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 in 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 primarily 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 rather 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 asso- ciated 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 con- duct 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 Universi- ty 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. 1

Public Health Relevance

There is currently no available treatment to directly inhibit or reverse cardiac fibrosis, which is a prolific complication of all forms of heart disease, irrespective of etiology. The current proposal will capitalize on the novel finding that the growth and survival factor neuregulin-1b is anti-fibrotic, a phenomenon that might be generalized to include fibrosis of other organs. Additional studies are particularly important, given the ongoing clinical trials of NRG treatment for systolic heart failure. 1

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
1K01HL121045-01
Application #
8616584
Study Section
Special Emphasis Panel (ZHL1-CSR-F (O2))
Program Officer
Wang, Wayne C
Project Start
2014-01-16
Project End
2018-12-31
Budget Start
2014-01-16
Budget End
2014-12-31
Support Year
1
Fiscal Year
2014
Total Cost
$130,775
Indirect Cost
$9,687
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Galindo, Cristi L; Kasasbeh, Ehab; Murphy, Abigail et al. (2014) Anti-remodeling and anti-fibrotic effects of the neuregulin-1? glial growth factor 2 in a large animal model of heart failure. J Am Heart Assoc 3:e000773