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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD024959-03
Application #
3325867
Study Section
Special Emphasis Panel (SRC (02))
Project Start
1989-01-01
Project End
1993-12-31
Budget Start
1991-01-01
Budget End
1991-12-31
Support Year
3
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of California Davis
Department
Type
Schools of Medicine
DUNS #
094878337
City
Davis
State
CA
Country
United States
Zip Code
95618
Coulter, C L; Read, L C; Barry, S J et al. (2001) Role of hypothalamic-pituitary axis in EGF action on maturation of adrenal gland in fetal rhesus monkey in vivo. Pediatr Res 50:210-6
Clyman, R I; Goetzman, B W; Chen, Y Q et al. (1996) Changes in endothelial cell and smooth muscle cell integrin expression during closure of the ductus arteriosus: an immunohistochemical comparison of the fetal, preterm newborn, and full-term newborn rhesus monkey ductus. Pediatr Res 40:198-208
Coulter, C L; Read, L C; Carr, B R et al. (1996) A role for epidermal growth factor in the morphological and functional maturation of the adrenal gland in the fetal rhesus monkey in vivo. J Clin Endocrinol Metab 81:1254-60
Edwards, L A; Read, L C; Nishio, S J et al. (1995) Comparison of the distinct effects of epidermal growth factor and betamethasone on the morphogenesis of the gas exchange region and differentiation of alveolar type II cells in lungs of fetal rhesus monkeys. J Pharmacol Exp Ther 274:1025-32
Goetzman, B W; Read, L C; Plopper, C G et al. (1994) Prenatal exposure to epidermal growth factor attenuates respiratory distress syndrome in rhesus infants. Pediatr Res 35:30-6
Ten Have-Opbroek, A A; Plopper, C G (1992) Morphogenetic and functional activity of type II cells in early fetal rhesus monkey lungs. A comparison between primates and rodents. Anat Rec 234:93-104
St George, J A; Read, L C; Cranz, D L et al. (1991) Effect of epidermal growth factor on the fetal development of the tracheobronchial secretory apparatus in rhesus monkey. Am J Respir Cell Mol Biol 4:95-101