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中文摘要
翻译
摘要 染色体重排在癌症中很常见,通常发生在癌症发生的早期。 它们通过改变癌基因和肿瘤的表达或功能来推动肿瘤的发展 通过拷贝数改变、形成致癌融合或通过改变 负责调节癌症基因的DNA元件。尽管作为一个众所周知的功能, 癌症是一百多年前发现的,这种常见的癌症标志至今还没有 在治疗上被剥削。现在,第一次,全基因组的技术进步 测序和用于精确定位的CRISPR技术的发展使 有可能识别和靶向肿瘤细胞中的染色体重排连接(CRJ)。在……里面 此外,最近在体内传递涉及纳米颗粒的CRIPR试剂方面的突破将 开辟临床应用新途径。在R21的应用中,我们提出了一种精确的CRISPR 旨在将特定于癌症的CRJ作为尚未开发的致命弱点的方法 都是肿瘤。这种基于CRISPR的精确度方法由一对CRJ靶向引导RNA组成 (GRNAs),它将dCas9结合的内切酶Fok1的两个部分结合在一起,导致其 激活和诱导致命性DNA双链断裂(DSB),特别是在癌细胞中。 无论肿瘤的驱动机制如何,CRJ的存在都将被选择性地利用 迫使这些癌细胞死亡。我们已经获得了成功锁定目标的原则证明 在结肠癌和膀胱癌细胞系中使用这种方法的CRJ。我们已经组装了一个多- 在CRISPR技术和设计、脂类纳米粒传递方面拥有专业知识的学科团队 系统和膀胱癌小鼠模型。有了这个团队,并有强有力的证据表明 在癌细胞系中用Fok1-dCas9高效靶向CRJ,我们现在准备开发 并使用最近开发的突破性脂质在临床前癌症模型中测试我们的方法 纳米颗粒输送技术。如果成功实施,这种改变范式的精确度- 靶向癌症治疗平台可能会在设计统一的治疗方案方面产生变革 所有癌症类型,与肿瘤的生物学无关。
英文摘要
ABSTRACT Chromosome rearrangements are common in cancers and typically occur early in carcinogenesis. They drive tumor development by altering the expression or function of oncogenes and tumor suppressor genes by copy number alterations, formation of oncogenic fusions or by alterations of DNA elements responsible for regulating cancer genes. Despite being a well-known feature of cancer, discovered over hundred years ago, this common cancer hallmark has not yet been therapeutically exploited. Now, for the first time, technological advancements in whole genome sequencing and the development of CRISPR technologies for precision targeting makes it possible to identify and target chromosome rearrangement junctions (CRJs) in tumor cells. In addition, recent breakthroughs in in vivo delivery of CRIPR reagents involving nanoparticles will open new avenues into clinical utilization. In this R21 application, we present a precision CRISPR approach that aims at targeting cancer-specific CRJs as an untapped Achilles heel common to all tumors. This CRISPR-based precision approach consists of pairs of CRJ-targeting guide RNAs (gRNAs) that bring together two parts of a dCas9-conjugated endonuclease, Fok1, leading to its activation and the induction of lethal DNA double strand breaks (DSBs) specifically in cancer cells. Regardless of the tumor-driving mechanism, the presence of CRJs will be exploited to selectively force these cancer cells to die. We have obtained proof-of-principle of the successful targeting of CRJs with this approach in both colon and bladder cancer cell lines. We have assembled a multi- disciplinary team with expertise in CRISPR technology and design, lipid nanoparticle delivery systems and bladder cancer mouse models. With this team in place and with strong evidence of efficient targeting of CRJs with Fok1-dCas9 in cancer cell lines, we are now primed to develop and test our approach in pre-clinical cancer models using recently developed breakthrough lipid nanoparticle delivery technologies. If successfully implemented, this paradigm-shifting precision- targeting cancer therapeutic platform could be transformative in designing uniform treatments for all cancer types irrespective of the biology of the tumor.
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Career Enhancement Program
Mapping of Novel Candidate Functional Elements with Bru-Seq Technology
Precision targeting of bladder cancer using CRISPR technology
Targeting the RNA Exosome for Cancer Therapeutics
国内基金
海外基金
企业绩效评价的DEA-Benchmarking方法及动态博弈研究
  • 批准号:
    70571028
  • 项目类别:
    面上项目
  • 资助金额:
    16.5万元
  • 批准年份:
    2005
  • 负责人:
    杨印生
  • 依托单位: