YAP介导脊髓损伤引起内源性干细胞-室管膜细胞增殖、分化促神经再生的作用和机制研究

室管膜细胞是脊髓内源性干细胞，在损伤时被激活、增殖和迁移至损伤区，分化为星形胶质细胞和少突胶质细胞，参与胶质疤痕形成，促进神经再生修复，然而损伤过程中其增殖和分化调控机制不清楚。本课题预实验发现:①转录共因子YAP表达于脊髓室管膜细胞，损伤引起YAP表达上调激活；②条件性敲除YAP不影响室管膜发育，但抑制损伤后胶质疤痕形成和神经再生；③YAP激动剂促进胶质疤痕形成和神经再生。拟将采用条件性敲除小鼠、脊髓损伤模型、细胞生物学等技术进一步检测室管膜细胞YAP在脊髓损伤神经再生修复中的作用；其次，揭示YAP介导室管膜细胞增殖和分化的调控分子机制；最后，明确激活YAP是否能促进损伤后室管膜细胞增殖和分化，促进胶质疤痕形成，进而改善神经再生修复功能。这些研究为脊髓损伤中室管膜细胞增殖和分化提供新的分子机制，并为脊髓损伤的治疗研究提供新思路和新药物靶点。

Ependymal cells are the endogenous stem cells in spinal cords, and activated, proliferate and migrate the injury sites after spinal cord injury (SCI), and then differentiate into astrocytes and oligodendrocytes, which promotes the neural regeneration and repair of SCI, however, it remains unclear that the moleulcar regulation mechanism of differentiation of ependymal cells after SCI. Our preliminary results have shown that: ① Co-transcription factor YAP (yes-associated proteins) was expressed in ependymal cells, and upregulated, activated through nuclear translocation by SCI; ②Conditional knockout YAP in ependymal cells did not affect the development of ependymal cells, but inhibited the formation of glial scars and neural regeneration after SCI;③YAP agonist promotes the formation of glial scars and neural regeneration after SCI. Next, we will further examine the roles of YAP signaling in ependymal cells for neural regeneration in SCI based on conditional knockout mice, SCI animal model, cellular and molecular technologies. Secondly, we will examine the molecular mechanism of YAP regulating the differentiation and proliferation of ependymal cells. Finally, we will exmamine whether activaiton of YAP signaling in ependymal cells promotes the proliferation and differentiation of ependymal cells, which then contributes to neural regeneration and functional recovery after SCI. These studies will provide novel insights for molecular regulation mechanism of proliferatin and differentiation of ependymal cells after SCI and new strategy and new drug target for SCI.