TLR4异常激活导致BM-MSCs衰老在SLE发生中的作用

项目名称： TLR4异常激活导致BM-MSCs衰老在SLE发生中的作用

项目编号： No.81471603

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 顾志峰

作者单位： 南通大学

项目金额： 80万元

中文摘要： 课题组前期研究表明SLE患者BM-MSCs是衰老的MSCs，参与狼疮发生发展，但衰老原因不明。预实验发现SLE患者骨髓上清液中HMGB-1等炎性因子高表达；SLE患者BM-MSCs内TLR4信号转导异常活化，作用于TLR4通路的mir146a显著低表达。据此提出HMGB-1通过激活TLR4信号转导导致SLE患者BM-MSCs衰老；mir146a通过调节TLR4信号转导参与其中的假说。课题组拟首先分析SLE患者BM-MSCs中TLR4表达异常与衰老的关系；在此基础上分析HMGB-1与TLR4结合及mir146a对TLR4信号转导调节在BM-MSCs衰老及免疫失能中的作用；最后在SLE动物模型内观察干预上述机制后BM-MSCs移植的疗效。本课题为阐明SLE患者BM-MSCs衰老机制提供实验基础，为寻找SLE治疗的新方法提供理论依据。

中文关键词： 系统性红斑狼疮；间充质干细胞；衰老；TLR4；炎症

英文摘要： Previous studies of our research group revealed the senescence of BM-MSCs from SLE patients, which participated in the development of SLE. However, the mechanism of the senescence remained uncertain. In the preliminary experiments, we discovered the high expression of inflammation factors, such as HMGB-1 in the supernate of SLE patients' bone marrow, the abnormal activation of TLR4 signal transduction in the BM-MSCs from SLE patients, and the distinctively low expression of the mir146a upon TLR4 pathway. Upon this, we proposed the hypothesis that HMGB-1 triggered the senescence of BM-MSCs from SLE patients through the activation of TLR4 signal transduction, and mir146a participated in the process through the inhibition of TLR4 signal transduction. To test our hypothesis, we conducted the following experiments: 1)We studied the correlation of the senescence with the abormal expression of TLR4 in the BM-MSCs from SLE patients. 2) On this basis, we analyzed the combination of HMGB-1and TLR4, the regulation of mir146a upon TLR4 signal transduction, and their effects on the BM-MSCs senescence and the immune dysfunction.3)Finally, we explored the effect in animal models by transplanting treated BM-MSCs. This project provided the experimental basis to understand the mechanism of SLE BM-MSCs senescence and the theoretical basis to seek new treatments of SLE.

英文关键词： systemic lupus erythematosus;mesenchymal stem cells;senescence;TLR4;inflammation