A Synthetic-Biology-Inspired Therapeutic Strategy for Targeting and Treating Hepatogenous Diabetes.
A Synthetic-Biology-Inspired Therapeutic Strategy for Targeting and Treating Hepatogenous Diabetes.
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DOI：
10.1016/j.ymthe.2016.11.008
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发表时间：
2017-02
期刊：
影响因子：
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通讯作者：
Shuai Xue;Jianli Yin;Jiawei Shao;Yuanhuan Yu;Linfeng Yang;Yidan Wang;Mingqi Xie;M. Fussenegger;Haifeng Ye
中科院分区：
文献类型：
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作者：
Shuai Xue;Jianli Yin;Jiawei Shao;Yuanhuan Yu;Linfeng Yang;Yidan Wang;Mingqi Xie;M. Fussenegger;Haifeng Ye
肝源性糖尿病是一种复杂的疾病，其典型特征是2型糖尿病和多种肝脏疾病同时存在。在这个病理生理网络中，主要的致病决定因素是胰岛素抵抗（IR），这是一种无症状的疾病状态，在这种状态下，靶组织中的胰岛素信号受损会引发各种器官功能障碍。然而，靶向IR的药物治疗仍然有限，通常不适用于肝病患者。齐墩果酸（OA）是一种从植物中提取的三萜，作为一种安全但作用缓慢的治疗多种肝脏疾病的药物，在中药中经常被使用。在这里，我们利用OA和胰高血糖素样肽1 （GLP-1）在缓解IR和改善肝脏和胰腺功能方面的一致药理活性，并使用合成生物学启发的设计原则来设计治疗基因回路，使两种药物协同作用。尤其值得一提的是，在肝源性糖尿病小鼠中，OA触发了短时间的人GLP-1 （shGLP-1）表达，迅速并同时减轻了许多疾病特异性代谢衰竭，而OA或shGLP-1单药治疗未能达到相应的治疗效果。总的来说，这项工作表明，合理设计的合成基因回路能够通过多种单一治疗方法的靶向效果，以协同方式治疗多因素疾病。
Hepatogenous diabetes is a complex disease that is typified by the simultaneous presence of type 2 diabetes and many forms of liver disease. The chief pathogenic determinant in this pathophysiological network is insulin resistance (IR), an asymptomatic disease state in which impaired insulin signaling in target tissues initiates a variety of organ dysfunctions. However, pharmacotherapies targeting IR remain limited and are generally inapplicable for liver disease patients. Oleanolic acid (OA) is a plant-derived triterpenoid that is frequently used in Chinese medicine as a safe but slow-acting treatment in many liver disorders. Here, we 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. In particular, OA-triggered short human GLP-1 (shGLP-1) expression in hepatogenous diabetic mice rapidly and simultaneously attenuated many disease-specific metabolic failures, whereas OA or shGLP-1 monotherapy failed to achieve corresponding therapeutic effects. Collectively, this work shows that rationally engineered synthetic gene circuits are capable of treating multifactorial diseases in a synergistic manner by multiplexing the targeting efficacies of single therapeutics.