我们以及其他学者的研究均提示：脑缺血后神经细胞周期激活，导致神经元凋亡、胶质细胞增殖形成胶质瘢痕。细胞周期素依赖性激酶CDKs/细胞周期素cyclins共同促进细胞周期进展。我们前期临床试验发现了一个新的microRNA494参与了急性缺血性脑卒中的发生，动物实验发现其可以减轻脑缺血损伤，靶向抑制CDK6、UBE2L6、HDAC3，提示miR-494可能在脑缺血细胞周期调控中发挥重要作用。本项目拟验证假说：miR-494①靶向抑制CDK6、和/或FGF16-Ras-ERK-MYC通路、和/或PTEN-AKT-mTOR-S6k通路；②靶向抑制UBE2L6，上调神经细胞中的HIF-1α表达，进而上调p21和p27蛋白水平，抑制CDK2活性；③靶向抑制HDAC3，下调CDK1蛋白水平，介导神经元、星型胶质细胞细胞周期阻滞，减轻神经元凋亡和胶质瘢痕形成，促进神经功能恢复，为脑卒中治疗提供新靶点。

We and other investigations suggested that the activation of nerve cell cycle following cerebral ischemia led to neuronal apoptosis, glial cell proliferation and the formation of glial scar. The cyclin-dependent kinases (CDKs) and cyclins jointly promoted the cell cycle progression. Our preliminary clinical trial found a new microRNA- miR-494, which involved in the occurrence of acute ischemic stroke. In our animal experiment, miR-494 could relieve cerebral ischemia injury through inhibiting CDK6, UBE2L6 and HDAC3,which suggested that miR-494 might play an important role in the regulation of cell cycle following cerebral ischemia. This project intends to verify the following hypothesis: ①miR-494 targetedly suppresses CDK6, and/or FGF16-Ras-ERK-MYC pathway, and/or PTEN-AKT-mTOR-S6k pathway; ②miR-494 targetedly inhibits UBE2L6, upregulates the HIF-1α expression in nerve cells, thereby increases the p21 and p27 protein levels and inhibits CDK2 activity; ③miR-494 targetedly represses HDAC3 and downregulates the CDK1 protein level. These all mediate the cell cycle arrest of neurons and astrocytes, reduce the neuronal apoptosis and glial scar formation, promote the recovery of neurological function and provide new targets for the treatment of ischemic stroke.