DEVELOPMENTAL ESTROGENIZATION OF RAT PROSTATE

描述：大鼠生命早期短暂接触雌激素(发育期 雌激素化)会导致前列腺癌的永久性改变 与增生性疾病、不典型增生和 随着年龄的增长而发生腺癌。因此，人们假设早些时候 在发育关键期接触雌激素可能是一种诱因 前列腺增生症和/或前列腺癌的致病因素。这个项目的长期目标是 研究的目的是阐明细胞和分子机制 新生儿雌激素最初会印记或改变前列腺。在 在过去的资助期，我们收集了重要的证据表明，早期 雌激素暴露中断了分支形态发生的过程，改变了 与发芽的前列腺管和阻塞相关的间质细胞学 阻止前列腺上皮细胞进入正常分化途径。 这些变化在一定程度上是通过短暂和永久的方式进行的。 前列腺中类固醇受体表达的紊乱。证据亦包括 有文献表明，转化生长因子β在间质和上皮之间的旁分泌通讯 细胞在新生儿雌激素化后被打断。初步证据 现在让我们假设下游的几条关键的发展路径 类固醇受体的作用在雌激素作用后发生永久性改变 曝光。这项建议侧重于进一步描述特定的 参与前列腺形态发生的发育基因受 雌激素。新建议的具体目标是：具体目标1：确定 胎儿和新生儿雌激素对血管内皮生长因子表达的调节作用 前列腺同源异型盒基因(Hox 13和Nkx3.1)在前列腺形态发生和发育中的作用 上皮分化。具体目标2：确定 分泌型调控基因(Shh，Wnts，BMPs， 及其介导上皮-间充质的同源受体 在前列腺发育过程中的沟通。体内和体外模型 将被用来研究这些元素的时间和空间表达 发育基因及其荷尔蒙调节。方法包括 随后进行了免疫细胞化学、原位杂交、激光捕获显微镜 经RT-PCR、Northern和Western分析，受体拮抗剂和微粉化 配体或抗体的应用。这些研究都与正常和 前列腺的病理发育。结果将进一步定义 雌激素对早期前列腺癌作用机制的研究 发展，并导致更好地理解激素和 增龄性前列腺发育异常的发育基础，尤其是在 前列腺癌的形成。

DESCRIPTION: Brief exposure of rats to estrogen 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 estrogens initially imprint or transform the prostate gland. In the past grant periods, we have collected significant evidence to show that early estrogen exposure interrupts the process of branching morphogenesis, alters stromal cytology associated with the budding prostatic ducts and blocks certain prostatic epithelial cells from entering a normal differentiation pathway. These alterations are mediated, in part, through transient and permanent perturbations in steroid receptor expression in the prostate. Evidence also documents that TGFbeta paracrine communication between stromal and epithelial cells is interrupted following neonatal estrogenization. Preliminary evidence now leads us to hypothesize that several key developmental pathways downstream of steroid receptor action are permanently altered following estrogenic exposure. This proposal focuses on further characterizing specific developmental genes involved in prostate morphogenesis that are regulated by estrogens. The specific aims of the new proposal are: Specific Aim 1: Determine the regulatory role of fetal and neonatal estrogen on the expression of prostate homeobox genes (Hox 13 and Nkx3.1) during prostatic morphogenesis and epithelial differentiation. Specific Aim 2: Determine the effects of developmental estrogenization on secreted regulatory genes (Shh, Wnts, BMPs, Fgf) and their cognate receptors which mediate epithelial-mesenchymal communication during prostate development. Both in vivo and in vitro models will be employed to investigate the temporal and spatial expression of these developmental genes and their hormonal regulation. Methods include immunocytochemistry, in situ hybridization, laser capture microscopy followed by RT-PCR, Northern and Western analysis, receptor antagonists and micronized ligand or antibody applications. These studies are related to the normal and pathologic development of the prostate gland. Results will further define the mechanism of action 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.