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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Pharmaceutically controlled designer circuit for the treatment of the metabolic syndrome
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Pharmaceutically controlled designer circuit for the treatment of the metabolic syndrome

机译：药物控制的设计者回路，用于代谢综合征的治疗

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摘要

Synthetic biology has significantly advanced the design of genetic devices that can reprogram cellular activities and provide novel treatment strategies for future gene- and cell-based therapies. However, many metabolic disorders are functionally linked while developing distinct diseases that are difficult to treat using a classic one-drug-one-disease intervention scheme. For example, hypertension, hyperglycemia, obesity, and dyslipidemia are interdependent pathologies that are collectively known as the metabolic syndrome, the prime epidemic of the 21st century. We have designed a unique therapeutic strategy in which the clinically licensed antihyperten-sive drug guanabenz (Wytensin) activates a synthetic signal cascade that stimulates the secretion of metabolically active peptides GLP-1 and leptin. Therefore, the signal transduction of a chimeric trace-amine-associated receptor 1 (cTAAR1) was functionally rewired via cAMP and cAMP-dependent phosphokinase A (PKA)-mediated activation of the cAMP-response element binding protein (CREB1) to transcription of synthette promoters containing CREB1-specific cAMP response elements. Based on this designer signaling cascade, it was possible to use guanabenz to dose-dependently control expression of GLP-1-FC_(mIgG)-Leptin, a bifunctional therapeutic peptide hormone that combines the glucagon-like peptide 1 (GLP-1) and leptin via an IgG-Fc linker. In mice developing symptoms of the metabolic syndrome, this three-in-one treatment strategy was able to simultaneously attenuate hypertension and hyperglycemia as well as obesity and dyslipidemia. Using a clinically licensed drug to coordinate expression of therapeutic transgenes combines drug- and gene-based therapies for coordinated treatment of functionally related metabolic disorders.
机译：合成生物学大大提高了遗传设备的设计，可以重新编程细胞活动并为未来基于基因和细胞的疗法提供新颖的治疗策略。然而，许多新陈代谢疾病在功能上联系在一起，同时发展出独特的疾病，这些疾病很难使用经典的“一药一病”干预方案来治疗。例如，高血压，高血糖症，肥胖症和血脂异常是相互依存的疾病，统称为21世纪主要流行的代谢综合征。我们设计了一种独特的治疗策略，在该策略中，临床许可的降压药瓜纳本斯（Wytensin）激活合成信号级联反应，从而刺激代谢活性肽GLP-1和瘦蛋白的分泌。因此，嵌合的痕量胺相关受体1（cTAAR1）的信号转导通过cAMP和cAMP依赖性磷酸激酶A（PKA）介导的cAMP反应元件结合蛋白（CREB1）的激活在功能上进行了重新合成。含有CREB1特异性cAMP反应元件的启动子。基于该设计者的信号级联反应，有可能使用瓜纳贝斯剂量依赖性地控制GLP-1-FC_（mIgG）-Leptin的表达，GLP-1-FC_（mIgG）-Leptin是一种双功能治疗性肽激素，结合了胰高血糖素样肽1（GLP-1）和瘦蛋白通过IgG-Fc接头。在出现代谢综合征症状的小鼠中，这种三合一治疗策略能够同时减轻高血压和高血糖症以及肥胖和血脂异常。使用临床许可的药物来协调治疗性转基因的表达，结合了基于药物和基于基因的疗法，以协调治疗功能相关的代谢性疾病。

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  • 作者

    Haifeng Ye; Ghislaine Charpin-El Hamri; Katharina Zwicky; Matthias Christen; Marc Folcher; Martin Fussenegger;

  • 作者单位

    Department of Biosystems Science and Engineering, Swiss Federal Institute of Technology Zurich, CH-4058 Basel, Switzerland;

    Departement Genie Biologique, Institut Universitaire de Technologie, F-69622 Villeurbanne Cedex, France;

    Department of Biosystems Science and Engineering, Swiss Federal Institute of Technology Zurich, CH-4058 Basel, Switzerland;

    Department of Biosystems Science and Engineering, Swiss Federal Institute of Technology Zurich, CH-4058 Basel, Switzerland;

    Department of Biosystems Science and Engineering, Swiss Federal Institute of Technology Zurich, CH-4058 Basel, Switzerland;

    Department of Biosystems Science and Engineering, Swiss Federal Institute of Technology Zurich, CH-4058 Basel, Switzerland,Faculty of Science, University of Basel, CH-4058 Basel, Switzerland;

  • 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

    synthetic gene circuits; prosthetic networks; gene regulation; gene expression;

    机译：合成基因电路;假肢网络;基因调控;基因表达;

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