Making hypomorphic tumor supressors in vivo using RNAi

利用 RNAi 在体内制造亚型肿瘤抑制因子

基本信息

  • 批准号:
    7223476
  • 负责人:
  • 金额:
    $ 88.42万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2004
  • 资助国家:
    美国
  • 起止时间:
    2004-04-01 至 2009-03-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Tumor suppressors act as components of complex networks whose overall function can be impaired by many different genetic or epigenetic alterations. While many of these alterations have been elegantly recapitulated in mouse, existing technology has been limited in its ability to model the significant range and complexity of gene suppression that occurs during neoplastic progression. The recent development of retroviral systems capable of mediating stable gene silencing has vastly increased our capacity to recreate the precise gene expression profiles seen in tumor cells. We propose to exploit the emerging power of RNA interference (RNAi) to study tumor suppressor gene networks in vivo, in particular, the impact of tumor suppressor hypomorphs on tumor development and responses to cancer therapy. Our team includes investigators that have been pioneers in establishing methods for using short hairpin RNAs (shRNAs) to stably suppress gene function in culture cells and in animals. As well as investigators with substantial expertise in modeling cancer and cancer therapy in the mouse who have successfully demonstrated that shRNAs can create 'epi-allelic' series of hypomorphs that produce distinct tumor phenotypes in vivo. Our experimental approach will be to: 1) develop RNAi technology for suppressing gene function in both chimeric (genetic mosaic) and germline settings; 2) use conditional systems to determine the extent to which tumor suppressor gene inactivation is required for tumor maintenance, and the consequences of gene reactivation on tumor behavior; 3) use this technology to produce an 'epi-allelic' series of tumor suppressor hypomorphs that may produce different pathologies depending on the strength of suppression; 4) take advantage of new shRNA libraries presently capable of targeting cancer relevant genes in the mouse genome (and likely to expand genome-wide) to conduct unbiased genetic screens for modulators of tumor phenotypes; 5) build upon our previous success with the hematopoeitic system to model carcinomas, with a particular emphasis on developing rapid methods to evaluate genetic interactions during breast carcinogenesis and therapy. We expect that these studies will provide new insights into how tumor suppressor networks are disabled during the development of particular neoplasias, and ultimately identify key nodes in these networks that may be sensitive to therapeutic intervention. Moreover, they will produce new mouse models of human cancer that can be used to understand treatment responses and as preclinical models for testing novel therapies.
描述(由申请人提供): 肿瘤抑制因子作为复杂网络的组成部分,其整体功能可能受到许多不同遗传或表观遗传改变的损害。虽然这些改变中的许多已经在小鼠中优雅地重现,但现有技术在模拟肿瘤进展期间发生的基因抑制的显著范围和复杂性方面受到限制。最近开发的逆转录病毒系统能够介导稳定的基因沉默,极大地提高了我们的能力,重新创建精确的基因表达谱中看到的肿瘤细胞。我们建议利用RNA干扰(RNAi)的新兴力量来研究体内肿瘤抑制基因网络,特别是肿瘤抑制基因亚型对肿瘤发展和癌症治疗反应的影响。我们的团队包括研究人员,他们是建立使用短发夹RNA(shRNAs)稳定抑制培养细胞和动物中基因功能的方法的先驱。以及在小鼠中建模癌症和癌症治疗方面具有丰富专业知识的研究人员,他们已经成功地证明了shRNAs可以产生一系列“表观等位基因”的亚型,这些亚型在体内产生不同的肿瘤表型。我们的实验方法将是:1)开发RNAi技术,用于抑制嵌合体中的基因功能,(遗传嵌合体)和种系设置; 2)使用条件系统来确定肿瘤维持所需的肿瘤抑制基因失活的程度,以及基因再激活对肿瘤行为的后果; 3)使用该技术产生一系列“表观等位基因”的肿瘤抑制子亚型,其可根据抑制的强度产生不同的病理; 4)利用目前能够靶向小鼠基因组中癌症相关基因的新的shRNA文库,(并且可能在全基因组范围内扩展)对肿瘤表型的调节剂进行无偏倚的遗传筛选; 5)建立在我们以前成功的造血系统模型癌症,特别强调开发快速方法来评估乳腺癌发生和治疗过程中的遗传相互作用。我们期望这些研究将为肿瘤抑制网络在特定肿瘤形成过程中如何失能提供新的见解,并最终确定这些网络中可能对治疗干预敏感的关键节点。此外,他们将产生新的人类癌症小鼠模型,可用于了解治疗反应,并作为临床前模型用于测试新的疗法。

项目成果

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SCOTT W. LOWE其他文献

SCOTT W. LOWE的其他文献

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{{ truncateString('SCOTT W. LOWE', 18)}}的其他基金

Mechanisms of p53 Engagement and Action at the Benign-to-Malignant Transition in Sporadic Tumorigenesis
p53在散发性肿瘤发生良性向恶性转变中的参与和作用机制
  • 批准号:
    10720034
  • 财政年份:
    2023
  • 资助金额:
    $ 88.42万
  • 项目类别:
Systematic characterization of cancer variants using single-cell functional genomics
使用单细胞功能基因组学对癌症变异进行系统表征
  • 批准号:
    10599180
  • 财政年份:
    2022
  • 资助金额:
    $ 88.42万
  • 项目类别:
Systematic characterization of cancer variants using single-cell functional genomics
使用单细胞功能基因组学对癌症变异进行系统表征
  • 批准号:
    10358184
  • 财政年份:
    2022
  • 资助金额:
    $ 88.42万
  • 项目类别:
Project 2: Defining and exploiting genetic dependencies in complex karyotype AML
项目 2:定义和利用复杂核型 AML 中的遗传依赖性
  • 批准号:
    10474281
  • 财政年份:
    2021
  • 资助金额:
    $ 88.42万
  • 项目类别:
Impact of the aging niche on cancer phenotypes probed using mouse cancer models produced by somatic engineering.
使用体细胞工程产生的小鼠癌症模型探讨衰老生态位对癌症表型的影响。
  • 批准号:
    10355559
  • 财政年份:
    2021
  • 资助金额:
    $ 88.42万
  • 项目类别:
Rapid and flexible precision oncology mouse models of epithelial malignancies epithelial malignancies
快速灵活的上皮恶性肿瘤精准肿瘤学小鼠模型
  • 批准号:
    10318154
  • 财政年份:
    2020
  • 资助金额:
    $ 88.42万
  • 项目类别:
Toward development of senolytic CAR T cells
致力于开发 senolytic CAR T 细胞
  • 批准号:
    10599858
  • 财政年份:
    2020
  • 资助金额:
    $ 88.42万
  • 项目类别:
Toward development of senolytic CAR T cells
致力于开发 senolytic CAR T 细胞
  • 批准号:
    10161683
  • 财政年份:
    2020
  • 资助金额:
    $ 88.42万
  • 项目类别:
Rapid and flexible precision oncology mouse models of epithelial malignancies epithelial malignancies
快速灵活的上皮恶性肿瘤精准肿瘤学小鼠模型
  • 批准号:
    10545181
  • 财政年份:
    2020
  • 资助金额:
    $ 88.42万
  • 项目类别:
Rapid and flexible precision oncology mouse models of epithelial malignancies epithelial malignancies
快速灵活的上皮恶性肿瘤精准肿瘤学小鼠模型
  • 批准号:
    9886845
  • 财政年份:
    2020
  • 资助金额:
    $ 88.42万
  • 项目类别:

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在创新的 3D 离体肺转移模型中,肺微环境影响乳腺癌细胞的转移行为
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Tumor cell-derived mechanisms underlying lung-specific metastatic behavior of breast cancer cells: Role of ALDH1A1, CD44 and other stem cell related factors.
乳腺癌细胞肺特异性转移行为的肿瘤细胞衍生机制:ALDH1A1、CD44 和其他干细胞相关因子的作用。
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  • 项目类别:
    Studentship Programs
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