TOPK调节CRMP-2磷酸化介导脑缺血再灌注新生神经元极化的分子机制

神经元极化是脑缺血损伤后新生神经元形成有功能的突触、整合至原有的神经环路中并存活下来的结构基础。脑衰反应调节蛋白-2（CRMP-2)，是一种微管相关蛋白，在神经元发育过程中参与神经元极化。T-LAK细胞源蛋白激酶（TOPK）高度表达于成年脑组织中增殖期的神经前体细胞，作用于微管相关蛋白参与有丝分裂过程中的胞浆分裂。我们前期发现TOPK在脑缺血-再灌注后可以促进组蛋白去乙酰化酶HDAC1和HDAC2磷酸化而抑制其活性，进一步质谱分析发现HDAC1和HDAC2均与CRMP-2特异结合。本项目拟利用离体和在体实验，验证假说：TOPK通过作用于CRMP-2发挥促进新生神经元极化并提高其存活率的作用，最终减轻脑缺血损伤并促进神经功能恢复，为脑缺血-再灌注损伤后内源性新生神经元替代治疗提供理论依据和治疗靶点。

Neuronal polarity is the structural basis that the newly-generated neurons form functional synapse,integrate in old neuronal circuits and survive following ischemic brain injury. CRMP-2，a microtubule-associated protein, involves in neuronal polarity during neuronal development. TOPK is highly enriched in the proliferating progenitors in the adult brain. It acts on microtubule-associated protein and promotes cytokinesis during mitosis. We previously found that TOPK promoted the phosphorylation of HDAC1/HDAC2 and inhibited their activity. The futher mass spectrometry demonstrated that both HDAC1and HDAC2 bonded to CRMP-2 specificly. In the present study, we will verify the following hypothesis: TOPK promotes neuronal polarity and improves their survival following cerebral ischemia-reperfusion via regulating CRMP-2 by using in vivo and in vitro experiments. It will alleviate ischemic brain injury, promote functional recovery and provide a theoretical basis and new therapeutic target for replacement therapy using endogenous neurogenesis following cerebral ischemia-reperfusion.