CD44/透明质酸偶联激活PI3K/Akt信号通路对提高肠干细胞修复放射性肠损伤的作用机制研究

项目名称： CD44/透明质酸偶联激活PI3K/Akt信号通路对提高肠干细胞修复放射性肠损伤的作用机制研究

项目编号： No.81502751

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 常鹏宇

作者单位： 吉林大学

项目金额： 18万元

中文摘要： 我们前期已建立小鼠CD44阳性肠干细胞的分选培养体系，但目前尚未见使用该细胞修复放射性肠损伤的研究报道。为此，本项目将对这一问题展开研究并探索CD44阳性肠干细胞在损伤环境下抵御凋亡的机制。CD44为透明质酸的受体。二者偶联所介导的细胞黏附及抗凋亡作用在肿瘤转移模型中被证实；其中，细胞凋亡抗性提高系PI3K/Akt通路激活所致。这是开展本项目的理论基础。我们通过建立以透明质酸为基础的‘细胞迁徙’和‘细胞抗凋亡’体外模型，分别研究CD44/透明质酸偶联对促进肠干细胞定植的作用；及其激活PI3K/Akt通路对提高肠干细胞凋亡抗性的分子机制。另外，建立放射性肠损伤NOD/SCID小鼠模型，以Cd44基因敲除肠干细胞为对照；通过比较CD44阳性肠干细胞和CD44阴性肠干细胞在损伤部位的定植效率、凋亡数量和表达PI3K/Akt通路下游相关凋亡分子水平的差异，评价CD44阳性肠干细胞修复肠损伤的优势。

中文关键词： 肠干细胞；放射性肠损伤；CD44；透明质酸；信号通路

英文摘要： In our preliminary work, the system for both sorting and culturing murine CD44-positive intestinal stem cells had been established. However, no one reports the results indicating whether the intestinal stem cells have therapeutic potentials for radiation-induced intestinal injury. To this end, we plan to do this research aiming at determining the therapeutic effects of CD44-positive intestinal stem cells on injured epithelium induced by ionizing irradiation, and exploring the intrinsic mechanisms by which intestinal stem cells repair epithelial injuries. CD44, a surface antigen, is the receptor of hyaluronic acid. Coupling between CD44 and hyaluronic acid will initiate the adhensive process of cancer cells and increase their anti-apoptotic potentials, which is predominantly driven by PI3K/Akt signalling pathway. On this basis, we attempt to establish the hyaluronic acid based models of 'Cell-migration' and ‘Anti-apoptosis’ in vitro for mimicking the adhension of intestinal stem cells to injured sites in vivo, and exploring mechanism by which PI3K/Akt enhances capability of intestinal stem cells in defensing injured milieu-induced cell-apoptosis. In vivo, we try to establish a NOD/SCID mouse model of radiation-induced intestinal injury to determine the therapeutic effects of CD44-positive intestinal stem cells on epithelial injuries. By comparing to the intestinal stem cells of Cd44 gene knock-out, we try to evaluate the advantages of CD44-positive intestinal stem cells in the following aspects, including their engrafting efficacies in injured sites, their apoptosis and the expressions of apoptosis-related molecules downstreaming of PI3K/Akt signalling pathway.

英文关键词： Intestinal stem cell;Radiation-induced intestinal injury;CD44;Hyaluronic acid;Signalling pathway