Telomerase function in human tumor and stem cell biology

端粒酶在人类肿瘤和干细胞生物学中的功能

基本信息

  • 批准号:
    9069780
  • 负责人:
  • 金额:
    $ 34.18万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-06-01 至 2020-05-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): The crucial role of telomerase in stem cell maintenance and tumorigenesis has long been recognized. Human pluripotent stem cells have active telomerase and therefore long-term renewal capacity, but most human somatic cells lack telomerase function and therefore have a limited capacity for renewal. Patients with telomerase deficiencies that cause bone marrow failure, aplastic anemia and pulmonary fibrosis have accelerated telomere shortening, which gives rise to these tissue failures. Opposite to this effect is the telomerase reactivation that underlies the proliferative immortality of most human cancers. Despite these strong implications for human health, we lack understanding of the molecular mechanisms by which human cells regulate telomerase activity to ensure tissue homeostasis and how its dysfunction can lead to tumorigenesis. The natural regulation of telomerase activity in human tissue and the impact of telomere shortening on untransformed human cells can only be studied in a primary human stem cell system. Until recently, technical limitations, especially the inefficiency of genetic manipulation, have impeded the use of human stem cells as research tools. We have overcome this by establishing the use of site-specific nucleases to efficiently genetically engineer human pluripotent stem cells (hPSCs). This technology allows us, for the first time, to investigate two key regulatory events of human telomerase function in a genetically defined human stem cell system: its transcriptional regulation and the recruitment of telomerase to telomeres. The experiments described in Aim 1 use genetically engineered hPSCs to elucidate the molecular mechanisms that transcriptionally regulate telomerase in stem cells and how the expression of telomerase is silenced upon differentiation. The experiments outlined in Aim 2 will reveal the mechanisms that control telomerase recruitment to telomeres and the mechanisms utilized by telomere-binding proteins to regulate telomerase activity after this recruitment step. These experiments will uncover how human stem cells establish a telomere length set-point that provides a sufficient telomere reserve for human tissue regeneration while also functioning as a tumor suppressor mechanism by ultimately restricting the proliferative capacity of differentiated cell lineages. In Aim 3 we will identify the genetic alterations that led to telomerase-independent immortalization by the induction of the alternative telomere maintenance pathway, which is used by the minority of cancers that have not reactivated telomerase expression. Taken together, the experiments described here will use a genetically defined human stem cell model system to elucidate the tightly regulated steps in the telomere maintenance pathway and to mechanistically understand how mutations in this pathway promote cancer formation. Such a complete mechanistic understanding will open novel avenues of telomere maintenance inhibition as specific anti-cancer therapeutics that do not compromise the long-term proliferation of normal stem cells.
 描述(申请人提供):端粒酶在干细胞维持和肿瘤发生中的关键作用早已被认识。人类多能干细胞具有活性端粒酶,因此具有长期更新能力,但大多数人类体细胞缺乏端粒酶功能,因此具有有限的更新能力。端粒酶缺陷导致骨髓衰竭、再生障碍性贫血和肺纤维化的患者端粒缩短加速,从而导致这些组织衰竭。与这种效果相反 是端粒酶的重新激活,这是大多数人类癌症增殖永生的基础。尽管这些对人类健康的强烈影响,我们缺乏对人类细胞调节端粒酶活性以确保组织稳态的分子机制以及其功能障碍如何导致肿瘤发生的理解。人类组织中端粒酶活性的自然调节和端粒缩短对未转化人类细胞的影响只能在原代人类干细胞系统中进行研究。直到最近,技术限制,特别是遗传操作的效率低下,阻碍了人类干细胞作为研究工具的使用。我们通过使用位点特异性核酸酶来有效地遗传工程改造人类多能干细胞(hPSC)来克服这一问题。这项技术使我们能够,第一次,调查两个关键的调控事件的人端粒酶功能的基因定义的人类干细胞系统:其转录调控和端粒酶端粒的招聘。目的1中描述的实验使用基因工程化的hPSC来阐明转录调节干细胞中端粒酶的分子机制以及端粒酶的表达如何在分化时沉默。目标2中概述的实验将揭示控制端粒酶募集到端粒的机制以及端粒结合蛋白在该募集步骤后调节端粒酶活性的机制。这些实验将揭示人类干细胞如何建立端粒长度设定点,该设定点为人类组织再生提供足够的端粒储备,同时还通过最终限制分化细胞谱系的增殖能力来发挥肿瘤抑制机制的作用。在目标3中,我们将确定通过诱导替代端粒维持途径导致端粒非依赖性永生化的遗传改变,该途径被少数未重新激活端粒酶表达的癌症所使用。 总之,这里描述的实验将使用遗传定义的人类干细胞模型系统来阐明端粒维持途径中的严格调控步骤,并从机制上理解该途径中的突变如何促进癌症形成。这样一个完整的机制的理解将开辟新的途径端粒维持抑制作为特定的抗癌治疗,不损害正常干细胞的长期增殖。

项目成果

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Dirk Hockemeyer其他文献

Dirk Hockemeyer的其他文献

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{{ truncateString('Dirk Hockemeyer', 18)}}的其他基金

Biology and Biotechnology of Cell and Gene Therapy
细胞和基因治疗生物学和生物技术
  • 批准号:
    10621376
  • 财政年份:
    2021
  • 资助金额:
    $ 34.18万
  • 项目类别:
Biology and Biotechnology of Cell and Gene Therapy
细胞和基因治疗生物学和生物技术
  • 批准号:
    10410353
  • 财政年份:
    2021
  • 资助金额:
    $ 34.18万
  • 项目类别:
Telomerase function in human tumor and stem cell biology
端粒酶在人类肿瘤和干细胞生物学中的功能
  • 批准号:
    9270521
  • 财政年份:
    2015
  • 资助金额:
    $ 34.18万
  • 项目类别:
Telomerase function in human tumor and stem cell biology
端粒酶在人类肿瘤和干细胞生物学中的功能
  • 批准号:
    8942587
  • 财政年份:
    2015
  • 资助金额:
    $ 34.18万
  • 项目类别:

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