The myocardium possesses an inherent capacity for cellular replacement, yet this reparative process is inadequate to cope with acute injury or chronic stress. Remarkable advances are evident in the use of donated stem cell populations or expression of paracrine factors (or both) to enhance myocardial repair, but efficacy of adoptively transferred cells to generate new myocardium remains modest. Moreover, several studies indicate that repair stems predominantly from recruitment of endogenous cells activated by cellular or molecular therapeutic interventions. The overarching premise of this program is that endogenous myocardial reparative mechanisms become compromised by pathologic stimuli leading to a downward spiral of cardiac insufficiency linked to inadequate cellular replacement. Therefore, functional restoration of myocardial repair will inevitably require deciphering the molecular signaling that impairs cellular replacement and healing. Project 1 (Sussman) examines the role of extracellular matrix. Project 2 (Heller Brown) focuses upon G-protein coupled receptor signaling. Project 3 (Glembotski) is concerned with secretion / cardiokine synthesis, and Project 4 (Gustafsson) delineases the role of mitochondrial function in the regenerative process. Relieving pathologic impediments to cellular replacement will increase formation of functional myocardium and improve hemodynamic performance. Concurrent enhancement therapies to potentiate healing can then benefit from improved endogenous functional repair, leading to more effective compensation of the heart to pathologic stress. Pathological signals that impair survival, proliferation, migration, commitment, or integration of endogenous replacement cells into the stressed myocardium need to be defined, mitigated, and optimally reversed in order to restore myocardial repair. Projects in this program will demonstrate molecular mechanisms responsible for loss of reparative capacity that create nonpermissive conditions for expansion or retention of cardiogenic cells. The goal of this program will be to delineate these deleterious signaling mechanisms and determine how they can be overcome to restore endogenous cellular repair processes that heal the damaged heart.

Public Health Relevance

The possibility of regenerative medicine for treatment of heart disease is now being realized in early clinical studies, but the greatest limitation to efficient myocardial regeneration is the poor functional performance of the stem cell population. To overcome this roadblock, the molecular mechanisms that hamper myocardial healing need to be defined and manipulated in order to maximize the reparative potential of the heart. (End of Abstract)

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL085577-07
Application #
8734473
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Wong, Renee P
Project Start
2006-07-01
Project End
2018-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
7
Fiscal Year
2014
Total Cost
$1,708,124
Indirect Cost
$264,020
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
Lampert, Mark A; Gustafsson, Åsa B (2018) Balancing Autophagy for a Healthy Heart. Curr Opin Physiol 1:21-26
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
Parker, Sarah J; Stotland, Aleksandr; MacFarlane, Elena et al. (2018) Proteomics reveals Rictor as a noncanonical TGF-? signaling target during aneurysm progression in Marfan mice. Am J Physiol Heart Circ Physiol 315:H1112-H1126
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
Yu, Olivia M; Benitez, Jorge A; Plouffe, Steven W et al. (2018) YAP and MRTF-A, transcriptional co-activators of RhoA-mediated gene expression, are critical for glioblastoma tumorigenicity. Oncogene 37:5492-5507
Gude, Natalie A; Firouzi, Fareheh; Broughton, Kathleen M et al. (2018) Cardiac c-Kit Biology Revealed by Inducible Transgenesis. Circ Res 123:57-72
Shires, Sarah E; Gustafsson, Åsa B (2018) Regulating Renewable Energy: Connecting AMPK?2 to PINK1/Parkin-Mediated Mitophagy in the Heart. Circ Res 122:649-651

Showing the most recent 10 out of 162 publications