The adult mammalian heart shows little or no significant natural regeneration of the major structural cells, the cardiomyocytes, after injury. This regenerative deficiency is highly relevant to human disease, given that ischemic myocardial infarction and scarring is the leading cause of morbidity and mortality in the United States. A few years ago, we found that the teleost zebrafish displays a highly efficient regenerative response after partial resection of the cardiac ventricle. Cardiac regeneration in zebrafish is hyperplastic, involving creation of new cardiomyocytes with little or no scarring. In our published and preliminary studies, we have focused on the following key questions about zebrafish heart regeneration. First, how does injury activate local regenerative replacement of cardiac muscle? Second, what are the cellular origins of newly regenerated muscle and other cardiac tissues? Third, how do we use the information we gain about heart regeneration to experimentally block or enhance regenerative events? Our experiments have revealed new responses by the major cardiac cellular constituents during regeneration, including myocardium, epicardium, endocardium, and vasculature. The goals of the current proposal are to investigate and understand these cellular responses at high resolution, and to define a catalog of molecular factors that modulate regenerative capacity. 1) We will define the lineage potential of cardiac cells during heart regeneration, using new technology for the lineage tracing of adult zebrafish cells. 2) We will define immediate and regenerative cardiac cell type-specific responses to injury, using high- resolution techniques for gene expression profiling. 3) We will enhance regenerative efficacy by molecular manipulations targeted to the injury site, based on our identification of several factors predicted to positively impact regenerative events. With this approach, we will test the hypothesis that trauma stimulates dynamic molecular changes in cardiac tissue that initiate cardiogenesis at the injury site. Our work will provide a detailed understanding of myocardial regeneration and identify important molecular regulators, information that will lead to approaches for comprehending, and possibly enhancing, the limited regenerative response displayed by humans after myocardial infarction.

Public Health Relevance

Our work will provide a detailed understanding of myocardial regeneration and identify important molecular regulators, information that will lead to approaches for comprehending, and possibly enhancing, the limited regenerative response displayed by humans after myocardial infarction.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL081674-08
Application #
8258270
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Krull, Holly
Project Start
2005-08-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
8
Fiscal Year
2012
Total Cost
$386,100
Indirect Cost
$138,600
Name
Duke University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Schindler, Yocheved L; Garske, Kristina M; Wang, Jinhu et al. (2014) Hand2 elevates cardiomyocyte production during zebrafish heart development and regeneration. Development 141:3112-22
Johnson, Aaron N; Mokalled, Mayssa H; Valera, Juliana M et al. (2013) Post-transcriptional regulation of myotube elongation and myogenesis by Hoi Polloi. Development 140:3645-56
Choi, Wen-Yee; Gemberling, Matthew; Wang, Jinhu et al. (2013) In vivo monitoring of cardiomyocyte proliferation to identify chemical modifiers of heart regeneration. Development 140:660-6
Fang, Yi; Gupta, Vikas; Karra, Ravi et al. (2013) Translational profiling of cardiomyocytes identifies an early Jak1/Stat3 injury response required for zebrafish heart regeneration. Proc Natl Acad Sci U S A 110:13416-21
Le, Xiuning; Pugach, Emily K; Hettmer, Simone et al. (2013) A novel chemical screening strategy in zebrafish identifies common pathways in embryogenesis and rhabdomyosarcoma development. Development 140:2354-64
Wang, Jinhu; Karra, Ravi; Dickson, Amy L et al. (2013) Fibronectin is deposited by injury-activated epicardial cells and is necessary for zebrafish heart regeneration. Dev Biol 382:427-35
Gemberling, Matthew; Bailey, Travis J; Hyde, David R et al. (2013) The zebrafish as a model for complex tissue regeneration. Trends Genet 29:611-20
Guner-Ataman, Burcu; Paffett-Lugassy, Noelle; Adams, Meghan S et al. (2013) Zebrafish second heart field development relies on progenitor specification in anterior lateral plate mesoderm and nkx2.5 function. Development 140:1353-63
Gupta, Vikas; Gemberling, Matthew; Karra, Ravi et al. (2013) An injury-responsive gata4 program shapes the zebrafish cardiac ventricle. Curr Biol 23:1221-7
Yin, Viravuth P; Lepilina, Alexandra; Smith, Ashley et al. (2012) Regulation of zebrafish heart regeneration by miR-133. Dev Biol 365:319-27

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