This proposal describes a 3 year training program for the development of an independent academic career in Neonatology. Dr. Trent E. Tipple has completed structured fellowship training in Neonatal-Perinatal medicine and is currently a full time faculty member of the Center for Perinatal Research and the Section of Neonatology at Nationwide Children's Hospital. His interest in lung development began during pediatric residency when he appreciated the association between bronchopulmonary dysplasia (BPD), a chronic lung disease of prematurity, and pulmonary oxygen toxicity. During fellowship, Dr. Tipple's investigations focused on the role of thioredoxin-dependent mechanisms in defense against hyperoxic lung injury in mice. His immediate goal is to learn theories and applications of molecular and cellular biology that may be applied to investigations of the thioredoxin system. His long-term goal is to integrate whole animal, molecular, and cell culture techniques to develop focused independent investigations of the role of the thioredoxin system in lung development. Newborn mice exposed to hyperoxia (FiO2=0.85) exhibit alterations in lung development similar to human infants with BPD. This proposal tests the hypothesis that hyperoxia inhibits the age-related developmental decrease in pulmonary thioredoxin interacting protein (Txnip) expression through MAPK activation and that sustained Txnip expression directly contributes to altered lung development and lung growth arrest seen in the newborn mouse model of BPD. In this proposal, Dr. Tipple will test the hypotheses that 1) p38 MAPK activation is required for hyperoxia-induced Txnip expression and that 2) postnatal type II cell-specific genetic Txnip deletion will improve lung growth in the newborn mouse model of BPD. This work will be conducted under the primary mentorship of Dr. Yusen Liu, a recognized expert in MAPK signaling, and co-mentors with expertise in different aspects of pulmonary biology. The Research Institute at Nationwide Children's Hospital provides an ideal setting in which to conduct the proposed research program. Guidance from his advisory committee coupled with coursework and technical training in molecular and cellular techniques will enable Dr. Tipple to advance his ability to conduct studies of lung development that will form the foundation for the development of interventions that prevent BPD.
Bronchopulmonary dysplasia (BPD) is a chronic lung disease of premature infants that results in injured and underdeveloped lungs. The causes of BPD are not well understood. The studies described in this grant proposal investigate the contribution of thioredoxin interacting protein to abnormal lung development seen in a mouse model that mimics BPD.
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