01
Project End
2013-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
3
Fiscal Year
2010
Total Cost
$403,925
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
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