The anti-fibrotic effects of neuregulin in the heart

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DESCRIPTION (provided by applicant): Neuregulin-1(NRG) is a growth and survival factor that is critical for cardiac development, as well as cardiac repair after injury. Based on recent i vivo studies, we have made the novel discovery that NRG treatment results in less cardiac fibrosis subsequent to experimentally induced heart attack. Follow-up experiments showed that NRG inhibits the transition of rat primary cardiac fibroblasts to myofibroblasts, the cells primariy responsible for the massive collagen deposition that characterizes fibrotic scarring. NRG signaling most likely occurs via binding to the ErbB3 receptor, which is expressed by cardiac fibroblasts. Cardiac fibrosis is thought to be irreversible, and the current dogma regarding myofibroblasts is that these pro- fibrotic cells cannot revert to a fibroblast phenotype, but rathe die or become quiescent. Our finding is highly significant, because the possibility of preventing and/or reversing cardiac fibrosis would greatly contribute to recovery after heart injury. Moreover, NRG-inducible anti-fibrotic signaling has broad implications beyond the heart, including other forms of fibrotic organ dysfunction. This study will address the hypothesis that NRG signaling regulates fibrosis via direct effects on cardiac fibroblasts. This is an especially timely line of questioning, because recombinant NRG is currently being tested in clinical trials of systolic heart dysfunction. The efficacy of NRG as a post-injury treatment in animals and preliminary studies that demonstrate NRG ameliorates the development of cardiac fibrosis secondary to injury has led us to propose the following: Specific Aim 1: To examine the effect of exogenous NRG treatment on cardiac fibroblasts by testing the hypothesis that cardiac fibroblasts respond to NRG treatment by activation of anti-fibrotic signaling pathways. Specific Aim 2: To test the role of NRG signaling in the development of cardiac fibrosis in response to the pro-fibrotic aldosterone/high salt diet (ALDOST) model. Specific Aim 3: To develop a conditional fibroblast-specific ErbB3-knockout (KO) mouse to determine the contribution of ErbB3 signaling in cardiac fibroblasts to post-myocardial infarction (MI) cardiac fibrosis. In addition to providing new mechanistic insight into the inhibition of the myofibroblast phenotype associated with adverse remodeling and cardiac fibrosis, the proposed project will serve as a springboard from which to launch my career as an independent investigator. My mentor's laboratory is an ideal setting to conduct these studies, and my mentoring committee includes experts in fibrotic cell signaling, cardiac fibrosis, the hypertension rat model and transgenic mouse studies that are proposed in the application. Vanderbilt University is more than adequately equipped to support the proposed research, which will provide the fuel for my own line of investigation that is distinct from my mentor's research that focuses on NRG signaling in cardiomyocytes and stem cell biology. I sincerely thank the reviewers for their time and consideration. (End of Abstract)