The long range objectives of this project are two-fold: (1) to elucidate the mechanisms by which estrogens control DNA replication and (2) to elucidate the mechanism(s) by which estrogens delay DNA replication in certain subsets of target cells. This proposal focuses on the relationships between estrogens, polypeptide growth factors such as epidermal growth factor (EGF), and uterine hypertrophy/hyperplasia.
The specific aims are: (1) To determine if receptors for EGF and other growth factors are present in uterine membranes and to analyze their properties; (2) To determine if estrogens regulate receptor and/or growth factor levels; (3) To determine if estrogen induced increases in growth factors/receptors play a cause-effect role in regulating cellular hypertrophy and hyperplasia; (4) To determine if hypothyroidism prevents a normal uterine response to estradiol by decreasing basal and/or estrogen stimulated increases in growth factors/receptors; (5) To determine in the uterine luminal epithelium (LE) the precise pharmacokinetic relationships between the prolonged presence of estrogen-receptor complexes and the delay and subsequent initiation of DNA synthesis, the number of cells in the growth fraction, and cell death; (6) To determine in the LE the molecular basis by which the prolonged presence of estrogen-receptor complexes causes the delay or """"""""inhibition"""""""" in the onset of DNA synthesis; and (7) To determine in the LE if cellular events associated with the """"""""inhibitory"""""""" effect of estrogens prevent increases in growth factors/receptors and/or oppose cellular responses to growth factors. The methods to achieve these goals include: (1) biochemical/immunological measurement and analysis of EGF receptors; (2) hybridizations to measure the levels of EGF receptor messenger RNA; and (3) measurements of mitotic indices, labelling indices, DNA synthesis and DNA polymerase activity to assess uterine hypertrophy and hyperplasia. The studies are related to the normal and pathological growth and development of the female reproductive tract, and to potential side effects associated with the pharmacological use of estrogens. Since these studies deal with basic mechanisms by which cells respond to estrogens, they may be potentially related to the general mechanisms by which estrogens affect growth and development in all tissues (e.g., pituitary and breast) under normal and pathological conditions.
