Estradiol 17-beta (E2) and progesterone (P) are the major hormonal regulators of epithelial proliferation, morphogenesis, cytodifferentiation and secretory activity in the vagina and uterus. E2 and P effects in these organs are mediated through estrogen receptors (ER) and progesterone receptors (PR), respectively. ER and PR are located in both epithelial and stromal cells of the uterus and vagina, but some evidence indicates that certain effects of these hormones on uterine and vaginal epithelium may be mediated indirectly through stromal ER and PR. In this proposal, we will utilize the estrogen receptor knockout (ERKO) mouse in conjunction with tissue separation/recombination techniques to produce uterine and vaginal tissue recombinants that express ER in both stroma and epithelium, in only the stroma or the epithelium, or in neither of these cells types. These tissue recombinants will then be grafted in vivo, and used to directly determine whether the effects of E2 on uterine epithelial secretory protein production, apoptosis and progesterone receptor up- regulation are mediated through ER in the epithelium or stroma. The role of EGF receptor signalling in stromal and epithelial tissue for mediating the effects of E2 will also be determined. Vaginal tissue recombinants prepared with control and ERKO tissue will be used to determine the role of epithelial ER in vaginal stratification, cornification and mucification. Similar experiments will be performed using tissue from progesterone receptor knockout (PRKO) mice to determine if the effects of P on vaginal mucification and E2-induced uterine epithelial proliferation are mediated through stromal or epithelial PR. This work will be of vital importance for understanding the basic mechanisms by which E2 and P normally control developmental events in vaginal and uterine epithelium. Additionally, this work is potentially important clinically for diseases such as endometriosis, which involves aberrant proliferation of uterine epithelium, and for female reproductive cancers, which are almost exclusively of epithelial origin, since E2 appears to act at least as a permissive agent in these diseases and P may antagonize the effects of E2.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Reproductive Biology Study Section (REB)
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Bellino, Francis
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University of Illinois Urbana-Champaign
Veterinary Sciences
Schools of Veterinary Medicine
United States
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