This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Bronchopulmonary dysplasia (BPD) is the chronic lung disease that follows mechanical ventilation and oxygen therapy for respiratory failure in premature newborns. Characterized by dysmorphic lung vascular growth and decreased alveolarization, BPD is a complex disease with interactions between genetic and environmental factors contributing to its pathobiology. Clinical studies strongly support a genetic basis for BPD, but genetic risk factors that contribute to the pathogenesis or severity of BPD are unknown. Over the past several years, our lab and others have implicated a critical role for impaired angiogenesis in the pathogenesis of BPD. Vascular endothelial growth factor (VEGF) is a potent endothelial cell mitogen and survival factor that stimulates lung angiogenesis and maintains vascular function. VEGF stimulates angiogenesis through upregulation of endothelial nitric oxide synthase (eNOS), which increases nitric oxide (NO) production. Experimental models of BPD in several species have shown that impaired VEGF signaling, decreased eNOS gene expression, and decreased NO bioavailability due to high oxidant stress (due to increased generation of superoxide from inflammation and decreased scavenging by superoxide dismutase (SOD)) increase susceptibility of the developing lung for pulmonary hypertension, impaired angiogenesis and reduced alveolarization. Clinically, reduced lung VEGF expression has been found in infants dying with BPD and pulmonary vascular disease. Inhaled NO therapy enhances alveolar and vascular growth and lowers pulmonary vascular resistance in animal models of BPD, further suggesting that reduced NO production or bioavailability may contribute to chronic lung disease in premature newborns. Additional laboratory studies have further demonstrated critical interactions between VEGF-NO signaling and other angiogenic molecules, including the angiopoietin-Tie 2 system, endothelin-1, and prostacyclin, in lung growth and structure. Based on these findings, we hypothesize that early pulmonary vascular disease contributes to the incidence and severity of BPD, and that genetic variations that impair the VEGF-NO pathways and angiogenic signaling increase the susceptibility of premature newborns for the development of BPD. In these pilot studies, we will carefully characterize the clinical phenotype and subtypes of BPD through precise determination of oxygen requirement, early morbisities and serial echocardiograms and infant pulmonary function tests. Using the quatitative pehenotype, we will identify early angiogenic biomarkers and variations in angiogenic genes that are associated with BPD. For the genetic studies, we will employ a combined population based and family based association test (involving the collection of DNA from mother, father, and affected child trios), utilizing DNA from subjects enrolled into a prospective observational study of premature newborns at the University of Colorado who are at high risk for developing BPD and pulmonary hypertension. This pilot study is intended to determine the feasibility of such a project and to obtain preliminary data and identify trends in both biomarker and genetic data in order to narrow the scope and adequately power a larger more complete study evaluating these study questions. This pilot study is structured in such a way that these data can also be used by the subsequent larger study.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
General Clinical Research Centers Program (M01)
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Special Emphasis Panel (ZRR1-CR-9 (01))
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University of Colorado Denver
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