Cardiovascular disease is the leading cause of death worldwide. This research proposal focuses on the systemic inflammatory response that can result from myocardial infarction (MI) or coronary artery bypass grafting (CABG), a common surgical intervention to treat or prevent MI. The goal of this research is to better understand the molecular signals controlling resolution of the systemic inflammatory response. This project seeks to define the activity of the cardioactive growth factor Neuregulin-1? (NRG) on the monocyte ERBB3 receptor, and the impact of this pathway on the inflammatory response in cardiovascular disease. The hypothesis is that: 1) NRG/ERBB3 signaling promotes resolution of the inflammatory response and 2) circulating NRG and monocyte ERBB3 expression may be independent predictors of the inflammatory response following MI and CABG, with low NRG/ERBB3 signaling indicating high risk for an unrestrained systemic inflammatory response. To test this hypothesis and to investigate the role of NRG/ERBB3 signaling, blood samples will be studied from human patients undergoing CABG prior to surgery, during surgery, and at 4-8, 24, and 96 hours after surgery. These samples will be analyzed for expression of inflammatory cytokines and other markers of inflammation and cardiac injury, and for correlation with circulating NRG or monocyte ERBB3 expression. In addition, monocytes will be treated with increasing doses of recombinant NRG and tested for inflammatory cytokine production in the presence of an inflammatory stimulus. In parallel, complementary studies will employ a mouse model of induced MI in the setting of genetic ablation of monocyte ERBB3 expression, accomplished by crossing a floxed ERBB3 mouse strain with a LysMCre driver strain. In this study, multiparametric myeloid cell analysis will be performed by flow cytometry to determine the extent of inflammatory cell infiltration into cardiac tissue at day 5. Structural and functional changes in the myocardium will be assessed by echocardiography at baseline and during subsequent stages of cardiac remodeling at day 7, 14 and 28 after MI. Scar tissue formation will be assessed by Masson's trichrome staining at day 28 after MI. This project will produce novel data about the currently uncharacterized roles of NRG and ERBB3 in the inflammatory response to MI and CABG, and will have broad relevance for the management of other types of systemic inflammatory processes. Through a combination of multidisciplinary mentoring, a thorough scientific investigation, participation in scientific meetings, focused instruction in manuscript and grant writing, and education on responsible conduct of research, these studies and the accompanying training plan will prepare the applicant for a nationally competitive and independent career in translational cardiovascular research.
Heart attack or open heart surgery sometimes leads to an overwhelming systemic inflammatory response that can cause organ failure or death. Understanding the signals that control the inflammatory response will lead to therapies that improve outcomes for these patients. The goal of this study is to investigate the role of the Neuregulin/ERBB3 signaling pathway in resolving the systemic inflammatory response.
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