RKIP介导的神经细胞自噬调节对脑卒中的保护作用及机制

脑卒中在我国发病率高、致残率高，严重影响患者的生活质量和寿命。我们前期研究发现：1）Raf激酶抑制蛋白（RKIP）对缺血性脑卒中有显著保护作用；2）RKIP通过调节ERK和NF-κB通路降低糖氧剥夺模型对神经细胞的损伤，同时可调节小胶质细胞的活化从而保护神经细胞。有趣的是RKIP的保护作用优于相关下游通路的抑制剂，提示RKIP很可能在多层面起到保护神经的作用。我们进而发现RKIP与自噬相关蛋白LC3II存在明显相互作用，推测其通过调节自噬流清除细胞内导致细胞死亡物质的积累从而保护神经细胞。本课题拟在前期研究基础上利用多种分子和细胞生物学技术，通过体外糖氧剥夺模型和大脑中动脉栓塞模型，探讨高表达RKIP对缺血性脑卒中的保护作用与调节神经细胞自噬之间的关系，揭示RKIP通过LC3分子自噬途径对缺血性脑卒中保护作用的分子机制。本研究可发现影响脑卒中发生发展的关键靶点，为脑卒中的防治提供新的思路。

Stroke has high morbidity and disability rate in China and seriously affects the quality of life and life span of patients. Our previous studies have shown that: 1) Raf kinase inhibitor protein (RKIP) has a significant protective effect on ischemic stroke; 2) RKIP attenuated the damage to nerve cells by oxygen glucose deprivation and blocked the activation of microglia. The protective effect of RKIP on nerve cells were mediated by inhibiting ERK and NF-κB activation. Interestingly, the protective effect of RKIP is better than the effect of the pathways inhibitors, which may suggest that RKIP plays a role in protecting nerves with multiple layers. Next we found that RKIP could interact with autophagy related protein LC3II which implied that RKIP may involve in the autophagy regulation. We speculated that RKIP might accelerate the clearance of intracellular autophagosomes accumulation and protect nerve cells. Based on our previous studies, we will use molecular and cellular biological approaches to investigate the how RKIP regulates autophagy in oxygen glucose deprivation cell model and rat ischemic MCAO stroke animal model. We will also explore the molecular mechanism how the interaction between RKIP and LC3 contribute to the regulation of autophagy pathway. In the present study, we can find out the key targets and mechanisms of the pathogenesis of stroke and provide new insights for the prevention and treatment of stroke.