DEVELOPMENTAL ESTROGENIZATION OF THE RAT PROSTATE

大鼠生命早期短暂接触雌激素(发育期 雌激素化)会导致前列腺癌和 与增生性、不典型增生和 随着年龄的增长而发生腺癌。因此，我们假设 在发育关键期早期接触雌激素可能是一种 前列腺增生症和/或前列腺癌的易感因素。长期的 这项研究的目的是阐明细胞和 新生儿雌激素最初印记或影响的分子机制 改变前列腺体。初步数据显示，早些时候 雌激素暴露中断了分支形态发生的过程，并 阻止某些前列腺上皮细胞进入正常 分化途径。雌激素作用的目标似乎是 导管周围的平滑肌细胞表明雌激素的作用是 通过旁分泌因子进行调节。这项建议的重点是进一步 鉴定参与分化的转录因子， 即雄激素受体和维甲酸受体，并定义 调节雌激素效应的旁分泌信号机制。这个 具体目的有1)确定致病的分子机制(S 新生儿期前列腺细胞AR蛋白表达降低 雌激素暴露的半衰期研究，多聚体分布 分析和RNA电泳迁移率改变分析，2)确定 转化生长因子β1和胰岛素样生长因子在新生儿雌激素作用中的作用 前列腺癌形态发生与上皮分化的研究 免疫细胞化学，Western和Northern分析，RT-PCR，核运行- 在检测和体外培养技术上，3)确定 新生儿细胞外基质成分的雌激素化 或前列腺组织中细胞外基质成分的细胞受体使用 免疫细胞化学、原位杂交、RT-PCR、生化分析、 差异显示和器官培养，以及4)确定 新生儿雌激素暴露对维甲酸及其受体水平的影响 应用RT-PCR、免疫细胞化学、原位杂交技术 杂交、生化分析和器官培养技术。这些 研究与正常和病理的发展有关。 前列腺癌。研究结果将进一步明确雌激素的作用机制 在早期发育过程中对前列腺采取行动，并导致更好的 对异常的激素和发育基础的认识 前列腺发育随年龄增长，尤其是在前列腺的形成过程中 腺癌。

Brief exposure of rats to estrogens early in life (developmental estrogenization) leads to permanent alterations in the prostate gland and is associated with an increased incidence of hyperplasia, dysplasia and adenocarcinoma with aging. Accordingly, it has been hypothesized that early estrogen exposure during developmental critical periods may be a predisposing factor for BPH and/or prostatic carcinoma. The long-term objectives of this investigation are to elucidate the cellular and molecular mechanisms by which neonatal estrogen initially imprint or transform the prostate gland. Preliminary data indicate that early estrogen exposure interrupts the process of branching morphogenesis and blocks certain prostatic epithelial cells from entering a normal differentiation pathway. The target for estrogen's effects appear to be the periductal smooth muscle cells indicating that estrogen's effects are mediated through paracrine factors. This proposal focuses on further characterizing the transcription factors involved in differentiation, namely androgen receptor and retinoic acid receptors, and defining the paracrine signaling mechanisms which mediate estrogen's effects. The Specific Aims are 1) Determine the molecular mechanism(s) which cause reduction of AR protein expression in prostatic cells following neonatal exposure to estrogen using half-life studies, polysome distribution analysis and RNA electrophoretic mobility shift assays, 2) Determine the role of TGFbeta1 and KGF in mediating the effects of neonatal estrogen on prostatic morphogenesis and epithelial differentiation using immunocytochemistry, Western and Northern analysis, RT-PCR, nuclear run- on assays and in vitro culture techniques, 3) Determine the effect of neonatal estrogenization on components of the extracellular matrix (ECM) or cell receptors for ECM components in prostatic tissue using immunocytochemistry, in-situ hybridization, RT-PCR, biochemical assays, differential display and organ culture, and 4) Determine the effect of neonatal estrogen exposure on the levels of retinoic acid and receptors in the developing prostate using RT-PCR, immunocytochemistry, in-situ hybridization, biochemical assays and organ culture techniques. These studies are related to the normal and pathologic development of the prostate gland. Results will further define the mechanism of estrogen's actions on the prostate during early development and lead to a better understanding of the hormonal and developmental basis for abnormal prostatic growth with aging, particularly in the formation of prostatic adenocarcinoma.