Infants with congenital diaphragmatic hernia (CDH) die from inadequate lung function, which is a combination of 1) pulmonary hypertension of the newborn. The pulmonary hypoplasia is characterized by immature, small lungs. We have demonstrated the efficacy of prenatal glucocorticoid therapy in accelerating pulmonary maturation in CDH lung in fetal rats and sheep. We have further shown that prenatally administered antioxidants , particularly vitamin E, accelerate prenatal growth of CDH-associated hypoplastic lungs in vitro and in vivo. We have demonstrated significant differences in the levels of mitogen- activated protein (MAP) kinase phosphorylation (extracellular signal regulated protein kinases, ERK-1 and -2) between CDH and normal fetal lungs, and have shown increased phosphorylation towards that observed normally, in CDH lungs after treatment with vitamin E in vivo. We hypothesize that important regulators and pathways of normal and hypoplastic fetal lung growth converge on the mitogen-activated protein (MAP) kinase pathways. We further hypothesize that antioxidants stimulate hypoplastic fetal lung growth via the MAP kinase cascade, and, in particular, via up-regulation of the MAP kinase kinases (MEK +) and Raf-1. We propose to define the molecular mechanism(s) in the rodent responsible for the salutary effects of the anti-oxidants and define the modulators of signal transduction pathways responsible for CDH- associated pulmonary hypoplasia. We will reestablish that the observed stimulation of embryonic lung growth by antioxidants occurs via a reductant mechanism and determine where antioxidants impact the MAP kinase pathways. We will establish the role of other candidate genes and pathways in fetal lung hypoplasia, define whether differences exist in gene expression patterns in the various rodent CDH models, and study in the rodent model worthy candidate genes identified in Projects I, II, and IV. We hope that these studies will provide new insights into the mechanisms of prenatal lung growth control. These, in turn, can provide a platform for the future development of prenatal targeted therapies.
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