MECHANISM OF ESTROGEN ACTION IN UTERUS AND VAGINA

雌二醇17-β（E2）和孕酮（P）是主要的激素 上皮细胞增殖，形态发生， 阴道和子宫中的细胞分化和分泌活动。 这些器官中的E2和P效应通过雌激素介导 受体（ER）和孕激素受体（PR）。ER和 PR位于子宫的上皮细胞和基质细胞中， 阴道，但一些证据表明，这些的某些影响， 子宫和阴道上皮的激素可能是间接介导的 通过基质ER和PR。在本提案中，我们将利用 雌激素受体敲除（ERKO）小鼠结合组织 分离/重组技术， 在基质和上皮中表达ER的组织重组体， 仅在基质或上皮中，或在这两种细胞类型中均不存在。 然后将这些组织重组体移植到体内，并用于 直接确定E2对子宫上皮细胞的影响 分泌蛋白的产生、细胞凋亡和孕酮受体的上调- 调节通过上皮或基质中的ER介导。的 表皮生长因子受体信号在间质和上皮组织中的作用 还将确定介导E2的作用。阴道组织 用对照和ERKO组织制备的重组体将用于 确定上皮ER在阴道分层中的作用， 角化和粘液化。将进行类似的实验 使用来自孕酮受体敲除（PRKO）小鼠的组织， 确定P对阴道粘液化和E2诱导的 子宫上皮细胞增殖是通过间质或 这项工作将是至关重要的理解 E2和P正常控制发育的基本机制 阴道和子宫上皮中的事件。此外，这项工作是 对于子宫内膜异位症等疾病具有潜在的临床重要性， 其涉及子宫上皮的异常增殖，并且对于 女性生殖系统癌症，几乎完全是上皮性的 起源，因为E2似乎至少作为一个许可剂，在这些 P可拮抗E2的作用。

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.