调控IRF3介导小胶质细胞向M2方向极化改善放射性脑损伤的机制研究

项目名称： 调控IRF3介导小胶质细胞向M2方向极化改善放射性脑损伤的机制研究

项目编号： No.81471249

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： 唐亚梅

作者单位： 中山大学

项目金额： 70万元

中文摘要： 我们前期数据提示放射后小胶质细胞（MG）存在损伤性M1（表现为分泌炎症因子，同时吞噬力下降致有害代谢物蓄积加重损伤）和保护性M2（分泌抑炎因子同时吞噬力升高）两种表型，调控M1向M2方向极化是潜在治疗策略，但何时进行调控，怎样调控值得进一步研究。转录因子IRF3具有抑制MG分泌炎症因子同时促进抗炎因子分泌的特性，是使MG向M2极化的理想调控靶点。本课题拟：①研究放射后 M1/M2表型变化，明确极化表型时相及调控切入点；②通过IRF3 -/-细胞及基因敲除动物，探讨上调IRF3后MG分泌因子谱及吞噬能力变化，证实上调IRF3后MG表型由M1向M2转变，并研究其信号机制；③上调IRF3使MG向M2方向极化，抑制MG分泌炎症递质，提高MG吞噬力，通过神经元共培养、髓鞘形成共培养，轴突和髓鞘染色及神经元损伤病理检查，阐明上调IRF3促进M2极化改善脑损伤的机制，为放射性脑损伤的治疗提供新的突破口。

中文关键词： 放射性脑损伤；小胶质细胞；干扰素调节因子3；极化

英文摘要： Preliminary data and literatures indicated that radiation activated microglia have two phenotype, pro-inflammatory M1 and anti-inflammatory M2. Modulation of the phenotypic variation from M1 to M2 will be potential therapeutic stratergy for radiation induced brain injury(RI). However, when and how to modulate the transformation remains unknown. IRF3 is an ideal target to promote M2 phenotype, for it can suppress secrection of inflammatory factors, yet enhance the production of anti-inflammatory cytokines. We aim to firstly confirm the temporal change of microglia phenotype. By using IRF3-/-cells and gene knockout animal model, we will further study the level of pro-inflammatory and anti-inflammatory cytokines secreted by microglia, as well as its phagocytosis ability. Remyelination and axon regeneration would be examined to evaluate the effect of modulation of microglia phenotype variation from M1 to M2 in RI. The study would provide evidence for targeting phenotype variation of microglia as the further treatment strategy of RI.

英文关键词： radiation-induced brain injury;microglia;Interferon regulatory factor 3;polarization