Development Estrogenization of the Rat Prostate Gland

大鼠前列腺的发育雌激素化

基本信息

批准号：
8010059
负责人：
Gail S Prins
金额：
$ 0.9万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-01-15 至 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8010059
关键词：
Adenocarcinoma Age Aging Androgens Animals Cells Complex Cytology Data Defect Development Developmental Gene Disease Disease susceptibility Dose Dysplasia Epithelial Epithelial Cells Epithelial-Stromal Communication Estrogens Exhibits Family Gene Expression Genes Gland Glycoproteins Goals Growth Hormonal Hormones Human Hyperplasia In Vitro Incidence Investigation Lead Lesion Life Lobe Mammary gland Mediating Mediator of activation protein Modeling Molecular Morphogenesis Morphology Movement Neonatal Organ Organ Culture Techniques Organogenesis Pathologic Pathway interactions Pattern Phenotype Play Predisposing Factor Process Progesterone Prostate Prostate carcinoma Prostatic Prostatic Diseases Prostatic Intraepithelial Neoplasias Rattus Regulation Research Retinoids Rodent Rodent Model Role Series Signal Pathway Signal Transduction Specificity Steroid Receptors Steroids Structure System Tissues Transgenic Mice Tretinoin Uterus Withdrawal base cancer type critical developmental period imprint in vivo Model member morphogens programs receptor receptor expression

项目摘要

Brief exposure of rats to high doses of estrogens early in life (developmental estrogenization) leads to permanent alterations in the prostate gland and is associated with hyperplasia, dysplasia and adenocarcinoma with aging. Accordingly, it is 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. Neonatal estrogen exposure interrupts branching morphogenesis, alters stromal cytology and blocks certain prostatic epithelial cells from entering a normal differentiation pathway. These effects are lobe-specific which serves as a useful model for heterogeneous diseases in different zones of the human prostate gland. We have determined that estrogen exposure drastically alters prostatic steroid receptor expression which effectively switches prostate development from an androgen-dominated process to one regulated by estrogens, progesterone, and retinoids. We propose that the net result of this regulatory shift is that downstream organizational signals which normally dictate prostate development during discrete temporal windows are permanently and irretrievably altered. We have presently identified lobe-specific expression alterations in several morphoregulatory genes as a result of estrogenization which partially elucidates this phenomenon. To further understand this process, the present proposal will focus on the roles of Wnt genes and retinoic acids as mediators of developmental estrogenization of the rodent prostate gland. Specific Aim 1: Determine the roles for canonical and noncanonical Wnt morphogens during prostate development. Specific Aim 2: Determine whether neonatal estrogenization of the prostate is mediated through alterations in Wnt signaling. Specific Aim 3: Determine the role of retinoids in mediating the estrogen-induced alterations of developmental genes in the separate prostate lobes. Several in vitro and in vivo models including transgenic mice will be employed to identify specific roles for prostatic Wnt genes during prostate development and to determine whether they are necessary and sufficient for the estrogenized phenotype. The roles of retinoic acids via their cognate receptors in directly mediating changes in prostate development initiated by estrogen exposure will be assessed with organ culture studies and several in vivo models. These studies are related to the normal and pathologic development of the prostate gland. Results will further define the mechanisms of estrogen's actions on the prostate gland during early development and lead to a better understanding of the hormonal and developmental basis for abnormal prostate growth with aging.

大鼠在生命早期短暂接触高剂量雌激素（发育性雌激素化）会导致前列腺发生永久性改变，并与衰老过程中的增生、发育不良和腺癌相关。因此，推测发育关键期的早期雌激素暴露可能是 BPH 和/或前列腺癌的诱发因素。这项研究的长期目标是阐明新生儿雌激素最初印记或转化的细胞和分子机制。前列腺。新生儿雌激素暴露会中断分支形态发生，改变基质细胞学并阻止某些前列腺上皮细胞进入正常分化途径。这些效应是叶特异性的，可作为人类前列腺不同区域异质性疾病的有用模型。我们已经确定，雌激素暴露会极大地改变前列腺类固醇受体的表达，从而有效地将前列腺发育从雄激素主导的过程转变为受雌激素、黄体酮和类维生素A调节的过程。我们认为，这种监管转变的最终结果是，通常在离散时间窗口内决定前列腺发育的下游组织信号被永久且不可挽回地改变。我们目前有确定了由于雌激素化而导致的几个形态调节基因的脑叶特异性表达改变，这部分阐明了这种现象。为了进一步了解这一过程，本提案将重点关注 Wnt 基因和视黄酸作为啮齿动物前列腺发育雌激素化介质的作用。具体目标 1：确定经典和非经典 Wnt 形态发生素在前列腺发育过程中的作用。具体目标2：确定新生儿前列腺雌激素化是否是通过 Wnt 信号传导的改变介导的。具体目标 3：确定类视黄醇在介导雌激素诱导的前列腺各叶发育基因改变中的作用。将采用包括转基因小鼠在内的几种体外和体内模型来鉴定前列腺 Wnt 基因在前列腺发育过程中的特定作用，并确定它们是否是必需的和足以达到雌激素化表型。视黄酸通过其同源受体在直接介导雌激素暴露引发的前列腺发育变化中的作用将通过器官培养研究和几种体内模型进行评估。这些研究与前列腺的正常和病理发育有关。结果将进一步明确雌激素在早期发育过程中对前列腺的作用机制，并有助于更好地了解随着衰老而异常前列腺生长的激素和发育基础。

项目成果

期刊论文数量（49）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Disruption of growth hormone signaling retards prostate carcinogenesis in the Probasin/TAg rat.

生长激素信号传导的破坏可延缓 Probasin/TAg 大鼠的前列腺癌发生。

DOI：
10.1210/en.2007-1410
发表时间：
2008
期刊：
Endocrinology
影响因子：
4.8
作者：
Wang,Zhuohua;Luque,RaulM;Kineman,RhondaD;Ray,VeraH;Christov,KonstantinT;Lantvit,DanielD;Shirai,Tomoyuki;Hedayat,Samad;Unterman,TerryG;Bosland,MaartenC;Prins,GailS;Swanson,StevenM
通讯作者：
Swanson,StevenM

Development, progression, and androgen-dependence of prostate tumors in probasin-large T antigen transgenic mice: a model for prostate cancer.

前列腺癌大T抗原转基因小鼠中前列腺肿瘤的发生、进展和雄激素依赖性：前列腺癌模型。

DOI：
发表时间：
1998
期刊：
Laboratory investigation; a journal of technical methods and pathology
影响因子：
0
作者：
Kasper,S;Sheppard,PC;Yan,Y;Pettigrew,N;Borowsky,AD;Prins,GS;Dodd,JG;Duckworth,ML;Matusik,RJ
通讯作者：
Matusik,RJ

Estrogen action and prostate cancer.