醛糖还原酶基因敲除促进脑梗死后神经元存活和轴突发芽的分子机制研究

脑梗死是威胁人类健康的五大病因之一。脑梗死后神经元的存活和轴突发芽对运动功能恢复起关键性作用。醛糖还原酶在氧化应激、炎症反应中都发挥重要作用。我们前期研究发现，脊髓损伤后，AR基因敲除通过增加损伤区局部小胶质/巨噬细胞向M2型极化，进而促进小鼠运动功能恢复。视神经损伤后，AR基因敲除可促进视神经节细胞的存活及轴突再生。然而AR基因敲除是否能促进脑梗死后轴突发芽还不清楚，在小胶质细胞中，AR缺失或抑制，可激活CREB信号通路，CREB在轴突再生具有重要作用。因此我们推测，脑梗死后，AR基因敲除可能通过激活CREB信号通路，促进轴突发芽。本实验拟在前期工作基础上，利用AR基因敲除小鼠，AAV病毒轴突顺行和逆行标记技术，从运动动能、形态学、分子生物学方面，研究AR基因敲除促进轴突发芽的分子机制，为以后临床应用AR抑制剂治疗脑梗死提供理论依据和实验证据。

Stroke is one of the top five causes that threaten human health. The neuronal survival and the axon sprouting after stroke play a key role in motor function recovery. Aldose reductase (AR) plays an important role in oxidative stress and inflammatory response. Our previous study showed that after spinal cord injury, AR knockout promotes motor function recovery by increasing microglia/macrophages polarizing to M2 type. After the optic nerve injury, AR knockout can promote the survival and axonal regeneration of the retinal ganglion cells. However, it is unclear whether AR knockout can promote axonal sprouting after stroke. In microglia, AR deletion or inhibition can activate CREB signaling pathway, which plays an important role in axon regeneration. Therefore, we hypothesize that after stroke, AR knockout may promote axonal sprouting by activating the CREB signaling pathway. Based on the previous work, this project will use AR knockout mice, axon antegrade and retrograde labeling techniques, behavioral tests, histology, molecular biology, to study the mechanism of AR in promoting axon sprouting. This study will provide experimental evidence for the clinical application of AR inhibitors in the treatment of stroke.