This proposal outlines a career development plan for the applicant, an academic neonatologist with a longstanding commitment to understanding the pathogenesis of neonatal pulmonary vascular remodeling and whose goal is to become an independent investigator. Under the mentorship of established investigators and a multidisciplinary advisory committee, the candidate will pursue a program of education (coursework, conferences, seminars) and a research project addressing the cellular and molecular mechanisms of neonatal hypoxia-mediated pulmonary vascular remodeling (HPVR), which predisposes to the important clinical problem of neonatal pulmonary hypertension. HPVR is characterized by thickening of small pulmonary arteries due to cellular proliferation and deposition of extracellular matrix (ECM) proteins. ECM protein deposition and turnover are regulated by matrix metalloproteinases (MMPs). The candidate has developed innovative neonatal mouse (in vivo) and cell culture (in vitro) models to evaluate neonatal HPVR. The candidate has made the novel observations that MMP-2 is the principal MMP both in vitro and in vivo and that hypoxia increases MMP-2 while concomitantly decreasing its inhibitor [tissue inhibitor of metalloproteinases (TIMP)-2]. In addition, the candidate has shown that specific ECM proteins including collagens (CN), periostin (PN), fibronectin (FN-1), and thrombospondin (TSP-1) are increased, while other ECM proteins either do not change [e.g. osteopontin (OPN)] or decrease [e.g. tenascin-c (TN-C)] in response to hypoxia. The objective of this project is to determine the mechanisms by which hypoxia alters ECM deposition during HPVR, with specific focus on the role of MMP-2 in this process.
The Specific Aims are: (1) To test the hypothesis that chronic hypoxia-induced pulmonary arterial medial thickening, cellular proliferation, and ECM molecule deposition are decreased in neonatal C57BL/6 mice treated with MMP inhibitors (MMP-2 I) and in MMP-2 -/- (MMP-2 null) mice as compared to neonatal wild-type (WT) mice, and (2) To test the hypothesis that hypoxia increases MMP-2 synthesis/activation and downstream ECM molecule expression by increasing endothelin-1 (ET-1) and activation of the phosphoinositide 3-kinase (PI3K) and mitogen activated protein kinase (MAPK) pathways. Determination of the mechanisms of ECM protein deposition in the neonatal pulmonary vasculature will provide essential information on normal pulmonary vascular development and lead to the development of new therapies for HPVR. ? ?
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