基底刚度影响抗肿瘤药物效果的生物力药理学研究

项目名称： 基底刚度影响抗肿瘤药物效果的生物力药理学研究

项目编号： No.31470905

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 生物科学

项目作者： 韩东

作者单位： 国家纳米科学中心

项目金额： 90万元

中文摘要： 基底刚度作为肿瘤微环境中重要的力学参数，在肿瘤发生、发展的病生理过程中起着重要的作用。本项目拟以生物力药理学理论为构架，运用生物信息学分析方法，着重研究基底刚度影响抗肿瘤药物效果的分子生物学机制。具体内容包括（1）制备可控刚度的丙烯酰胺凝胶基底，并培养肿瘤细胞；（2）进行不同刚度基底上抗肿瘤药物（顺铂、Lapatinib）作用与否SK-BR-3细胞内差异表达基因的鉴定、生物信息学的分析和验证；（3）探讨特定基因所在信号通路在刚度影响肿瘤细胞生长中的作用；（4）阐明特定基因所在信号通路在刚度影响抗肿瘤药物杀伤SK-BR-3细胞效果的作用。最终构建力学因素参与的肿瘤发生、发展特异性信号网络，为肿瘤早期诊断、治疗及预后改善提供新靶点。同时，确定特定基因及所在信号通路在力学因素影响肿瘤细胞性状及对抗肿瘤药物反应中的作用，拓展目前以塑料培养板为常规的体外药敏实验方法，建立更加合理和全面的药物筛选体系

中文关键词： 生物力药理学；刚度；抗肿瘤药；生物信息学；药物筛选

英文摘要： Substrate stiffness as a crucially mechanical parameter within tumor microenvironments plays an important role in the pathophysiological process of tumor genesis and its development. This project intends to base on the theory framework of mechanopharmacology, focusing on the molecular mechanism on the antitumor drug response of tumor cells on different substrate stiffness by means of bioinformatics analysis methods. The plan includes the follow contents: (1) Fabricate the substrates with different stiffness by acrylamide gel and then culture the tumor cells on these stiffness-controlled substrates. (2) Carry out the identification of differentially expressed genes, bioinformatics analysis and validation in order to reveal the response of SK-BR-3 cells on the different substrate stiffness to antitumor drugs (including Cisplatin and Lapatinib). (3) Investigate the signaling pathways decided by specific genes which mediate the impact of substrate stiffness on tumor cell growth. (4) Clarify what are specific signaling pathways to mediate the response of SK-BR-3 cells cultured on different substrate stiffness to the antitumor drugs. Based on the results mentioned above, we can finally construct the signaling network of how the mechanical factors mediate both tumor genesis and its development, providing new targets for cancer early diagnosis, treatment and prognosis estimate. Meantime, this project may improve the better understanding of how the mechanical properties influent the response of tumor cells to antitumor drugs, developing a more rational and comprehensive antitumor drug screening system based on the substrates with variable stiffness, instead of the current conventional plastic culture plates in vitro.

英文关键词： mechanopharmacology;stiffness;antitumor drug;bioinformatics;drug screening