摘要
四环素调控系统与有效的时间和剂量的转基因表达的调节是非常有用的新的生理/病理生理学实验模型和基因疗法的发展。慢病毒载体具有改进的四环素调控的启动子有助于克服存在的局限性,如在没有药物的基础活动,弱诱导性或不稳定的转基因表达。比较传统的和基于慢病毒载体在体内提高四环素调控的启动子,我们研究了强力霉素调控基因转移和表达水平在长期的小鼠移植模型,证明改进后的T11启动子慢病毒载体具有高效性和高水平基因转移。动物具有较高的基因表达水平和载体的拷贝数时,需要扭转后去除转基因表达多西环素的时间增加。从实验和对照小鼠中外周血白细胞和脾细胞检查发现类似的细胞谱系分布的转基因阳性和阴性细胞群,但增加了变异的髓系和淋巴系转基因阳性骨髓细胞检测细胞的百分比。然而,移植后七个月没有发现总骨髓细胞的血统偏差,也没有造血疾病的迹象.。我们的研究结果表明,T11四环素调控的启动子功能能提高转基因在小鼠移植模型表达。所建立的系统允许四环素调节实验模型的进一步发展去调查正常和恶性造血。
关键词: 四环素调控的启动子,慢病毒,造血,小鼠移植模型,基因转移,多西环素。
Current Gene Therapy
Title:Comparison of Tetracycline-regulated Promoters in Lentiviral-based Vectors in Murine Transplantation Studies
Volume: 16 Issue: 4
Author(s): Maike Stahlhut, Teng-Cheong Ha, Michael Morgan, Axel Schambach, Olga S. Kustikova
Affiliation:
关键词: 四环素调控的启动子,慢病毒,造血,小鼠移植模型,基因转移,多西环素。
摘要: Tetracycline-regulated systems with efficient temporal and dose regulation of transgene expression are useful for development of new physiologic/pathophysiologic experimental models and gene therapy approaches. Lentiviral vectors with improved tetracycline-regulated promoters help to overcome the existing limitations such as basal activity in the drug absence, poor inducibility or unstable transgene expression. To compare conventional and improved tetracycline-regulated promoters in lentiviral based vectors in vivo, we investigated doxycycline-regulated gene transfer/expression levels in a long-term murine transplantation model and demonstrated that the lentiviral vector with the improved T11 promoter exhibited more efficient inducibility and higher gene transfer level. The time required to reverse transgene expression after doxycycline removal was increased for animals with higher gene expression levels and vector copy numbers. Examination of peripheral blood leukocytes and splenocytes revealed similar cell lineage distributions for transgene positive and negative cell populations from experimental and control mice, but increased variability in the percentages of myeloid and lymphoid cells was detected in transgene positive bone marrow cells. However, no indication of lineage bias in total bone marrow cells and no signs of hematopoietic disease were observed seven months after transplantation. Our results showed that the T11 tetracycline-regulated promoter enabled improved transgene expression in a murine transplantation model. The established system allows further development of tetracycline-regulated experimental models to investigate normal and malignant hematopoiesis.
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Maike Stahlhut, Teng-Cheong Ha, Michael Morgan, Axel Schambach, Olga S. Kustikova , Comparison of Tetracycline-regulated Promoters in Lentiviral-based Vectors in Murine Transplantation Studies, Current Gene Therapy 2016; 16 (4) . https://dx.doi.org/10.2174/1566523216666161013125215
DOI https://dx.doi.org/10.2174/1566523216666161013125215 |
Print ISSN 1566-5232 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5631 |
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