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 #
5R01HL081674-07
Application #
8109920
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Wang, Lan-Hsiang
Project Start
2005-08-01
Project End
2014-04-30
Budget Start
2011-05-01
Budget End
2012-04-30
Support Year
7
Fiscal Year
2011
Total Cost
$390,000
Indirect Cost
Name
Duke University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Mokalled, Mayssa H; Poss, Kenneth D (2018) A Regeneration Toolkit. Dev Cell 47:267-280
Cao, Jingli; Poss, Kenneth D (2018) The epicardium as a hub for heart regeneration. Nat Rev Cardiol 15:631-647
Walton, Eric M; Cronan, Mark R; Cambier, C J et al. (2018) Cyclopropane Modification of Trehalose Dimycolate Drives Granuloma Angiogenesis and Mycobacterial Growth through Vegf Signaling. Cell Host Microbe 24:514-525.e6
Karra, Ravi; Foglia, Matthew J; Choi, Wen-Yee et al. (2018) Vegfaa instructs cardiac muscle hyperplasia in adult zebrafish. Proc Natl Acad Sci U S A 115:8805-8810
Cao, Jingli; Wang, Jinhu; Jackman, Christopher P et al. (2017) Tension Creates an Endoreplication Wavefront that Leads Regeneration of Epicardial Tissue. Dev Cell 42:600-615.e4
Karra, Ravi; Poss, Kenneth D (2017) Redirecting cardiac growth mechanisms for therapeutic regeneration. J Clin Invest 127:427-436
Yang, Xinan H; Nadadur, Rangarajan D; Hilvering, Catharina Re et al. (2017) Transcription-factor-dependent enhancer transcription defines a gene regulatory network for cardiac rhythm. Elife 6:
Chen, Chen-Hui; Poss, Kenneth D (2017) Regeneration Genetics. Annu Rev Genet 51:63-82
Tzahor, Eldad; Poss, Kenneth D (2017) Cardiac regeneration strategies: Staying young at heart. Science 356:1035-1039
Goldman, Joseph Aaron; Kuzu, Guray; Lee, Nutishia et al. (2017) Resolving Heart Regeneration by Replacement Histone Profiling. Dev Cell 40:392-404.e5

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