Chronic lung disease (CLD) is an important cause of morbidity and mortality in surviving very low birth weight (VLBW) infants and in some full-term infants with PPHN. Development of clinical interventions that will prevent or treat this disorder requires a basic understanding of the cell and molecular mechanisms of cell injury and repair in the lung. Through collaborations with SCOR laboratory scientists (LS), clinical Core (CC) investigators will provide expertise to formulate scientific questions in a clinically-relevant manner and to facilitate the transfer to the clinical setting of new knowledge generated in the laboratory. The three Joint Program in Neonatology (JPN) NICUs provide the source populations for present and future clinical studies. These three units at Beth Israel, Brigham and Women~s Hospital, and Children~s Hospital, total more than 80 NICU beds, and in-total admit nearly 2000 infants annually. Approximately 80% of the infants admitted to JPN NICUs are inborn. The clinical Core consists of investigators with experience and active involvement in current clinical research in the NICU. Three CC colleagues (Van Marter, Pagano and Allred) have the advantage of their established NICU-based research collaboration which has continued for more that 10 successive years. Parad is a neonatologist and bench researcher who also has participated in NICU-based clinical trials and who enjoys a close working relationship on the clinical services with Van Marter. As a group, they draw on more than 4 decades of experience in clinical research in the NICU and bring to the SCOR both a well- developed model for multidisciplinary collaboration and practical knowledge of the nuances of clinical investigations involving NICU patients. Three initial clinical projects will parallel laboratory studies; additional studies are anticipated as new data are generated. First, to test the hypothesis that extracellular effector molecules contribute to lung injury, the relationship between the evolution of CLD and the production of syndecans, proteoglycans that regulate the action of growth factors, proteases/antiproteases, chemokines and extracellular matrix components; and syndecan-inducers will be measured in sequential tracheal aspirate samples in a population-based study of all intubated VLBW infants who have no congenital anomalies and are admitted to JPN NICUs (LS: Bemfield). Next, we will use the same design to assess the role of heparin-binding epidermal growth factor (HB-EGF) in BPD pathogenesis in the same population (LS: Klagsbrun). This hypothesis is especially intriguing since HBEGF is a potent smooth muscle cell mitogen that is induced by hyperoxia, a well recognized cause of CLD in both the pre- and full-term infant. Third, to test the hypotheses that I) vascular endothelial growth factor (VEGF) levels are elevated in PPHN, ii) VEGF is reduced by inhaled nitric oxide (iNO), and iii) iNO inhibits platelet activation and aggregation, we will first conduct a case- control comparison of plasma VEGF levels using the conventionally- treated PPHN cases enrolled in our clinical trial of iNO and comparison group of healthy age-matched controls. The second and third hypotheses will be evaluated by comparing VEGF levels and platelet activation and aggregation in iNO and conventionally treated subjects in our ongoing randomized clinical trial of iNO for PPHN ILS: Kourembanas). This SCOR offers a unique opportunity to unite established laboratory and clinical scientists in the common purpose to discover new and effective ways to prevent and treat CLD.
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