The ultimate objective of this proposal is to understand how estrogen regulates mucus glycoprotein biosynthesis in different endocervical cell populations. This understanding is critical to fertility/infertility regulation in the endocervix. Specifically what is desired is an understanding of estrogen regulation of two rate-limiting enzymes, namely, N-acetylgalactosaminyl:polypeptide transferase, the enzyme responsible for the initiation of mucin-type O-glycosylation or new chain synthesis; and N-acetyl glucosaminyltransferase, an enzyme involved in the elongation of mucin-type oligosaccharides. This goal will be achieved by measuring enzyme activities, under optimal conditions in the endocervical epitherlial-stromal complex of adult, neonatal and diethylstilbestrol-treated animals. The principal focus will be on determining if the activity of one or both of these enzymes is estrogen-dependent and/or progesterone-antagonized. The three-step approach will include: 1) the measurement of potential differences in enzyme activities in ultrastructurally distinct epithelial cell populations isolated by unit gravity sedimentation. Hormone dependent changes in the activity of one or both of these enzymes will be measured in different endocervical epithelial cell populations, from animals in contrasting hormonal states, i.e., estrogen-dominated (estrous), progesterone-dominated (5-day pseudopregnant) and ovariectomized, steroid treated. 2) Using neonatal animals it will be possible to determine if the acquisition of estrogen receptor by individual epithelial cells precedes the onset of glycoprotein biosynthesis. Potential changes in N-acetylgalactosaminyl:polypeptide transferase or N-acetylglucosaminyltransferase activities will be used as markers for estrogen action during postnatal differentiation of specific glycoprotein-synthesizing endocervical epithelial cell populations. 3) In an attempt to broaden the perspective, the early teratogenic effect of diethylstilbestrol on the cellular composition of the endocervical epithelium will be compared with its effect on N-aceytlgalactosaminyl:polypeptide transferase and or N-acetylglucosaminyltransferase activities.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Modified Research Career Development Award (K04)
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Reproductive Endocrinology Study Section (REN)
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Texas Tech University
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Hayward-Lester, A; Hewetson, A; Beale, E G et al. (1996) Cloning, characterization, and steroid-dependent posttranscriptional processing of RUSH-1 alpha and beta, two uteroglobin promoter-binding proteins. Mol Endocrinol 10:1335-49
Kleis-SanFrancisco, S; Hewetson, A; Chilton, B S (1993) Prolactin augments progesterone-dependent uteroglobin gene expression by modulating promoter-binding proteins. Mol Endocrinol 7:214-23
Chilton, B S; Deeb, E A; Dalley, B K (1991) Progesterone regulates epidermal growth factor receptor on mucous secreting cells in the rabbit endocervix. Endocrinology 129:2094-100
Randall, G W; Daniel Jr, J C; Chilton, B S (1991) Prolactin enhances uteroglobin gene expression by uteri of immature rabbits. J Reprod Fertil 91:249-57
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Chilton, B S; Kaplan, H A; Lennarz, W J (1988) Estrogen regulation of the central enzymes involved in O- and N-linked glycoprotein assembly in the developing and the adult rabbit endocervix. Endocrinology 123:1237-44
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Chilton, B S; Williams, N D; Cobb, A D et al. (1987) Ligand-receptor dissociation: a potential mechanism for the attenuation of estrogen action in the juvenile rabbit uterus. Endocrinology 120:750-7
Chilton, B S; Daniel Jr, J C (1987) Differences in the rabbit uterine response to progesterone as influenced by growth hormone or prolactin. J Reprod Fertil 79:581-7