原儿茶酸基因网络调控系统的设计、构建及其用于肥胖治疗的研究

项目名称： 原儿茶酸基因网络调控系统的设计、构建及其用于肥胖治疗的研究

项目编号： No.31470834

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 心理学

项目作者： 叶海峰

作者单位： 华东师范大学

项目金额： 90万元

中文摘要： 利用合成生物学原理可以设计出多种基因环路调控系统，这些调控系统可用于细胞行为重编程，从而为未来基于基因和细胞的生物治疗提供新策略。本项目利用合成生物学手段设计、构建原儿茶酸(PCA)调控转基因表达基因环路并用于肥胖治疗。首先，利用合成生物学和工程学设计理念，把相关基因模块合理组装成一个PCA调控的网络控制元件；其次，将此合成控制元件上载到哺乳动物细胞中并研究PCA调控基因表达的可调性、可逆性等动力学特征；再次，利用细胞微囊包裹技术将含有该控制元件的工程化动物细胞移植到小鼠体内，并研究该控制元件在PCA的调控下，小鼠体内的基因表达动力学特征；最后，通过肥胖小鼠腹腔注射PCA或口服PCA、绿茶调控体内融合蛋白Fc-Adiponectin的表达，降血脂、降血糖达到治疗肥胖的目的。本研究提出的以人工构建PCA调控的肥胖治疗基因环路为基础的细胞治疗策略，将为人类健康提供新途径。

中文关键词： 哺乳动物合成生物学；基因环路；基因调控；原儿茶酸；细胞治疗

英文摘要： Synthetic biology has significantly advanced the rational design of trigger-controlled gene circuits that can reprogram cell activities and provide novel therapeutic strategies for future gene- and cell-based therapies. In this study, we aim to construct a protocatechuic acid (PCA) regulated transgene expression system for obesity treatment. First, capitalizing on the principle of synthetic biology and engineering, we can design and create novel gene circuits with new function by integrating well-studied gene modules. Second, the PCA regulated synthetic gene device could be uploaded into mammalian cells to study the tunability and reversibility of transgene expression controlled by PCA. Third, the microencapsulated mammalian cells containing the PCA-trigger device could be further implanted into mice and study the transgene expression kinetics triggered by PCA. Lastly, obesity model mice implanted with Fc-adiponectin expression circuits regulated by PCA and treated by either intraperitoneal injection of PCA or oral administration of PCA or green tea, we can study the fatty acids and glucose levels in the blood and achieve the purpose of obesity treatment. Synthetic gene switches using food metabolites as trigger compounds provide new opportunities for future gene- and cell-based therapies to improve human health.

英文关键词： mammalian synthetic biology;gene circuit;gene regulation;protocatechuic acid;cell therapy