MECHANISM OF ESTROGEN ACTION IN UTERUS AND VAGINA

雌激素在子宫和阴道中的作用机制

• 批准号: 2624055
• 负责人: Paul S. Cooke
• 金额: $ 15.53万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-15 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2624055
• 关键词: epithelium; estrogen receptors; estrogens; genetically modified animals; hormone regulation /control mechanism; laboratory mouse; progesterone; progesterone receptors; stromal cells; transfection; uterus; vagina

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.

雌二醇 17-β (E2) 和孕酮 (P) 是主要的激素 上皮增殖、形态发生的调节因子， 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 效应是通过雌激素介导的 分别是受体（ER）和孕激素受体（PR）。急诊室和 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 子宫和阴道上皮上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) 小鼠与组织结合 生产子宫和阴道的分离/重组技术 在基质和上皮细胞中表达 ER 的组织重组体 仅存在于间质或上皮细胞中，或不存在于这两种细胞类型中。 然后这些组织重组体将被移植到体内，并用于 直接判断E2对子宫上皮细胞是否有影响 分泌蛋白的产生、细胞凋亡和孕激素受体上调 调节是通过上皮或间质中的 ER 介导的。这 EGF受体信号传导在基质和上皮组织中的作用 E2 的调节作用也将被确定。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， 角化和粘化。将进行类似的实验 使用孕激素受体敲除 (PRKO) 小鼠的组织 确定 P 对阴道粘液化和 E2 诱导的影响是否 子宫上皮增殖是通过基质或 上皮PR。这项工作对于理解 E2和P正常控制发育的基本机制 阴道和子宫上皮的事件。另外，这项工作是 对于子宫内膜异位症等疾病具有潜在的重要临床意义， 这涉及子宫上皮的异常增殖，并且 女性生殖系统癌症，几乎全部是上皮性癌症 起源，因为 E2 似乎至少在这些方面充当了许可代理人 疾病和 P 可能会拮抗 E2 的作用。