Heart disease is among the leading causes of disability and mortality in United States and worldwide. After ischemic injury, human hearts cannot regenerate and heal by scarring, which gradually leads to cardiac dysfunction. Replacing the damaged myocardium with new cardiomyocytes and neovascularization may restore cardiac function. By contrast to mammals, zebrafish hearts have remarkable regenerative capacity, completely regenerating lost tissue after surgical resection. Very little is known about the molecular and cellular mechanisms of heart regeneration in zebrafish. During this process, embryonic epicardial and pericyte/mesenchymal markers are upregulated, suggesting that the epicardium is activated and undergoes an epithelial-to-mesenchymal transition (EMT) to form new blood vessels. We found platelet-derived growth factors (PDGFs) are important for heart regeneration. Blocking PDGF signaling caused impaired new blood vessel formation and decreased DNA synthesis in cardiomyocytes during zebrafish heart regeneration. We hypothesize that PDGF signaling is required for epicardial cell proliferation, epicardial EMT, and cardiomyocyte proliferation. We propose to characterize the functions of PDGFR2 signaling in epicardial cell proliferation, EMT, and new blood vessel formation in vivo (Aim 1) and in vitro (Aim 2). We further propose to determine the function of PDGFR1 signaling in zebrafish cardiomyocytes and cardiac progenitors (Aim 3). Our unique zebrafish heart regeneration model and parallel in vitro and in vivo approaches will allow us to determine the molecular and cellular mechanisms of zebrafish heart regeneration. Our long-term goal is the development of novel therapeutic approaches for heart diseases in the future.

Public Health Relevance

Regenerative medicine holds a great deal of promise for treating congenital and degenerative diseases. The goal of this proposal is to determine the molecular and cellular mechanisms of heart regeneration in zebrafish, an organism with a natural regenerative ability. We expect the proposed research can lead to findings that may enhance regenerative capacity in diseased human hearts in the future.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL096121-03
Application #
8215709
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Schramm, Charlene A
Project Start
2010-02-01
Project End
2015-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
3
Fiscal Year
2012
Total Cost
$401,965
Indirect Cost
$143,312
Name
Children's Hospital of Los Angeles
Department
Type
DUNS #
052277936
City
Los Angeles
State
CA
Country
United States
Zip Code
90027
Rubin, Nicole; Harrison, Michael R; Krainock, Michael et al. (2016) Recent advancements in understanding endogenous heart regeneration-insights from adult zebrafish and neonatal mice. Semin Cell Dev Biol 58:34-40
Harrison, Michael R M; Bussmann, Jeroen; Huang, Ying et al. (2015) Chemokine-guided angiogenesis directs coronary vasculature formation in zebrafish. Dev Cell 33:442-54
Zhao, Yu; Cao, Hung; Beebe, Tyler et al. (2015) Dry-contact microelectrode membranes for wireless detection of electrical phenotypes in neonatal mouse hearts. Biomed Microdevices 17:40
Darehzereshki, Ali; Rubin, Nicole; Gamba, Laurent et al. (2015) Differential regenerative capacity of neonatal mouse hearts after cryoinjury. Dev Biol 399:91-9
Cao, Hung; Yu, Fei; Zhao, Yu et al. (2014) Wearable multi-channel microelectrode membranes for elucidating electrophysiological phenotypes of injured myocardium. Integr Biol (Camb) 6:789-95
Li, Rongsong; Beebe, Tyler; Jen, Nelson et al. (2014) Shear stress-activated Wnt-angiopoietin-2 signaling recapitulates vascular repair in zebrafish embryos. Arterioscler Thromb Vasc Biol 34:2268-75
Gamba, Laurent; Harrison, Michael; Lien, Ching-Ling (2014) Cardiac regeneration in model organisms. Curr Treat Options Cardiovasc Med 16:288
Huang, Ying; Harrison, Michael R; Osorio, Arthela et al. (2013) Igf Signaling is Required for Cardiomyocyte Proliferation during Zebrafish Heart Development and Regeneration. PLoS One 8:e67266
Rubin, Nicole; Darehzereshki, Ali; Bellusci, Saverio et al. (2013) FGF10 Signaling Enhances Epicardial Cell Expansion during Neonatal Mouse Heart Repair. J Cardiovasc Dis Diagn 1:
Lien, Ching-Ling; Harrison, Michael R; Tuan, Tai-Lan et al. (2012) Heart repair and regeneration: recent insights from zebrafish studies. Wound Repair Regen 20:638-46

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