Fas/FasL介导小胶质细胞-T细胞Crosstalk与缺血性脑免疫炎症的研究

脑免疫炎症反应是影响缺血性卒中预后的主要因素。小胶质细胞与T细胞Crosstalk与卒中后脑免疫炎症的发生发展和转归密切相关。我们首先发现，下调FasL抑制卒中后免疫炎症及小胶质细胞与T细胞相互作用，保护缺血性脑损伤，此作用不依赖Fas/FasL诱导的细胞凋亡途径。本课题在前期工作基础上，采用FasL基因突变小鼠、T细胞，胶质细胞FasL基因条件敲除鼠以及GFP鼠，制备基因条件敲除的原代共培养细胞和体内外脑缺血模型，在整体、细胞和分子水平研究Fas/FasL介导小胶质细胞与T细胞Crosstalk在缺血性免疫炎症中的重要作用，阐明调控机制，并临床转化研究。本研究将揭示FasL调控卒中后免疫细胞功能在缺血性脑免疫炎症机制中的重要地位；提出FasL在脑-免疫细胞网络中调控免疫细胞功能的新理念；建立以FasL、小胶质细胞、T细胞功能标志物为卒中后患者脑功能评估指标，指导临床靶向性治疗和预后评估。

Post-stroke immune and inflammatory response plays an important role in the prognosis of ischemic stroke. Crosstalk between microglia and T lymphocytes correlates to the development of ischemic brain immune and inflammation. We first investigated that down-regulation of FasL could inhibit post-stroke immune and inflammatory response and the interaction between microglia and T lymphocytes in Gld mice. Moreover, FasL mutation protected against ischemic brain damage independent of Fas/FasL induced apoptosis. Based on our previous researches, Gld, FasLf/f,LCKcre, FasLf/f,NestinCre and GFP mice will be used to establish ischemic models in vivo and in vitro. We will investigate FasL mediated post-stroke crosstalk between microglia and T lymphocytes at tissue, cellular and molecular levels and its relation to the development of ischemic stroke. We will demonstrate that FasL is a key regulator in immune and inflammatory response following stroke and find the relevant mechanism; and will propose the new concept that FasL could modulate the crosstalk and function of immune cells in the immune and inflammatory network; and set up new bio-markers relating to FasL, microglia and T lymphocytes function, which could be used for targeted therapy and prognosis evaluation in the clinic.