NEONATAL DES INDUCED UTERINE DYSPLASIA/NEOPLASIA

当仓鼠用合成雌激素治愈尿道时， 右己烯雌酚（UES），他们的子宫一致表现出严重的 对雌激素的增生/肿瘤反应。 两种 替代工作假说应该解释这种现象：1）直接 作用新生仓鼠的细胞生理学和/或组成 子宫被DES损伤直接和永久地改变， 成年生物体对雌激素的总体增殖反应变得不典型， 或2）间接作用子宫增重活性由雌激素介导 主要是通过或与其他未识别的因素一起， 新生儿DES治疗永久性改变了水平或功能活动 这些因素。 测试这些假设将开始（具体目标#1）， 监测对照组和DES愈合组新生儿子宫的形态发生 不要把动物移植到对侧的颊囊里， 对照和DES处理的卵巢切除和雌激素- 更换 为了证实和扩展研究结果（具体目标#2）， 对照组子宫间质和上皮异型重组 和DES处理的动物，并将其形态发生 研究：a）在体外使用补充有子宫组织提取物的培养基 和/或来自特定目标#1和B）中使用的相同宿主群的血清， 体内（在颊囊内），使用与特定目标中相同的宿主组 #1. 因为这种方法的组合依赖于很少的，如果有的话， 假设并适应体内和体外观察结果，公司 应该得出结论，哪个备选假设是最好的。 有效的. 最后（具体目标#3），我们将测试是否改变表达 已知的调节基因参与了非典型雌激素 经DES处理的仓鼠中成年子宫的反应性。 我们将 开始与c-myc c-tos和c-jun原癌基因加上p53抗 癌基因 它们的表达将在RVA和蛋白质水平上探测， 以及在整个器官和细胞特异性水平使用北方印迹 分析、原位杂交、免疫沉淀/Western印迹分析 和免疫组织 这些研究应有助于 我们的长期目标是：（1）了解基本的 雌激素调节子宫生长和形态发生的机制， 2)识别负责的机械改变 这一过程退化到不受调节的肿瘤状态。 这些 在生物医学上是重要的，因为1）成功的受孕和妊娠 需要正常的子宫形态和功能，2）雌激素依赖性 子宫肿瘤的发病率和死亡率 在当代美国社会。

When hamsters are healed neonatally with the synthetic estrogen, dethylstibestrol (UES), their uteri consistent exhibit a severe hyperplastic/neoplastic response to estrogen in adulthood. One of two alternatives 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 organism 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 healed donot animals that are transplanted into the contralateral cheek pouches of control and DES-treated mature hosts that are ovariectomized and 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 #1. Because this combination of approaches relies on few, if any, a prior assumptions and accommodates both in vivo and in vitro observations, firm conclusions should be reached about which alternative hypothesis is most valid. Lastly (Specific Aim #3), we will test whether altered expression of known regulatory genes is involved in the atypical estrogen responsiveness of adult uteri in neonatally DES treated hamsters. We will begin with the c-myc c-tos and c-jun proto-oncogenes plus the p53 anti- oncogene. Their expression will be probed at the RVA and protein level as well as at the whole-organ and cell specific level using Northern blot analysis, in situ hybridization, immunoprecipitation/Western blot analysis and immunohistochemistry. Together these studies should contribute significantly to our long-term objectives of 1) understanding the basic mechanisms whereby estrogen regulates uterine growth and morphogenesis and 2) identifying mechanistic alterations that are responsible for degeneration of this process to the unregulated neoplastic state. These are biomedically important because 1) successful conception and gestation demands normal uterine form and function, and 2) estrogen-dependent uterine neoplasms ar responsible for considerable morbidity and mortality in contemporary American society.