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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG015500-01
Application #
2624055
Study Section
Reproductive Biology Study Section (REB)
Program Officer
Bellino, Francis
Project Start
1997-09-15
Project End
2001-08-31
Budget Start
1997-09-15
Budget End
1998-08-31
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Illinois Urbana-Champaign
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
Kurita, Takeshi; Mills, Alea A; Cunha, Gerald R (2004) Roles of p63 in the diethylstilbestrol-induced cervicovaginal adenosis. Development 131:1639-49
Cunha, Gerald R; Cooke, Paul S; Kurita, Takeshi (2004) Role of stromal-epithelial interactions in hormonal responses. Arch Histol Cytol 67:417-34
Sato, Tomomi; Wang, Guimin; Hardy, Matthew P et al. (2002) Role of systemic and local IGF-I in the effects of estrogen on growth and epithelial proliferation of mouse uterus. Endocrinology 143:2673-9
Kurita, T; Wang, Y Z; Donjacour, A A et al. (2001) Paracrine regulation of apoptosis by steroid hormones in the male and female reproductive system. Cell Death Differ 8:192-200
Cooke, P S; Heine, P A; Taylor, J A et al. (2001) The role of estrogen and estrogen receptor-alpha in male adipose tissue. Mol Cell Endocrinol 178:147-54
Kurita, T; Cooke, P S; Cunha, G R (2001) Epithelial-stromal tissue interaction in paramesonephric (Mullerian) epithelial differentiation. Dev Biol 240:194-211
Kurita, T; Lee, K; Saunders, P T et al. (2001) Regulation of progesterone receptors and decidualization in uterine stroma of the estrogen receptor-alpha knockout mouse. Biol Reprod 64:272-83
Buchanan, D L; Sato, T; Peterson, R E et al. (2000) Antiestrogenic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin in mouse uterus: critical role of the aryl hydrocarbon receptor in stromal tissue. Toxicol Sci 57:302-11
Zhai, P; Eurell, T E; Cotthaus, R et al. (2000) Effect of estrogen on global myocardial ischemia-reperfusion injury in female rats. Am J Physiol Heart Circ Physiol 279:H2766-75
Zhai, P; Eurell, T E; Cooke, P S et al. (2000) Myocardial ischemia-reperfusion injury in estrogen receptor-alpha knockout and wild-type mice. Am J Physiol Heart Circ Physiol 278:H1640-7

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