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. ? ?

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HD046513-05
Application #
7383181
Study Section
Pediatrics Subcommittee (CHHD)
Program Officer
Raju, Tonse N
Project Start
2004-04-01
Project End
2009-03-31
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
5
Fiscal Year
2008
Total Cost
$127,073
Indirect Cost
Name
University of Alabama Birmingham
Department
Pediatrics
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Kandasamy, Jegen; Roane, Claire; Szalai, Alexander et al. (2015) Serum eotaxin-1 is increased in extremely-low-birth-weight infants with bronchopulmonary dysplasia or death. Pediatr Res 78:498-504
Olave, Nelida; Nicola, Teodora; Zhang, Wei et al. (2012) Transforming growth factor-? regulates endothelin-1 signaling in the newborn mouse lung during hypoxia exposure. Am J Physiol Lung Cell Mol Physiol 302:L857-65
Maheshwari, Akhil; Kelly, David R; Nicola, Teodora et al. (2011) TGF-ýý2 suppresses macrophage cytokine production and mucosal inflammatory responses in the developing intestine. Gastroenterology 140:242-53
James, Masheika L; Ross, A Catharine; Bulger, Arlene et al. (2010) Vitamin A and retinoic acid act synergistically to increase lung retinyl esters during normoxia and reduce hyperoxic lung injury in newborn mice. Pediatr Res 67:591-7
Ambalavanan, Namasivayam; El-Ferzli, George T; Roane, Claire et al. (2009) Nitric oxide administration using an oxygen hood: a pilot trial. PLoS One 4:e4312
Nicola, Teodora; Hagood, James S; James, Masheika L et al. (2009) Loss of Thy-1 inhibits alveolar development in the newborn mouse lung. Am J Physiol Lung Cell Mol Physiol 296:L738-50
El-Ferzli, George T; Philips 3rd, Joseph B; Bulger, Arlene et al. (2009) A pumpless lung assist device reduces mechanical ventilation-induced lung injury in juvenile piglets. Pediatr Res 66:671-6
El-Ferzli, George T; Philips 3rd, Joseph B; Bulger, Arlene et al. (2009) Evaluation of a pumpless lung assist device in hypoxia-induced pulmonary hypertension in juvenile piglets. Pediatr Res 66:677-81
Ambalavanan, Namasivayam; Nicola, Teodora; Hagood, James et al. (2008) Transforming growth factor-beta signaling mediates hypoxia-induced pulmonary arterial remodeling and inhibition of alveolar development in newborn mouse lung. Am J Physiol Lung Cell Mol Physiol 295:L86-95
Ambalavanan, Namasivayam; Nicola, Teodora; Li, Peng et al. (2008) Role of matrix metalloproteinase-2 in newborn mouse lungs under hypoxic conditions. Pediatr Res 63:26-32

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