PID1基因介导胰岛素抵抗环境下肿瘤发生的机制及药物靶点研究

项目名称： PID1基因介导胰岛素抵抗环境下肿瘤发生的机制及药物靶点研究

项目编号： No.81673440

项目类型： 面上项目

立项/批准年度： 2017

项目学科： 医药、卫生

项目作者： 向明

作者单位： 华中科技大学

项目金额： 25万元

中文摘要： 糖尿病尤其是胰岛素抵抗可增加罹患肿瘤的风险性。胰岛素可与上皮组织胰岛素受体结合直接促进肿瘤形成，还可通过胰岛素样生长因子、异位激素和炎症因子等间接促发肿瘤形成。我们前期工作发现PID1基因既在胰岛素抵抗中发挥作用又在胰腺癌细胞中高表达。基于PID1连接的细胞增殖、免疫调控和胰岛素敏感性信号通路很可能关联糖尿病胰岛素抵抗与肿瘤形成，我们拟通过受体蛋白质芯片技术，液质联用和计算机运算分析临床样本、糖代谢关键细胞、免疫细胞和肿瘤细胞中PID1上下游作用分子及其结合蛋白；通过3D细胞培养研究高胰岛素或高糖环境下PID1及其通路在肿瘤干细胞分化、增殖和肿瘤形成方面所起的关键作用；最终通过建立体内胰岛素抵抗背景下肿瘤形成模型，研究PID1对肿瘤发生及免疫微环境和代谢微环境的调控方式，研究活性化合物的药理作用与机制，以确定靶向PID1调控通路发挥抗胰岛素抵抗和抗肿瘤作用的可能性。

中文关键词： PID1；肿瘤发生；胰岛素抵抗；药物靶点；机制研究

英文摘要： Diabetes, especially insulin resistance, increases the risk of tumor development. Insulin not only promotes neoplasia via insulin receptors on epithelial tissue directly, but also accelerates cancinogenesis by insulin growth factor, ectopic hormone and inflammatory factors indirectly. We previously reported that the gene named PID1, which can abet insulin resistance, was found highly expressed in pancreatic cancer cells. It is extremely possible that PID1, a gene involved in cell proliferation, immunoregulation and insulin sensitive signal pathway, may exert as the key regulator for the elevated cancer risk under insulin resistance. Hence, with the application of receptor protein chip, liquid chromatography tandem mass spectrometry and computer arithmetics, we are intend to explore the upstream and downstream molecules and receptor of PID1 in clinical samples and pivotal cells related to glycometabolism, immune cells and cancer stem cells, respectively. Then we plan to detect how the signal pathway of PID1 impacts the differentiation and proliferation of cancer cells and tumorigenesis in the high insulin or high glucose environment in vitro by three-dimensional cell culture. Afterwards, we are going to study the regulation mode of PID1 on tumorigenesis, immune and metabolic microenvironment, by establishing the oncogenesis murine model based on insulin resistance in vivo. Besides, we are aim to identify the possibility of PID1 as the target for finding active compounds with both anti-insulin resistant and anti-cancer effects by studying the pharmacological action and mechanism of the active compound.

英文关键词： PID1;Cancinogenesis;Insulin resistance;drug target;mechanism study