摘要
Synthetic biology has significantly advanced the design of genetic devices that can reprogram metabolic activities in mammalian cells and provide novel therapeutic strategies for gene-and cell-based therapies. Here we described two novel synthetic designer circuits for the treatment of diabetes related disorders. First, we have assembled an oleanolic acid(OA) controlled designer circuit which allowed OA-triggered sh GLP-1 expression in hepatogenous diabetic mice rapidly and simultaneously attenuated many disease-specific metabolic failures, such as glucose intolerance, insulin resistance, hyperglycemia, dyslipidemia and excessive liver enzyme levels, whereas OA monotherapy failed to achieve corresponding therapeutic effects. Therefore, in this study we have utilized the congruent pharmacological activities of OA and glucagon-like-peptide 1(GLP-1) in relieving IR and improving liver and pancreas functions and used a synthetic biology-inspired design principle to engineer a therapeutic gene circuit that enables a concerted action of both drugs. Second, we also have designed a synthetic mammalian self-adjusting circuit to sense and reverse the insulin resistance syndrome in different mouse models. We designed a synthetic insulin-sensitive transcription controller that self-sufficiently distinguished between physiological and pathological blood insulin levels and correspondingly fine-tuned the reversible transgene expression. In mice with insulin-resistant obesity(ob/ob) and diet-induced obesity(DIO), both of which develop acute hyperinsulinaemia, the synthetic insulin-sensing designer circuit reversed the insulin resistance syndrome by controlling the expression of Fc-adiponectin to attenuate insulin resistance and dyslipidaemia, respectively. By using FDA approved drugs as trigger switches or engineering synthetic gene network devices to sense pathologic markers and coordinate the expression of therapeutic transgenes may provide new opportunities for future gene-and cell-based treatments of multifactorial metabolic disorders.
Synthetic biology has significantly advanced the design of genetic devices that can reprogram metabolic activities in mammalian cells and provide novel therapeutic strategies for gene-and cell-based therapies. Here we described two novel synthetic designer circuits for the treatment of diabetes related disorders. First, we have assembled an oleanolic acid(OA) controlled designer circuit which allowed OA-triggered sh GLP-1 expression in hepatogenous diabetic mice rapidly and simultaneously attenuated many disease-specific metabolic failures, such as glucose intolerance, insulin resistance, hyperglycemia, dyslipidemia and excessive liver enzyme levels, whereas OA monotherapy failed to achieve corresponding therapeutic effects. Therefore, in this study we have utilized the congruent pharmacological activities of OA and glucagon-like-peptide 1(GLP-1) in relieving IR and improving liver and pancreas functions and used a synthetic biology-inspired design principle to engineer a therapeutic gene circuit that enables a concerted action of both drugs. Second, we also have designed a synthetic mammalian self-adjusting circuit to sense and reverse the insulin resistance syndrome in different mouse models. We designed a synthetic insulin-sensitive transcription controller that self-sufficiently distinguished between physiological and pathological blood insulin levels and correspondingly fine-tuned the reversible transgene expression. In mice with insulin-resistant obesity(ob/ob) and diet-induced obesity(DIO), both of which develop acute hyperinsulinaemia, the synthetic insulin-sensing designer circuit reversed the insulin resistance syndrome by controlling the expression of Fc-adiponectin to attenuate insulin resistance and dyslipidaemia, respectively. By using FDA approved drugs as trigger switches or engineering synthetic gene network devices to sense pathologic markers and coordinate the expression of therapeutic transgenes may provide new opportunities for future gene-and cell-based treatments of multifactorial metabolic disorders.
引文
1.Haifeng Ye*,Mingqi Xie,Shuai Xue,Ghislaine Charpin-El Hamri,Jianli Yin,Henryk Zulewskiand Martin Fussenegger*.Self-adjusting synthetic gene circuit for correcting insulin resistance.Nature Biomedical Engineering 1,0005,2016.(co-first and co-corresponding author)
2 .Shuai Xue,Jianli Yin,Jiawei Shao,Yuanhuan Yu,Linfeng Yang,Yidan Wang,Mingqi Xie,Martin Fussenegger and Haifeng Ye*,A synthetic biology-inspired therapeutic strategy for targeting and treating hepatogenous diabetes.Molecular Therapy,In press.DOI:http://dx.doi.org/10.1016/j.ymthe.2016.11.008(corresponding author)
3 .Mingqi Xie,Haifeng Ye,Hui Wang,Ghislaine Charpin-El Hamri,Claude Lormeau,Pratik Saxena,J?rg Stelling*and Martin Fussenegger*.β-cell-mimetic designer cells provide closed-loop glycemic control.Science 354:1296-1301(2016)