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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >A new model for studying tissue-specific mdr1a gene expression in vivo by live imaging
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A new model for studying tissue-specific mdr1a gene expression in vivo by live imaging

机译：通过实时成像研究体内组织特异性mdr1a基因表达的新模型

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摘要

Multidrug resistance continues to be a major impediment to successful chemotherapy in cancer patients. One cause of multidrug resistance is enhanced expression of the mdr1 gene, but the precise factors and physiological conditions controlling mdr1 expression are not entirely known. To gain a better understanding of mdr1 transcrip-tional regulation, we created a unique mouse model that allows noninvasive bioimaging of mdr1 gene expression in vivo and in real time. The model uses a firefly luciferase (fLUC) gene inserted by homologous recombination into the murine mdria genetic locus. The inserted fLUC gene is preceded by a neo expression cassette flanked by loxP sites, so that Cre-mediated recombination is required to configure the fLUC gene directly under the control of the endogenous mdr1a promoter. We now demonstrate that the mdr1a.fLUC knock-in is a faithful reporter for mdr1a expression in naieve animals, in which fLUC mRNA levels and luminescence intensities accurately parallel endogenous mdr1a mRNA expression. We also demonstrate xenobi-otic-inducible regulation of mdr1a.fLUC expression in real time, in parallel with endogenous mdria expression, resulting in a more detailed understanding of the kinetics of mdr1a gene induction. This mouse model demonstrates the feasibility of using bioimaging coupled with Cre/loxP conditional knock-in to monitor regulated gene expression in vivo. It represents a unique tool with which to study the magnitude and kinetics of mdria induction under a variety of physiologic, pharmacologic, genetic, and environmental conditions.
机译：多药耐药性仍然是癌症患者成功进行化疗的主要障碍。多药耐药的原因之一是mdr1基因表达增强，但是控制mdr1表达的确切因素和生理条件尚不完全清楚。为了更好地了解mdr1转录调控，我们创建了一个独特的小鼠模型，该模型允许在体内和实时进行mdr1基因表达的无创生物成像。该模型使用萤火虫荧光素酶（fLUC）基因，该基因通过同源重组插入鼠类mdria遗传基因座中。插入的fLUC基因之前是带有loxP位点侧翼的neo表达盒，因此需要Cre介导的重组以直接在内源性mdr1a启动子的控制下配置fLUC基因。现在，我们证明了mdr1a.fLUC敲入是纯天然动物中mdr1a表达的忠实报道者，其中fLUC mRNA水平和发光强度准确地平行于内源性mdr1a mRNA表达。我们还展示了与内源性mdria表达并行的mdr1a.fLUC表达实时异种生物诱导诱导调控，从而导致对mdr1a基因诱导动力学的更详细了解。该小鼠模型证明了结合使用生物成像和Cre / loxP条件敲入技术来监测体内受调节的基因表达的可行性。它代表了一种独特的工具，可用来在各种生理，药理，遗传和环境条件下研究mdria诱导的幅度和动力学。

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  • 作者

    Long Gu; Walter M. Tsark; Donna A. Brown; Suzette Blanchard; Timothy W. Synold; Susan E. Kane;

  • 作者单位

    Division of Tumor Cell Biology, Beckman Research Institute at City of Hope, 1500 East Duarte Road, Duarte, CA 91010;

    Department of Biology, Beckman Research Institute at City of Hope, 1500 East Duarte Road, Duarte, CA 91010;

    Division of Tumor Cell Biology, Beckman Research Institute at City of Hope, 1500 East Duarte Road, Duarte, CA 91010 Queen Mary's School of Medicine and Dentistry, Old Medical College Building, Turner Street, London E1 2AD, England;

    Department of Information Sciences, Beckman Research Institute at City of Hope, 1500 East Duarte Road, Duarte, CA 91010;

    Division of Clinical and Molecular Pharmacology, Beckman Research Institute at City of Hope, 1500 East Duarte Road, Duarte, CA 91010;

    Division of Tumor Cell Biology, Beckman Research Institute at City of Hope, 1500 East Duarte Road, Duarte, CA 91010;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    bioimaging; conditional knock-in; gene regulation; MDR1; multidrug resistance;

    机译：生物成像有条件的敲门;基因调控;MDR1;多药耐药;

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