The adult mammalian heart shows little or no significant natural regeneration of cardiac muscle after injury, and instead heals by scarring. This regenerative deficiency has enormous socioeconomic consequences, given that ischemic myocardial infarction is the leading cause of morbidity and mortality in the United States and over 5 million Americans suffer from heart failure. A decade ago, we found that the teleost zebrafish displays a robust regenerative response after partial resection of the cardiac ventricle, involving creation of new cardiomyocytes with little or no scarring. Pre-existing cardiomyocytes, not stem cells, are the primary source of new muscle during heart regeneration in zebrafish. Muscle regeneration is influenced by activities of the epicardium and endocardium, major non-muscle cells that line the cardiac chambers. There remain critical roadblocks to understanding how and why cardiac regeneration occurs. First, we know little about the regulatory mechanisms that control the competency of adult cardiomyocytes to proliferate in response to injury. Second, our understanding of the cellular and molecular components that stimulate regeneration by cardiomyocytes is insufficient. The goals of the current application are to address central questions about the source and stimuli for bona fide heart regeneration, using state-of-the-art screening and analysis tools in the zebrafish model system. 1) We will define chromatin regulatory signatures of heart regeneration by genome-wide profiling, and harness this information to identify enhancer elements that control gene expression during regeneration. 2) We will define the regenerative capacity of the epicardium, using new tools for visualizing and manipulating this important structure. 3) We will identify small molecule modulators of heart regeneration, using a new in vivo screening strategy that visualizes proliferating cardiomyocytes in live zebrafish. With these approaches, we will test the hypothesis that specialized injury cues activate dedicated cardiac muscle regeneration programs. Our work will provide a detailed understanding of cardiac regeneration and identify key regulators. These discoveries will inform approaches for comprehending and 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 key regulators. These discoveries will inform approaches for comprehending and enhancing the limited regenerative response displayed by humans after myocardial infarction. They are also likely to extend beyond cardiovascular biology and have relevance to the repair of other tissues.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CVRS-K (02))
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Krull, Holly
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Duke University
Anatomy/Cell Biology
Schools of Medicine
United States
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Chen, Chen-Hui; Poss, Kenneth D (2017) Regeneration Genetics. Annu Rev Genet 51:63-82
Goldman, Joseph Aaron; Kuzu, Guray; Lee, Nutishia et al. (2017) Resolving Heart Regeneration by Replacement Histone Profiling. Dev Cell 40:392-404.e5
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:
Karra, Ravi; Poss, Kenneth D (2017) Redirecting cardiac growth mechanisms for therapeutic regeneration. J Clin Invest 127:427-436
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
Tzahor, Eldad; Poss, Kenneth D (2017) Cardiac regeneration strategies: Staying young at heart. Science 356:1035-1039
Cao, Jingli; Navis, Adam; Cox, Ben D et al. (2016) Single epicardial cell transcriptome sequencing identifies Caveolin 1 as an essential factor in zebrafish heart regeneration. Development 143:232-43
Foglia, Matthew J; Poss, Kenneth D (2016) Building and re-building the heart by cardiomyocyte proliferation. Development 143:729-40
Mokalled, Mayssa H; Patra, Chinmoy; Dickson, Amy L et al. (2016) Injury-induced ctgfa directs glial bridging and spinal cord regeneration in zebrafish. Science 354:630-634
Cao, Jingli; Poss, Kenneth D (2016) Explant culture of adult zebrafish hearts for epicardial regeneration studies. Nat Protoc 11:872-81

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