Hyaline Membrane Disease (HMD) remains the leading cause of neonatal morbidity and mortality in the premature infant, despite recent therapeutic advances. A better understanding of the molecular mechanisms controlling lung maturation is critical for developing improved strategies to prevent and treat HMD. The main objective of this work is to define the cellular and molecular mechanisms controlling fetal lung differentiation as the lung prepares for surfactant synthesis. Previous work shows that epidermal growth factor (EGF) stimulates the development of cell-cell communications controlling lung maturation; and that androgen inhibits the development of those cell-cell communications. In this proposal it is hypothesized that the interaction of EGF with its receptor (EGF-R) is an important regulatory mechanism in fetal lung differentiation, and that androgen delays the development of this important regulatory mechanism. This hypothesis will be tested by addressing 3 Specific Aims. SA 1: Test the hypothesis that the EGF-R is developmentally regulated, consistent with a role in regulating the fibroblast-type II cell communications controlling fetal lung maturation. SA 2: Test the hypothesis that activation of the EGF-R by EGF regulates fibroblast-type II cell communications in fetal lung maturation. SA 3: Test the hypothesis that the mechanism by which androgen delays fibroblast-type II cell communication controlling lung maturation involves delaying the development of the EGF-R. The development of cell- specific (type II cell, fibroblast) EGF binding, EGF-R levels and EGF-R mRNA will be studied during fetal development, using receptor binding, immunoprecipitation, and Northern blot analysis. Cells deficient in EGF- R's will be replenished with intact, active EGF-R's, and the ability to influence cell-cell communications with EGF will be studied. EGF-R phosphorylation will be interrupted to learn about the importance of phosphorylation in control of lung maturation. The regulation of EGF-R development by hormones (androgen, glucocorticoids) and growth factors (EGF, TGFbeta) will be studied. These studies will further clarify the controls of fetal lung differentiation, and show how positive and negative regulatory controls become integrated to allow the normal progression of development. This will help develop better strategies for prevention of HMD, and will contribute to an improved understanding of control of fetal development.
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