Perinatal lung injury in premature neonates disrupts the normal sequence of lung development, resulting in bronchopulmonary dysplasia (BPD), the chronic lung disease of infancy characterized by impaired alveolarization and vascular growth. One of the long term objectives for this proposal is to define molecular mechanisms and genetic risk factors that predispose premature infants to BPD. By identifying the mechanisms of disease and the children at risk to develop BPD, it may be possible to intervene before irreversible damage occurs. The main hypothesis is that decreased production of the angiogenic factor, vascular endothelial growth factor (VEGF), and the signaling molecule, nitric oxide (NO), enhances the risk of the development of BPD in premature infants. This hypothesis will be tested through the following specific aims: 1) to determine if reduced levels of VEGF and NO (in plasma and tracheal secretions) in premature infants in the first weeks of life predict the development of BPD; 2) to determine if early abnormalities of VEGF and NO production lead to poor long-term cardiopulmonary outcome as defined by pulmonary function testing, hemodynamic assessment (echocardiography), and related morbidities (rates of respiratory infection and hospitalization, length of oxygen requirement) over the ensuing two years; 3) to gather information linking specific polymorphisms in the VEGF and eNOS genes to altered production of VEGF and NO and BPD, in order to design and power a prospective trial evaluating the role of genetic factors in BPD. These results will be crucial to developing potential therapies and treatment strategies to prevent BPD. Another objective of this application is to strengthen Dr. Mourani's approach to translational clinical investigation. Dr. Mourani will receive more formal training and education by taking courses and completing his Ph.D. in the University of Colorado's Clinical Science Program. In addition, he will actively participate and train in the Pediatric GCRC, and frequently interact with his sponsor, mentors, and collaborators.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23RR021921-04
Application #
7493449
Study Section
National Center for Research Resources Initial Review Group (RIRG)
Program Officer
Wilde, David B
Project Start
2005-08-16
Project End
2010-07-31
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
4
Fiscal Year
2008
Total Cost
$136,898
Indirect Cost
Name
University of Colorado Denver
Department
Pediatrics
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Wagner, Brandie D; Babinec, Ana E; Carpenter, Charlie et al. (2018) Proteomic Profiles Associated with Early Echocardiogram Evidence of Pulmonary Vascular Disease in Preterm Infants. Am J Respir Crit Care Med 197:394-397
Ehrmann, Daniel E; Mourani, Peter M; Abman, Steven H et al. (2018) Echocardiographic Measurements of Right Ventricular Mechanics in Infants with Bronchopulmonary Dysplasia at 36 Weeks Postmenstrual Age. J Pediatr 203:210-217.e1
Carlton, Erin F; Sontag, Marci K; Younoszai, Adel et al. (2017) Reliability of Echocardiographic Indicators of Pulmonary Vascular Disease in Preterm Infants at Risk for Bronchopulmonary Dysplasia. J Pediatr 186:29-33
Mourani, Peter M; Sontag, Marci K; Younoszai, Adel et al. (2015) Early pulmonary vascular disease in preterm infants at risk for bronchopulmonary dysplasia. Am J Respir Crit Care Med 191:87-95
Di Maria, Michael V; Younoszai, Adel K; Sontag, Marci K et al. (2015) Maturational Changes in Diastolic Longitudinal Myocardial Velocity in Preterm Infants. J Am Soc Echocardiogr 28:1045-52
Branchford, Brian R; Mourani, Peter; Bajaj, Lalit et al. (2012) Risk factors for in-hospital venous thromboembolism in children: a case-control study employing diagnostic validation. Haematologica 97:509-15
Baker, Christopher D; Balasubramaniam, Vivek; Mourani, Peter M et al. (2012) Cord blood angiogenic progenitor cells are decreased in bronchopulmonary dysplasia. Eur Respir J 40:1516-22
Manco-Johnson, Marilyn J; Wang, Michael; Goldenberg, Neil A et al. (2012) Treatment, survival, and thromboembolic outcomes of thrombotic storm in children. J Pediatr 161:682-8.e1
Gunville, Cameron F; Sontag, Marci K; Stratton, Kristin A et al. (2010) Scope and impact of early and late preterm infants admitted to the PICU with respiratory illness. J Pediatr 157:209-214.e1
Mourani, Peter M; Sontag, Marci K; Ivy, D Dunbar et al. (2009) Effects of long-term sildenafil treatment for pulmonary hypertension in infants with chronic lung disease. J Pediatr 154:379-84, 384.e1-2

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