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中文摘要
翻译
大鼠在生命早期短暂暴露于高剂量的雌激素(发育性雌激素化)会导致前列腺的永久性改变,并与增生、不典型增生和腺癌有关。因此,假设在发育关键时期早期雌激素暴露可能是前列腺增生和/或前列腺癌的易感因素。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
英文摘要
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.
期刊论文(49)
专著(0)
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会议论文
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: --
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.
雌激素作用和前列腺癌。
DOI: 10.1586/eem.11.20
发表时间: 2011-05
期刊: Expert review of endocrinology & metabolism
影响因子: 3.2
作者: [Nelles JL, Hu WY, Prins GS]
通讯作者: Prins GS
Distribution of androgen receptor-immunoreactive cells in the quail forebrain and their relationship with aromatase immunoreactivity.
鹌鹑前脑中雄激素受体免疫反应细胞的分布及其与芳香酶免疫反应性的关系。
DOI: --
发表时间: 1998
期刊: Journal of neurobiology
影响因子: --
作者: [Balthazart,J, Foidart,A, Houbart,M, Prins,GS, Ball,GF]
通讯作者: Ball,GF
共 24 条
    Estrogen Receptors in Human Prostate Stem-Progenitor Cells
    Estrogen Receptors in Human Prostate Stem-Progenitor Cells
    Estrogen Receptors in Human Prostate Stem-Progenitor Cells
    Estrogen Receptors in Human Prostate Stem-Progenitor Cells
    国内基金
    海外基金
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      JCZRQN202500010
    • 项目类别:
      省市级项目
    • 资助金额:
      --
    • 批准年份:
      2025
    • 负责人:
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    对香豆酸抑制AGE-RAGE-Ang-1通路改善海马血管生成障碍发挥抗阿尔兹海默病作用
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      2025JJ70209
    • 项目类别:
      省市级项目
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    • 批准年份:
      2025
    • 负责人:
      雷芬芳
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    AGE-RAGE通路调控慢性胰腺炎纤维化进程的作用及分子机制
    • 批准号:
      --
    • 项目类别:
      面上项目
    • 资助金额:
      --
    • 批准年份:
      2024
    • 负责人:
      万荣
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