糖尿病促进与加重缺血性脑损伤已得到了临床上的广泛证实，但目前还不清楚补体C3的活化是否参与了其损伤过程。我们前期预实验发现，糖尿病合并脑缺血时脑内C3的表达增加，而C3基因敲除能保护糖尿病加重的缺血性脑损伤并减少TLR2和TLR4（TLR2/4）的表达，而这可能与抑制C5L2、C3aR的激活有关。因此，根据已有的文献及课题组预实验，我们提出假设：糖尿病合并脑缺血时存在着C3的活化增强，其通过C3aR或C5L2等受体调节TLR2/4的功能，从而加重了缺血性脑损伤。我们拟利用C3基因敲除小鼠、RNA干扰、基因过表达等技术从整体、细胞和分子水平上对以上假设进行验证。本课题的完成，将进一步深入认识C3在中枢神经系统中的作用，并可从抑制C3的活化及其下游信号通路出发，为治疗糖尿病伴缺血性脑损伤等疾病提供新的方向。

Diabetes promoting and aggravating cerebral ischemia injury has been widely confirmed in the clinic, but whether the activating of complement component C3 (C3) was participating in it is still not know. Our preliminary data demonstrated that C3 was increased in diabetes ischemic brain injury, which was protected by C3 deficiency through inhibiting C5L2 or C3aR activity and decreasing TLR2 and TLR4 (TLR2/4) expression. Based on ours and other's work, we propose a hypothesis: diabetic cerebral ischemia increases C3 activity, by activating C3aR or C5L2, regulating TLR2/4 signalling, and then worsens the outcome of ischemia injury. In this project, C3 knockout mice, RNA interference and gene over-expression technology were used to explore the hypothesis. After proving the hypothesis, it will help to know the roles of C3 in central nervous system, and then provide a new way to treat cerebral ischemia injury associated with comorbid diabetes by blocking C3 activation or its downstream pathways.

补体C3（C3）是补体系统中的一个关键因子，广泛参与各种炎症相关疾病。但其在糖尿病脑缺血/再灌注（I/R）损伤发病机制中的作用尚不清楚。本研究发现补体C3活性增加与糖尿病脑缺血再灌注损伤有关，补体C3缺乏减轻缺血性脑缺血再灌注损伤。此外，补体C3促进缺血通过TLR2激活在糖尿病引起的神经细胞死亡。值得注意的是，在糖尿病小鼠，补体C3的招募和结合到TLR2，从而促进脑I/R损伤。另外，补体C3直接诱导TLR2的表达，在体内和体外通过p65磷酸化激活NF-κB信号通路。最后，系统地补充补体C3抑制剂对糖尿病小鼠脑缺血再灌注损伤的保护作用。因此，在糖尿病小鼠中，补体C3促进脑I/R损伤通过TLR2 / NFκB信号通路介导的，调节补体C3可能是糖尿病脑卒中治疗的新靶点。