The role of IL-33 in hyperoxia-induced neonatal lung injury and bronchopulmonary dysplasia

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PROJECT SUMMARY/ABSTRACT Summary of Proposal This is resubmission for an NIH Mentored Clinical Scientist Career Development Award for Laurie Eldredge, M.D., Ph.D., an Assistant Professor at the University of Washington and Seattle Children’s Hospital. Dr. Eldredge is establishing herself as in investigator in basic and translational research focused on the innate immune response in neonatal lung injury. This proposal builds upon her background in basic science including developmental immunology and her growing experience in translational research. The focus of this proposal is to investigate the role for the cytokine IL-33 in bronchopulmonary dysplasia (BPD). Dr. Eldredge has assembled a team of mentors for this critical period of career development, comprised of the following experts: Steven F. Ziegler, Ph.D. (co-mentor, basic scientist in immunological mechanisms of disease states), Jason S. Debley, M.D., M.P.H. (co-mentor, pediatric pulmonologist and translational researcher in asthma), Charles W. Frevert, D.V.M., ScD (advisory committee, veterinary pathologist and basic scientist in lung injury), Sandra E. Juul, M.D., Ph.D. (co-mentor, neonatologist and translational researcher in neonatal brain injury), Bonnie W. Ramsey, M.D. (advisory committee, pediatric pulmonologist and clinical/ translational researcher in Cystic Fibrosis), and Y.S. Prakash, M.D., Ph.D. (BPD translational research expert and external mentor). This multidisciplinary team is based at Benaroya Research Institute, Seattle Children’s Hospital and Research Institute, the University of Washington, and Mayo Clinic. Research Plan: This project proposes to investigate a novel role for the cytokine IL-33 in neonatal lung injury. Dr. Eldredge will use a unique combination of hyperoxia to model evolving BPD in mice and airway samples from human BPD patients to complete the following specific aims: Aim 1. Determine the rolesof monocyte/macrophage and epithelial cell specific IL-33 signaling in HILI. Aim 2. Determine whether monocyte and/or epithelial cell-derived IL-33 signaling contributes to BPD pathogenesis. These studies will yield important information about IL-33/ST2 signaling as a novel inflammatory pathway in BPD. Results will determine how IL-33 signaling and crosstalk in monocytes/macrophages and epithelial cells affect the neonatal immune response to hyperoxia-induced lung injury. These studies will also determine if IL- 33, its receptor ST2, or the downstream growth factor amphiregulin may be important BPD biomarkers, and whether modulation of IL-33 signaling may be a future therapy for these fragile infants. This translational research will form the basis for an NIH R01 application and a successful transition to scientific independence by the end of the five-year K08 award.