MECHANISMS OF EGF ACTION IN THE FETUS AND NEONATE

假设：表皮生长因子（EGF）刺激生长

Hypothesis: Epidermal Growth Factor (EGF) stimulates the growth and maturation of crucial fetal and infant tissues, actions that could lead to new modes of therapeutic intervention to improve the growth and development of premature human infants. Long-term Aims: To define the effects and mechanism of action of EGF on tissue growth and maturation in fetal and infant Rhesus monkeys, with particular emphasis on gut and lung development, and to explore the use of EGF for treatment of premature infants. Specific Aims: 1. To elucidate mechanisms of action of EGF in fetal monkeys and to differentiate the responses to amniotic fluid (oral) and systemic (parenteral) administration of EGF in fetal Rhesus monkeys. 2. To define the role of the adrenal axis in the mechanism of action of EGF in fetal monkeys; from the data of the preliminary studies, we postulate that changes in circulating adrenal hormones may mediate some of the responses to EGF, particularly in lung. 3. To determine if the prenatal developmental and growth responses to EGF confer any postnatal growth advantage in prematurely delivered Rhesus monkeys and to examine the importance of EGF in the transition between fetal and postnatal life; we postulate that EGF may have therapeutic applications to improve infant growth and development, particularly in the preterm infant. Methods: EGF will be given to fetal Rhesus monkeys via amniotic fluid (oral and respiratory route) or intraperitoneal (systemic) administration to determine which route is more effective. Some fetuses will receive an adrenal enzyme blocking agent to determine the role of the fetal adrenal gland, in particular the definitive zone, in the lung and gut maturation already demonstrated. All fetuses will be delivered by cesarean section at 78% of gestation; some will be used for tissue collection while other infants will be supported in a pri- mate neonatal intensive care unit to determine whether EGF confers a survival advantage to the premature monkeys. Lastly, a group of premature infants will be given only postnatal EGF to assets the effectiveness of EGF after birth. The physiologic and biochemical function of the lung, gut and adrenal gland will be studied, as will their histology. EGF and TGF-alpha mRNA will be studied in all animals to determine the control of gene expression in the primate.