Regulation of perinatal lung gene expression by oxygen

Boston University Medical Campus, Boston MA

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Abstract

DESCRIPTION (provided by applicant): The P02 of amniotic fluid is about 26 mm Hg at late term. At birth, the lung fills with ambient air which has a P02 of about 150mmHg. This sudden change in the oxygen environment of the lung results in a transiently altered redox state that is particularly intense in lung epithelial cells. We propose that this altered redox state, in part buffered by induction of antioxidant defenses during late fetal life, is also a "physiologic" stimulus for induction of additional antioxidant genes and genes associated with postnatal development of the lung. Using a suppression subtractive hybridization screen of fetal and newborn lung, we found 65 clones that represent genes potentially associated with events related to postnatal lung development. Our hypothesis is also supported by recent observations and by our own preliminary data in normal mice and in a mouse model of impaired glutathione metabolism we have developed. The GGT enu1 mouse displays altered expression of a number of genes that we propose are induced by redox stress related to impaired glutathione metabolism. Our preliminary data identifies a subset of these genes and of genes induced at birth that share a common redox-sensitive regulatory site in their promoters. We propose to study perinatal lung and epithelial cell redox state as well as lung and epithelial cell gene expression in the GGT enu1 mouse with decreased glutathione availability, and a glutathione peroxidase over-expressing mouse with excess glutathione availability. We will use reverse engineering techniques to identify lung and epithelial cell genes that are coordinately linked to redox state and use bioinformatic algorithms to identify potential shared regulatory elements in those genes. The function of these elements will be tested with in vitro DNA gel shift and footprint assays. The reversible nature of redox state and of gene expression and the link to identified regulatory regions will be determined in our mouse models.