This proposal combines basic and clinical research approaches to the development, injury and repair of the perinatal lung that underlie bronchopulmonary dysplasia (BPD) and pulmonary hypertension of the newborn (PPHN), the major causes of chronic lung disease (CLD) of infancy. Project 1 employs a mouse model of glucocorticoid deficiency based on targeted deletion of the corticotrophin-releasing hormone (CRH) gene. The role of glucocorticoids in normal and dysplastic fetal lung development will be analyzed by identifying cellular targets of steroid action, characterizing the role of cell-cell interactions and paracrine factors in downstream signaling, and determining whether lung-derived CRH plays a role in lung maturation. Project 2 analyzes the role of cell surface heparan sulfate proteoglycans, syndecans, their shedding into the extracellular spaces, and their inducers in modifying the action of heparin-binding effectors involved in the developmental response to injury. Project 3 explores the possibility that heparin- binding EGF-like growth factor (HB-EGF), a potent mitogen for smooth muscle (SM) cells, fibroblasts, and epithelial cells, is involved in the response of the lung to injury. Mechanisms that regulate HB-EGF synthesis and bioactivity in normal and abnormal lungs, and HB-EGF antagonists that might control abnormal lung cell proliferation will be studies. Projects 4 and 5 will function in concert to analyze the cellular and molecular mechanisms that the lung uses to control pulmonary vascular SM cell contractility and growth. These responses to injury become deregulated during the pathogenesis of PPHN. Project 4 focuses on gene regulation by hypoxia, and the interaction of endothelial-derived vasoconstrictors and vasodilators in a rat model of hypoxia-induced pulmonary remodeling as well as in infants with PPHN. Project 5 is based on the finding that changes in cell-extracellular matrix interactions in response to these endothelial-derived factors can modulate pulmonary vascular SM cell by altering integrin-dependent signaling mechanisms. These signals, elicited by ECM and soluble vasoagonists, may be blocked by integrin antagonists, possible inhibitors of hypoxia-induced pulmonary remodeling in the rat model. Each project will have a close collaboration with the Clinical Core which will (i) formulate testable clinical hypotheses based on insights from the laboratory studies, (ii) provide samples and data from patients with BPD and PPHN, and (iii) generate statistical analyses and study designs. Project 7, the Administrative Core, will orchestrate these interdisciplinary efforts, manage the distribution of funds and efforts and create a SCOR research community. Our integrated search approach to the critical problem of CLD of infancy will facilitate development of new methods for its prevention and therapy.
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