The transition from an in utero environment to life outside the womb is marked by a change from a relatively hypoxic environment (<3% oxygen) to a more oxidative atmospheric environment (21% oxygen). Lungs of prematurely born infants are underdeveloped with fewer alveoli and relatively lower expression of antioxidant enzymes. Consequently, premature infants are at a disadvantage in coping with this oxidative transition, even before therapeutic interventions such as supplemental oxygen (hyperoxia) and mechanical ventilation are considered. Bronchopulmonary dysplasia (BPD) is one possible result of sustained oxygen supplementation in premature infants, which is marked by alveolar simplification, pulmonary hypertension, and dysmorphic vascular growth. BPD adversely affects long-term lung function as evidenced by enhanced susceptibility to respiratory infection and development of an asthmatic-type syndrome. Thus, there is an urgent need to understand how oxygen tension regulates alveolar epithelial development and how environmental alterations result in newborn disease pathologies. Thiol modifications have been shown to play a major role in redox signaling pathways by regulating protein activity and are known to contribute to pulmonary disease pathologies. Thioredoxin-1 (Trxl) is a redox-sensitive protein containing a dithioldisulfide site responsible for oxidoreductase activity, making it a unique regulator of redox homeostasis since it can directly transcribe changes in oxygen tension (such as during birth or newborn oxidative injury) into developmental pathways by modifying thiol redox status. Therefore, we will test the hypothesis that newborn oxygen alters alveolar growth and development via Trx1. Goals of the proposed studies are to: 1) investigate redox proteomics of the nuclear compartment during hyperoxic injury;2) examine how Trx1 regulates alveolar development during neonatal hyperoxia;and, 3) identify Trx1-dependent redox-sensitive signaling pathways altered during hyperoxic treatment. By identifying cellular mechanisms underlying redoxdependent changes in pulmonary epithelial growth, we will develop innovate strategies designed to improve children's health.
By identifying redox-sensitive molecular networks during alveolar growth, these studies will enhance our understanding of redox switches during pulmonary development. These pathways could lead to the development of novel therapeutics for BPD and provide a cellular basis for treating other disease pathologies elicited by oxidative injury.
|Guo, Qiusha; Wang, Yinqiu; Tripathi, Piyush et al. (2015) Adam10 mediates the choice between principal cells and intercalated cells in the kidney. J Am Soc Nephrol 26:149-59|
|Kim, Dae In; Birendra, K C; Zhu, Wenhong et al. (2014) Probing nuclear pore complex architecture with proximity-dependent biotinylation. Proc Natl Acad Sci U S A 111:E2453-61|
|Haugrud, Allison B; Zhuang, Yongxian; Coppock, Joseph D et al. (2014) Dichloroacetate enhances apoptotic cell death via oxidative damage and attenuates lactate production in metformin-treated breast cancer cells. Breast Cancer Res Treat 147:539-50|
|Finn, R; Evans, C C; Lee, L (2014) Strain-dependent brain defects in mouse models of primary ciliary dyskinesia with mutations in Pcdp1 and Spef2. Neuroscience 277:552-67|
|Floen, Miranda J; Forred, Benjamin J; Bloom, Elliot J et al. (2014) Thioredoxin-1 redox signaling regulates cell survival in response to hyperoxia. Free Radic Biol Med 75:167-77|
|Surendran, Kameswaran; Vitiello, Seasson P; Pearce, David A (2013) Lysosome dysfunction in the pathogenesis of kidney diseases. Pediatr Nephrol :|