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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory Grants (P20)
Project #
5P20GM103620-02
Application #
8725210
Study Section
Special Emphasis Panel (ZGM1)
Project Start
Project End
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Sanford Research/Usd
Department
Type
DUNS #
City
Sioux Falls
State
SD
Country
United States
Zip Code
57104
White, Katherine A; Swier, Vicki J; Cain, Jacob T et al. (2018) A porcine model of neurofibromatosis type 1 that mimics the human disease. JCI Insight 3:
Anderson, Ruthellen H; Lensing, Cody J; Forred, Benjamin J et al. (2018) Differentiating Antiproliferative and Chemopreventive Modes of Activity for Electron-Deficient Aryl Isothiocyanates against Human MCF-7 Cells. ChemMedChem 13:1695-1710
Johnson, Tyler B; Mechels, Keegan; Anderson, Ruth Ellen et al. (2018) Characterization of a recurrent missense mutation in the forkhead DNA-binding domain of FOXP1. Sci Rep 8:16161
Brudvig, J J; Cain, J T; Sears, R M et al. (2018) MARCKS regulates neuritogenesis and interacts with a CDC42 signaling network. Sci Rep 8:13278
Roux, Kyle J; Kim, Dae In; Burke, Brian et al. (2018) BioID: A Screen for Protein-Protein Interactions. Curr Protoc Protein Sci 91:19.23.1-19.23.15
Hussain, Sajjad; Bedekovics, Tibor; Liu, Qiuying et al. (2018) UCH-L1 bypasses mTOR to promote protein biosynthesis and is required for MYC-driven lymphomagenesis in mice. Blood 132:2564-2574
Brudvig, J J; Cain, J T; Schmidt-Grimminger, G G et al. (2018) MARCKS Is Necessary for Netrin-DCC Signaling and Corpus Callosum Formation. Mol Neurobiol 55:8388-8402
Anderson, Ruthellen H; Kerkvliet, Jason G; Otta, Jaelin J et al. (2018) Generation of a CLTA reporter human induced pluripotent stem cell line, CRMi001-A-1, using the CRISPR/Cas9 system to monitor endogenous clathrin trafficking. Stem Cell Res 33:95-99
Lucido, Christopher T; Callejas-Valera, Juan L; Colbert, Paul L et al. (2018) ?2-Adrenergic receptor modulates mitochondrial metabolism and disease progression in recurrent/metastatic HPV(+) HNSCC. Oncogenesis 7:81
McKenzie, Casey W; Preston, Claudia C; Finn, Rozzy et al. (2018) Strain-specific differences in brain gene expression in a hydrocephalic mouse model with motile cilia dysfunction. Sci Rep 8:13370

Showing the most recent 10 out of 59 publications