Mechanistic Evaluation of the Androgen Receptor Inhibition Driven Hypoxic Prostate Microenvironment

雄激素受体抑制驱动的缺氧前列腺微环境的机制评估

基本信息

  • 批准号:
    2624496
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 依托单位国家:
    英国
  • 项目类别:
    Studentship
  • 财政年份:
    2021
  • 资助国家:
    英国
  • 起止时间:
    2021 至 无数据
  • 项目状态:
    已结题

项目摘要

Research context: The studentship will focus on understanding the role of the androgen receptor under concentrations of low oxygen that can be found within the prostate during various disease or treatment conditions. The androgen receptor is a key protein that under normal physiological conditions bind to testosterone to regulate the development and maintenance of the male phenotype. During different prostate diseases, including cancer, or treatment conditions such as radiation or androgen-deprivation therapy, a resulting change in oxygenation results and changes the biological response of the prostate cells and surrounding and supporting cells within the prostate.Research from our group and others have demonstrated that the androgen receptor signalling regulates the microenvironment of the prostate gland, whereby inhibition, either castration or therapeutically, results in rapid vascular atrophy and reduced microvessel density as a result of vascular endothelial cell death. This result, in part, from induction of signalling molecules within the prostate cells that are activated follow a change in oxygenation to increase cell proliferation, survival, angiogenesis, metabolism and invasion. Importantly, the genetic background of the prostate cells significantly contributes to the response to inhibitors of androgen receptor. Our lab focuses on PTEN, where its deficiency has been shown to be a major molecular hallmark for aggressive prostate cancer. Our research has shown that prostate cancer cells with PTEN-loss have increased abundance of angiogenic promoting factors that contribute to reduced efficacy of currently used treatments pf prostate cancer including radiotherapy and androgen receptor inhibitors. This context of PTEN-loss and increased angiogenic promoting factors is a focus of this study and may define a mechanism of resistance to androgen-signaling inhibitors, where we need further mechanistic understanding of contribution and role of PTEN-depleted tumour foci and the surrounding microenvironment on development and treatment resistance.Aims and objectives: The proposed body of work will characterize the influence of PTEN-loss on the remodelling of the prostate microenvironment and alterations in the immune cell component following androgen receptor inhibition alone and in combination with inactivation of angiogenesis promoting factors. Mechanistically the study will investigate various angiogenesis promoting factors and their redundancy within the prostate and importance of dual inhibition on the microenvironment and therapeutic response. Application and benefit: As part of this project, the student will develop several novel models of PTEN-deficient prostate cells that will be a resource to the research community and importantly model relevant biology and the microenvironment of the prostate. The research will provide insight into the mechanisms of redundancy that exist between angiogenesis promoting factors leading to insights into normal development, wound healing, inflammation and cancer biology.
研究背景:学生奖学金将重点了解在各种疾病或治疗条件下前列腺内低氧浓度下雄激素受体的作用。雄激素受体是一种关键蛋白质,在正常生理条件下与睾酮结合以调节男性表型的发育和维持。在不同的前列腺疾病(包括癌症)或放射治疗或雄激素剥夺疗法等治疗条件下,氧合会发生变化,并改变前列腺细胞以及前列腺内周围和支持细胞的生物反应。我们小组和其他人的研究表明,雄激素受体信号传导可调节前列腺的微环境,从而抑制或阉割或抑制前列腺的微环境。 在治疗上,由于血管内皮细胞死亡,导致快速血管萎缩和微血管密度降低。这在一定程度上是由于前列腺细胞内信号分子的诱导,这些信号分子在氧合变化后被激活,以增加细胞增殖、存活、血管生成、代谢和侵袭。重要的是,前列腺细胞的遗传背景显着影响对雄激素受体抑制剂的反应。我们的实验室专注于 PTEN,它的缺陷已被证明是侵袭性前列腺癌的主要分子标志。我们的研究表明,PTEN 缺失的前列腺癌细胞的血管生成促进因子丰度增加,导致目前使用的前列腺癌治疗(包括放射疗法和雄激素受体抑制剂)的疗效降低。 PTEN 缺失和血管生成促进因子增加的背景是本研究的重点,可能会定义对雄激素信号抑制剂的耐药机制,我们需要进一步从机制上理解 PTEN 缺失的肿瘤病灶和周围微环境对发育和治疗抵抗的贡献和作用。 目的和目标:拟议的工作主体将描述 PTEN 缺失对前列腺重塑的影响 单独抑制雄激素受体以及与血管生成促进因子失活相结合后微环境和免疫细胞成分的变化。从机制上讲,该研究将研究各种血管生成促进因子及其在前列腺内的冗余性,以及双重抑制对微环境和治疗反应的重要性。应用和益处:作为该项目的一部分,学生将开发几种 PTEN 缺陷前列腺细胞的新模型,这些模型将成为研究界的资源,并且重要的是模拟前列腺的相关生物学和微环境。该研究将深入了解血管生成促进因子之间存在的冗余机制,从而深入了解正常发育、伤口愈合、炎症和癌症生物学。

项目成果

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其他文献

吉治仁志 他: "トランスジェニックマウスによるTIMP-1の線維化促進機序"最新医学. 55. 1781-1787 (2000)
Hitoshi Yoshiji 等:“转基因小鼠中 TIMP-1 的促纤维化机制”现代医学 55. 1781-1787 (2000)。
  • DOI:
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    0
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LiDAR Implementations for Autonomous Vehicle Applications
  • DOI:
  • 发表时间:
    2021
  • 期刊:
  • 影响因子:
    0
  • 作者:
  • 通讯作者:
生命分子工学・海洋生命工学研究室
生物分子工程/海洋生物技术实验室
  • DOI:
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    0
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吉治仁志 他: "イラスト医学&サイエンスシリーズ血管の分子医学"羊土社(渋谷正史編). 125 (2000)
Hitoshi Yoshiji 等人:“血管医学与科学系列分子医学图解”Yodosha(涉谷正志编辑)125(2000)。
  • DOI:
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    0
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Effect of manidipine hydrochloride,a calcium antagonist,on isoproterenol-induced left ventricular hypertrophy: "Yoshiyama,M.,Takeuchi,K.,Kim,S.,Hanatani,A.,Omura,T.,Toda,I.,Akioka,K.,Teragaki,M.,Iwao,H.and Yoshikawa,J." Jpn Circ J. 62(1). 47-52 (1998)
钙拮抗剂盐酸马尼地平对异丙肾上腺素引起的左心室肥厚的影响:“Yoshiyama,M.,Takeuchi,K.,Kim,S.,Hanatani,A.,Omura,T.,Toda,I.,Akioka,
  • DOI:
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的其他文献

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  • 批准号:
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  • 财政年份:
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    --
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    Studentship
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核燃料模拟物的现场辅助烧结
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评估用于航空航天应用的新型抗疲劳钛合金
  • 批准号:
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  • 财政年份:
    2027
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