A central question in perinatal biology is the relationship of substrate supply to overall fetal growth and the development of specialized functions such as surfactant synthesis in lung. We will define relationships between substrate availability and growth factor influences on the biochemical and morphologic maturation of lung and test the hypothesis that substrate supply has important maturational influences, possibly modulated through the interaction of growth factors with receptors on the cell surface. These studies will be focused initially on epidermal growth factor. Two experimental models will be utilized: the fetus of the diabetic rat in which maturation is delayed and those with IUGR exhibiting accelerated maturation. We will characterize EGF binding to cell surface receptors in diabetic and IUGR pregnancies. This will include investigations of the ontogeny of EGF binding in control in experimental fetuses and the effect of insulin reversal of the diabetic state on receptor number and affinity. Immunocytochemical studies will be performed to permit localization of EGF receptors to particular cell types. Changes in EGF binding in diabetic and IUGR pregnancies will be correlated with influences of EGF on biochemical and morphologic maturation of lung. This will include investigation of EGF influences on glycogen regulatory enzymes and 3H-choline incorporation. Fetal injection techniques will be employed to examine direct influences of EGF on lung metabolism and maturation. In vitro experiments will be carried out to determine the effects of graded concentrations of glucose on maturational events in lung including influence on EGF binding and on the EGF receptor. Characteristics of the EGF receptor independent of binding assays will also be investigated. This includes measurements of EGF receptor autophosphorylation in the different models and electrophoretic and protein transfer studies to define possible differences in the receptor itself. We will initiate studies to define possible changes in the amounts of specific RNA's for the EGF receptor in normal lung and in response to diabetes and IUGR. These studies will define mechanisms by which alterations in nutrient supply (diabetes and IUGR) interact with normal maturational events. New information will be provided concerning the role of EGF during lung development which will permit a broader understanding of fetal maturation and growth.
