Rac1介导SDF-1/CXCR4轴参与脑梗塞后内源性神经干细胞迁移的作用及机制

After cerebral ischemia, the migration of endogenous neural stem cells (eNSCs) toward the ischemic zone is a critical process for neural regeneration and repair during recovery phase. The SDF-1/CXCR4 axis, a critical signaling pathway composed of chemokine SDF-1 and its receptor CXCR4, was demonstrated to promote migration of eNSCs after cerebral ischemia. Rac1 is an important intracellular protein down-stream of SDF-1/CXCR4 axis that regulates cell migration in diverse cell types. However, the role of Rac1 in migration of eNSCs after cerebral ischemia as well as its underlying molecular mechanisms was not well illustrated. Our preliminary study showed that the expression of Rac1 in ipsilateral SVZ was significantly elevated after cerebral ischemia, and inhibition of Rac1 suppressed the SDF-1/CXCR4 axis-induced NSC migration in vitro. In this research project, we will make a systematic analysis of the expression and activation pattern of Rac1 after cerebral ischemia, and illustrate the role of Rac1 in mediating SDF-1/CXCR4 axis to regulate eNSC migration after focal cerebral ischemia by both in vivo and in vitro studies. We believe this research project will contribute to unfold a novel mechanism of eNSC migration and may provide a potential target for neurological rehabilitation therapy after cerebral ischemia.

脑梗塞后，内源性神经干细胞向梗塞部位迁移对神经再生及修复十分关键。研究脑梗塞后内源性神经干细胞迁移的细胞分子机制对疾病治疗具有重要意义。趋化因子SDF-1及其受体CXCR4组成的SDF-1/CXCR4轴对脑梗塞后内源性神经干细胞迁移起重要作用。Rac1是调控细胞迁移的关键蛋白，也是SDF-1/CXCR4轴重要下游信号蛋白。但Rac1在脑梗后内源性神经干细胞迁移过程中的作用及其机制未见研究报道。我们初步研究发现Rac1在大鼠脑梗塞恢复期SVZ区表达明显升高，原代培养神经干细胞中抑制Rac1显著降低了由SDF-1/CXCR4轴诱导的细胞迁移。在本项目中，我们将系统分析脑梗塞后Rac1在内源性神经干细胞中的表达、活性变化模式，并通过体内体外研究阐明Rac1对脑梗塞后SDF-1/CXCR4轴调控内源性神经干细胞迁移的介导作用及其细胞分子机制，以期为脑梗塞康复治疗提供新的理论基础和药物靶点。

脑梗塞后神经损伤修复和内源性神经干细胞再生/迁移的机制尚不明确，寻找相关蛋白靶点，研究其分子机制并通对潜在靶向药物对相关蛋白进行调控从而促进神经损伤修复对于脑梗塞治疗的临床转化具有重要意义。本研究通过特异性药物激活潜在脑梗塞后神经修复相关蛋白Rac1，观察Rac1激活剂对大鼠脑梗塞后恢复期神经功能康复、血管再生、神经元轴突再生及内源性神经干细胞增值、迁移的影响。本研究还通过在体和体外实验探索了参与神经干细胞迁移的Rac1下游信号通路，并进一步应用特异性药物调控Rac1下游蛋白活性，观察其对脑梗塞后神经修复的治疗作用。本项目研究结果显示，Rac1是脑梗塞后恢复期神经损伤修复的重要靶蛋白，特异性激活Rac1蛋白能够促进脑梗塞大鼠神经功能恢复、神经元轴突再生、脑血管再生、神经干细胞增值和迁移。在脑梗塞恢复期，Rac1蛋白可能通过Pak1信号通路调控由SDF-1诱导的内源性神经干细胞迁移从而促进脑梗塞后神经修复的功能移有关。本项目研究还发现PTP1B是神经干细胞内Rac1的重要下游调控蛋白，特异性抑制PTP1B亦可促进脑梗塞后神经损伤修复和神经功能康复。本项目研究结果为脑梗塞康复治疗提供了新的理论基础和潜在药物靶点。