DEVELOPMENTAL ESTROGENIZATION OF RAT PROSTATE

描述：大鼠在生命早期短暂暴露于雌激素（发育 雌激素化）导致前列腺的永久性改变， 与增生、异型增生和 腺癌伴衰老。因此，有人推测， 发育关键期接触雌激素可能是诱发因素 BPH和/或前列腺癌的因子。这一长期目标 研究旨在阐明细胞和分子机制， 新生儿雌激素最初印记或转化前列腺。在 在过去的资助期间，我们收集了大量证据，表明早期 雌激素暴露中断了分支形态发生的过程，改变了 间质细胞学与出芽的前列腺导管相关， 前列腺上皮细胞进入正常分化途径。 这些变化是介导的，部分是通过短暂的和永久的， 前列腺中类固醇受体表达的扰动。证据还 证明了TGF β旁分泌在基质和上皮之间的通讯， 细胞在新生儿雌激素化后中断。初步证据 这让我们假设几个关键的发展途径下游 类固醇受体的作用是永久性改变后，雌激素 exposure.该提案侧重于进一步确定具体的 参与前列腺形态发生的发育基因， 雌激素新提案的具体目标是：具体目标1：确定 胎儿和新生儿雌激素对乳腺癌组织中 前列腺形态发生过程中的前列腺同源盒基因（Hox 13和Nkx3.1）， 上皮分化具体目标2：确定 分泌调节基因（Shh，Wnts，BMP， FGF）及其同源受体介导上皮-间质细胞质细胞间质细胞间质细胞质间质细胞间质细胞质间质细胞质细胞间质细胞间质细胞质间质细胞 前列腺发育过程中的沟通。体内和体外模型 将被用来调查这些时间和空间的表达 发育基因及其激素调节。方法包括 免疫细胞化学、原位杂交、激光捕获显微镜， 通过RT-PCR、北方和西方分析， 配体或抗体应用。这些研究与正常和 前列腺的病理发展。结果将进一步确定 雌激素对早期前列腺的作用机制 发展，并导致更好地了解激素和 随着年龄的增长，前列腺异常生长的发育基础，特别是在 前列腺腺癌的形成。

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.