GPR17在PVL新生大鼠脑白质损伤中的作用机制研究

Premyelinating olygodendrocytes (pre-OLs) are target cells during the development of periventricular leukomalacia (PVL). PreOLs death induced by activated microglia with infection/ inflammation plays an central role in the development and progress of PVL. G-protein coupled receptor 17(GPR17) is proved to be potent regulator for oligodendrocyte differentiation and myelination，and plays a role in regulation of microglial activation. However, the role of GPR17 in PVL remains unknown . In this research, with the small interfering RNA technique, we will study the effection on the differentiation of preOLs and on LPS-induced microglia activation by knockdown the GPR17 gene expression. By detecting Olig1 and ID2 gene expression and the cell viability of preOLs, we try to explore the intrinsic mechanism of the GPR17 effection on the preOLs. By examining the dynamic changes of the expression of GPR17 and Oligl gene, the numbers of pre-OLs and mature OLs,and the activation of microglias in PVL animal's brain white matter, we are expecting to figure out the internal relation of GPR17 and myelination disorder in PVL. Furthermore, we will study the effect on PVL by blocking GPR17 gene.It is expected to disclose the mechanism of the block of remyelination and myelin repair in PVL and provide the target for the prevention and treatment of PVL.

少突胶质细胞前体（preOLs）是PVL病变中关键的靶细胞，感染/炎症诱导小胶质细胞激活导致preOLs死亡，是感染型PVL发生发展的重要环节。GPR17是少突胶质细胞分化和髓鞘化的关键调节因子，同时参与调节小胶质细胞活化，但有关GPR17在PVL中的作用尚不清楚。本课题拟通过利用小干扰RNA技术，观察阻断GPR17基因对preOLs分化成熟的影响以及对LPS诱导小胶质细胞活化的影响，通过检测Olig1、ID4基因表达及preOLs细胞活率，进一步探讨GPR17对preOLs分化成熟影响的内在机制；通过观察PVL模型中GPR17和Olig1基因表达、preOLs和成熟OL细胞数目的动态变化、以及小胶质细胞激活的变化，探讨GPR17基因与PVL髓鞘损伤和修复的内在联系和相互影响；并研究阻断GPR17基因对PVL脑白质损伤后髓鞘再生修复的作用，籍以进一步阐明PVL损伤后再髓鞘化障碍的机制，并为未来PVL的防治提供新的靶点。