Novel therapeutic strategies for stimulating regeneration of human heart muscle would significantly improve clinical outcomes for patients experiencing a heart attack. In contrast to humans, adult zebrafish naturally regenerate their heart muscle following injury. Our lab recently discovered that the Notch signaling pathway becomes activated following cardiac injury in zebrafish and is required for stimulating growth of new cardiac muscle. The goal of this application is to gain new mechanistic insight into how Notch stimulates heart regeneration in fish with the long-term goal of informing new therapeutic strategies for redirecting or repurposing activated Notch for clinical benefit in humans.
Novel therapeutic strategies for stimulating regeneration of human myocardium would significantly improve clinical outcomes for myocardial infarction. A roadmap for achieving therapeutic myocardial regeneration exists in the remarkable capacity of the adult zebrafish heart to achieve near-complete regeneration following several forms of injury. In early 2014, our laboratory reported that partial resection of the zebrafish ventricle stimulates expression of Notch receptors in the endocardium and epicardium but not the myocardium. We also reported that ubiquitous inhibition of Notch signaling impairs regeneration by compromising cardiomyocyte proliferation. Based on these observations, we hypothesize that Notch signaling, induced by injury in the endocardium and epicardium, activates the production of an unidentified paracrine signal that stimulates cardiomyocyte proliferation. Despite preliminary support for this model, our hypothesis remains unproven. Our Specific Aims are designed to: 1) delineate the necessity and sufficiency of endocardial/epicardial Notch signaling for stimulating cardiomyocyte proliferation during heart regeneration, 2) dissect the role of chromatic remodeling in transcriptional activation of injury-induced loci, including notch1b, during zebrafish heart regeneration, and 3) identify Notch-targeted paracrine factors that stimulate cardiomyocyte proliferation during heart regeneration. Studies from other laboratories have documented active Notch signaling in the endocardium and epicardium of injured mammalian hearts where this pathway contributes to fibrosis/repair. Therefore, despite differential regenerative capacities, Notch signaling is a shared feature of the cardiac injury response across vertebrates. In the long run, deciphering the role of Notch signaling in zebrafish heart regeneration will inform therapeutic strategies for redirecting or repurposing activated Notch for clinical benefit.
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