The Effect of Hyperoxia on Neonatal Respiratory Progenitor Cell Function

Project summary/abstract This application presents a five year research career development plan focused on the study of neonatal respiratory progenitor cell function in response to hyperoxic conditions. The candidate is currently an Assistant Professor in Pediatrics in the division of Pediatric Pulmonology at Columbia University Medical Center. The current proposal outlines a plan to build on the candidate’s prior research and clinical experience with lung disease by merging two fields of interest, each represented by her mentor and co-mentor #1: mechanisms of lung injury and repair, and early lung development and progenitor cell function. Under the guidance of Drs. Jeanine D’Armiento and Wellington Cardoso, both well-established researchers and experienced mentors in their respective fields, the candidate plans to develop interdisciplinary and translational skills that will enable her to transition towards independent health-oriented research in mechanisms of injury and repair in the premature respiratory system. As obstetric and neonatal care advances, children born at earlier gestational ages are surviving longer. Bronchopulmonary dysplasia (BPD), a chronic lung disease that affects roughly 35% of extremely prematurely born children in the United States, is the most common complication of prematurity, and will likely remain so without significant biomedical advances in its management. Children with BPD are often oxygen dependent for long periods of time, and as respiratory care is largely supportive at this point, some require tracheostomy and prolonged mechanical ventilation. The developing lung and its progenitor cells are remarkably plastic, and a better understanding of the mechanisms by which post-natal lung development occurs in the face of injurious agents such as oxygen and mechanical ventilation can inform future therapies to promote healthy and functional lung growth. This research proposal aims to address these questions by studying the differentiation capacity and transcriptional profile of neonatal respiratory progenitor cells after hyperoxic exposure. The candidate and her mentoring and advisory team hypothesize that secreted frizzled-related protein 1 (SFRP1), a member of the Wnt signaling pathway, is central to regenerative capacity. More specifically, the aims of this proposal are 1) To determine the effect of hyperoxia on neonatal airway basal cell differentiation and Wnt signal gene expression, and 2) To determine the role of Sfrp1 in type 2 alveolar epithelial cell signaling during epithelial regeneration in a mouse model of neonatal hyperoxic lung injury. Through these scientific aims and training plan, the candidate intends to generate further hypotheses that will inform the future management of infants and children with BPD.