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Pathogenetic Mechanisms of Brochopulmonary Dysplasia

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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.

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