This project is designed to elucidate the mechanisms regulating normal fetal growth. Ten percent of human pregnancies result in growth-retarded infants, who have increased morbidity, mortality and congenital anomalies. Usually, the cause cannot be identified and no consensus exists as to which hormones might play critical roles. A unique fetal somatomedin (SM) is one possibility. Our primary objective is to continue to test the hypothesis that fetal SM is controlled by hormones other than growth hormone. While we have found two likely candidates, glucocorticoids and epidermal growth factor (EGF), we have decided to focus our studies on the latter. Others have implicated a fetal form of EGF in both the developmental and neoplastic processes. We are the first to suggest it as a regulator of SM secretion.
Our specific aims are: 1) Do the hormones which regulate SM change with gestational age? 2) What is the role of SM carrier proteins in fetal growth? 3) What is the relationship between SM and EGF in regulating fetal growth? Rat hepatocytes will be isolated from fetuses of different gestational ages and incubated in culture with various hormones, particularly EGF and dexamethasone. Mitogenic activity of conditioned medium will be assayed by the incorporation of 3H-thymidine into DNA. Total SM levels will be monitored by a competitive protein binding assay which does not discriminate between the various SM's. To characterize the fetal SM secretion, its levels will be assessed by the more specific rat IGF-II (MSA) and IGF-I (SM-C) radioimmunoassays. The relationship between SM secretion and hormonal binding to fetal hepatocytes will then be studied. SM carrier proteins also appear to modulate SM action. We will study their hormonal regulation and biochemical properties, the relationship between their levels in serum and fetal size, and their effect on mitogenic activity of SM. Lastly, the relationship between EGF and SM in regulating fetal growth will be evaluated. EGF levels will be measured by bioassay, radioreceptor assay, and radioimmunoassay in fetal serum and correlated with SM levels and fetal size. Fetal EGF will be extracted from fetal rats and its effect on SM secretion compared to that of adult EGF. The information learned should provide a scientific basis from which clinical methods can be devised to decrease fetal growth retardation.
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| Stred, S E; Benedict, M R; Kuehnling, E et al. (1987) Effect of growth hormone on growth and glucose tolerance of normal rats. Am J Dis Child 141:502-5 |
| Richman, R A; Benedict, M R; Florini, J R et al. (1985) Hormonal regulation of somatomedin secretion by fetal rat hepatocytes in primary culture. Endocrinology 116:180-8 |
| Ames, I H; Richman, R A; Gordon, G B et al. (1985) The influence of epidermal growth factor on surface morphology of fetal rat hepatocytes in primary culture. Scan Electron Microsc :1143-50 |
