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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Clinical Investigator Award (CIA) (K08)
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Special Emphasis Panel (ZHL1-CSR-U (F1))
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Colombini-Hatch, Sandra
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Nationwide Children's Hospital
United States
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Velten, Markus; Britt Jr, Rodney D; Heyob, Kathryn M et al. (2014) Maternal dietary docosahexaenoic acid supplementation attenuates fetal growth restriction and enhances pulmonary function in a newborn mouse model of perinatal inflammation. J Nutr 144:258-66
Britt Jr, Rodney D; Velten, Markus; Locy, Morgan L et al. (2014) The thioredoxin reductase-1 inhibitor aurothioglucose attenuates lung injury and improves survival in a murine model of acute respiratory distress syndrome. Antioxid Redox Signal 20:2681-91
Tipple, Trent E (2014) The thioredoxin system in neonatal lung disease. Antioxid Redox Signal 21:1916-25
Britt Jr, Rodney D; Velten, Markus; Tipple, Trent E et al. (2013) Cyclooxygenase-2 in newborn hyperoxic lung injury. Free Radic Biol Med 61:502-11
Raffay, Thomas M; Locy, Morgan L; Hill, Cynthia L et al. (2013) Neonatal hyperoxic exposure persistently alters lung secretoglobins and annexin A1. Biomed Res Int 2013:408485
Chen, Bernadette; Nelin, Viktoria E; Locy, Morgan L et al. (2013) Thioredoxin-1 mediates hypoxia-induced pulmonary artery smooth muscle cell proliferation. Am J Physiol Lung Cell Mol Physiol 305:L389-95
Britt Jr, Rodney D; Locy, Morgan L; Tipple, Trent E et al. (2012) Lipopolysaccharide-induced cyclooxygenase-2 expression in mouse transformed Clara cells. Cell Physiol Biochem 29:213-22
Heyob, Kathryn M; Rogers, Lynette K; Tipple, Trent E et al. (2011) Riboflavin supplementation does not attenuate hyperoxic lung injury in transgenic (spc-mt)hGR mice. Exp Lung Res 37:155-61
Rogers, Lynette K; Valentine, Christina J; Pennell, Michael et al. (2011) Maternal docosahexaenoic acid supplementation decreases lung inflammation in hyperoxia-exposed newborn mice. J Nutr 141:214-22
Rogers, Lynette K; Tipple, Trent E; Britt, Rodney D et al. (2010) Hyperoxia exposure alters hepatic eicosanoid metabolism in newborn mice. Pediatr Res 67:144-9