Self-adjusting synthetic gene circuit for correcting insulin resistance.
Self-adjusting synthetic gene circuit for correcting insulin resistance.
复制标题
用于纠正胰岛素抵抗的自我调节合成基因电路。
DOI：
10.1038/s41551-016-0005
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发表时间：
2017-01
影响因子：
28.1
通讯作者：
Fussenegger M
中科院分区：
文献类型：
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作者：
Ye H;Xie M;Xue S;Charpin-El Hamri G;Yin J;Zulewski H;Fussenegger M
通过使用合成生物学的工具，可以组装复杂的遗传装置来重新编程哺乳动物细胞的活动。在这里，我们证明了一个自我调节的合成基因电路可以被设计成在不同的小鼠模型中感知和逆转胰岛素抵抗综合征。通过功能上重新布线的丝裂原活化蛋白激酶（MAPK）信号通路，以产生MAPK介导的激活的杂交转录因子TetR-ELK 1，我们组装了一个合成的胰岛素敏感的转录控制装置，自给自足的生理和增加的血液胰岛素水平之间的区别，并相应地微调的可逆表达的治疗性转基因合成TetR-ELK 1特异性启动子。在急性实验性高胰岛素血症中，合成的胰岛素感应设计器电路通过协调胰岛素增敏化合物脂联素的表达来逆转胰岛素抵抗综合征。工程合成基因电路感测病理标志物和协调治疗转基因的表达可能为未来的多因素代谢紊乱的基因和细胞为基础的治疗提供了机会。
By using tools from synthetic biology, sophisticated genetic devices can be assembled to reprogram mammalian cell activities. Here, we demonstrate that a self-adjusting synthetic gene circuit can be designed to sense and reverse the insulin-resistance syndrome in different mouse models. By functionally rewiring the mitogen-activated protein kinase (MAPK) signalling pathway to produce MAPK-mediated activation of the hybrid transcription factor TetR-ELK1, we assembled a synthetic insulin-sensitive transcription-control device that self-sufficiently distinguished between physiological and increased blood insulin levels and correspondingly fine-tuned the reversible expression of therapeutic transgenes from synthetic TetR-ELK1-specific promoters. In acute experimental hyperinsulinemia, the synthetic insulin-sensing designer circuit reversed the insulin-resistance syndrome by coordinating expression of the insulin-sensitizing compound adiponectin. Engineering synthetic gene circuits to sense pathologic markers and coordinate the expression of therapeutic transgenes may provide opportunities for future gene- and cell-based treatments of multifactorial metabolic disorders.