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.

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 #
5K01HL121045-06
Application #
9412508
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Wang, Wayne C
Project Start
2014-01-16
Project End
2018-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
6
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
079917897
City
Nashville
State
TN
Country
United States
Zip Code
37232
Ryzhov, Sergey; Matafonov, Anton; Galindo, Cristi L et al. (2017) ERBB signaling attenuates proinflammatory activation of nonclassical monocytes. Am J Physiol Heart Circ Physiol 312:H907-H918
Zhang, Bo; Novitskaya, Tatiana; Wheeler, Debra G et al. (2017) Kcnj11 Ablation Is Associated With Increased Nitro-Oxidative Stress During Ischemia-Reperfusion Injury: Implications for Human Ischemic Cardiomyopathy. Circ Heart Fail 10:
Soslow, Jonathan H; Markham, Larry W; Burnette, W Bryan et al. (2017) Increased Number of Circulating CD8/CD26 T Cells in the Blood of Duchenne Muscular Dystrophy Patients Is Associated with Augmented Binding of Adenosine Deaminase and Higher Muscular Strength Scores. Front Pharmacol 8:914
Kirabo, Annet; Ryzhov, Sergey; Gupte, Manisha et al. (2017) Neuregulin-1? induces proliferation, survival and paracrine signaling in normal human cardiac ventricular fibroblasts. J Mol Cell Cardiol 105:59-69
Markham, Larry W; Brinkmeyer-Langford, Candice L; Soslow, Jonathan H et al. (2017) GRMD cardiac and skeletal muscle metabolism gene profiles are distinct. BMC Med Genomics 10:21
Rath, Rutwik; Lee, Jung Bok; Tran, Truc-Linh et al. (2016) Biomimetic microstructure morphology in electrospun fiber mats is critical for maintaining healthy cardiomyocyte phenotype. Cell Mol Bioeng 9:107-115
Stephenson, Matthew K; Lenihan, Sean; Covarrubias, Roman et al. (2016) Scanning Electron Microscopy of Macerated Tissue to Visualize the Extracellular Matrix. J Vis Exp :
Asson-Batres, Mary Ann; Ryzhov, Sergey; Tikhomirov, Oleg et al. (2016) Effects of vitamin A deficiency in the postnatal mouse heart: role of hepatic retinoid stores. Am J Physiol Heart Circ Physiol 310:H1773-89
Galindo, Cristi L; Soslow, Jonathan H; Brinkmeyer-Langford, Candice L et al. (2016) Translating golden retriever muscular dystrophy microarray findings to novel biomarkers for cardiac/skeletal muscle function in Duchenne muscular dystrophy. Pediatr Res 79:629-36
Pfaltzgraff, Elise R; Shelton, Elaine L; Galindo, Cristi L et al. (2014) Embryonic domains of the aorta derived from diverse origins exhibit distinct properties that converge into a common phenotype in the adult. J Mol Cell Cardiol 69:88-96

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