ESTROGEN-INDUCED NORMAL AND DYSPLASTIC UTERINE GROWTH

雌激素引起的正常和不典型子宫生长

• 批准号: 3426707
• 负责人: WILLIAM J HENDRY
• 金额: $ 4.97万
• 依托单位: WICHITA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-05-01 至 1993-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3426707
• 关键词: cell type; cheek pouch technique; diethylstilbestrol; epithelium; estrogens; gene expression; hamsters; histogenesis; histology; homologous transplantation; hormone regulation /control mechanism; hormone related neoplasm /cancer; hormone therapy; hyperplasia; implant; messenger RNA; neoplastic transformation; newborn animals; northern blottings; ovariectomy; protooncogene; reproductive tissue transplantation; stromal cells; tissue /cell culture; uterus; uterus preneoplastic state

When hamsters are treated neonatally with the synthetic estrogen, diethylstilbestrol (DES), their uteri consistently exhibit a severe hyperplastic/neoplastic response to estrogen in adulthood. One of two alternative working hypotheses should explain this phenomenon: 1) Direct Action - The cellular physiology and/or composition of the neonatal hamster uterus is directly and permanently altered by the DES insult such that the adult organ's overall proliferative response to estrogen becomes atypical, or 2) Indirect Action - Uterotrophic activity is mediated by estrogen primarily through or in conjunction with other unidentified factors, and neonatal DES treatment permanently alters the level or functional activity of such factors. Testing these hypotheses will begin (Specific Aim # 1) by monitoring the morphogenesis of neonatal uteri from control and DES-treated donor animals that are transplanted into the contralateral cheek pouches of control and DES-treated mature hosts that are either left intact, estrogen-deprived or estrogen-replaced. To confirm and extend the findings (Specific Aim #2), homotypic and heterotypic recombination of uterine stroma and epithelium from control and DES-treated animals will be performed and their morphogenesis will be studied: a) in vitro using media supplemented with uterine tissue extracts and/or serum from the same host groups used in Specific Aim # 1 and b) in vivo (within the cheek pouch, using the same host groups as in Specific Aim #l. Lastly (Specific Aim #3), Northern blot analysis will be used to consider the possibility that altered expression of two proto-oncogenes (c-myc and c-fos) may be involved in the atypical estrogen responsiveness of uteri in neonatally DES-exposed hamsters. Because this combination of approaches relies on few, if any, a priori assumptions and accommodates both in vivo and in vitro observations, firm conclusions should be reached about which alternative hypothesis is most valid. Such information should contribute significantly to the long-term objective of understanding how estrogen regulates uterine growth and morphogenesis. This objective is biomedically important because: 1) successful conception and gestation demands normal uterine form and function, and 2) estrogen-dependent uterine neoplasms are responsible for considerable morbidity and mortality in contemporary American society.

当仓鼠在新生儿期接受合成雌激素治疗时， 己烯雌酚（DES），她们的子宫始终表现出严重的 成年期对雌激素的增生/肿瘤反应。 两个之一 替代工作假设应该可以解释这种现象：1）直接 行动 - 新生儿的细胞生理学和/或组成 仓鼠子宫被 DES 侮辱直接且永久地改变，例如 成人器官对雌激素的整体增殖反应变成 非典型，或 2) 间接作用 - 子宫营养活性由以下因素介导 雌激素主要通过或与其他不明物质结合 因素，新生儿 DES 治疗永久改变水平或 此类因素的功能活动。 测试这些假设将开始 （具体目标#1）通过监测新生儿子宫的形态发生 对照和 DES 处理的供体动物被移植到 对照和 DES 处理的成熟宿主的对侧颊囊 要么保持完整，要么缺乏雌激素，要么被雌激素替代。 到 确认并扩展研究结果（具体目标#2）、同型和 对照子宫间质和上皮的异型重组 将进行 DES 处理的动物，并对其形态发生进行研究 研究：a) 在体外使用补充有子宫组织的培养基 来自特定目标#1中使用的相同宿主组的提取物和/或血清 b) 体内（在颊囊内，使用与中相同的宿主基团） 具体目标#l。 最后（具体目标 #3），Northern blot 分析将 用于考虑改变两个表达的可能性 原癌基因（c-myc 和 c-fos）可能与非典型癌有关 新生 DES 暴露仓鼠子宫的雌激素反应性。 因为这种方法的组合很少依赖于先验（如果有的话） 假设并适应体内和体外观察，坚定 应就哪种替代假设最有效得出结论 有效的。 这些信息应该对长期的发展有重大贡献。 目的是了解雌激素如何调节子宫生长和 形态发生。 这个目标在生物医学上很重要，因为：1) 成功的受孕和妊娠需要正常的子宫形态 功能，2) 雌激素依赖性子宫肿瘤负责 当代美国社会的发病率和死亡率相当高。