星形胶质细胞NDRG2调控谷氨酸转运体参与神经病理性痛慢性化转归过程的作用

Down-regulation of glutamate transporters in astrocytes is an important mechanism in the chronicity of pain, but the underlying cause is still unclear. The existing literature and have shown that NDRG2 was a cellular stress response gene which was specific expressed in astrocytes in the central nervous system. Substantial evidence has shown that NDRG2 expression significantly increased in spinal dorsal horn in SNL mice, a classical animal model of neuropathic pain (NP). Besides, our further studies and existing literature showed that the role of NDRG2 in NP is correlated with the inhibition of regulate glial glutamate transporter 1 (GLT-1) expression in astrocytes, which contributes to the chronicity of pain. Additionally, the up-regulation of spinal NDRG2 may regulate GLT-1 via JAK/STAT pathway. This project intends to deeply explore the role and mechanism of NDRG2 in the chronicity of NP using a combination of the behavioral, morphological, molecular biological, cell biological and electrophysiological techniques including the astrocyte specific ndrg2 knockout mice and lentiviral transfection and interference in vitro and in vivo. Our study could provide new clues on the mechanism of the chronicity of NP and new insights into diagnosis and treatment for NP.

星形胶质细胞中谷氨酸转运体GLT-1表达降低导致突触间隙谷氨酸持续堆积是神经病理性痛（NP）由急性向慢性转化的重要机制，但发生原因不清。已有的文献发现NDRG2作为一种细胞应激基因，在神经系统中特异性表达于星形胶质细胞。我们前期的预实验发现SNL疼痛模型小鼠脊髓背角中NDRG2表达显著增高，提示NDRG2参与了疼痛进展过程。进一步的文献回顾及预实验发现，NDRG2在NP的慢性化转归过程中可能通过JAK/STAT通路参与了星形胶质细胞内GLT-1的调控，导致了突触间隙谷氨酸堆积。本课题拟在前期研究基础上，综合利用分子生物学、细胞生物学、神经生物学和动物行为学等方法以及慢病毒转染、在体微透析等技术，在体外星形胶质细胞和NDRG2基因敲除鼠以及SNL模型鼠水平，证实NDRG2在NP慢性化转归过程中的作用及机制，为开发更为有效的NP防治策略提供新的靶点。

星形胶质细胞中谷氨酸转运体表达降低是神经病理性痛（NP）由急性向慢性转化的重要机制，但发生原因不清。已有的文献和我们的研究表明：NDRG2作为一种细胞应激基因，在神经系统中特异性表达于星形胶质细胞，NP模型动物脊髓背角中NDRG2表达显著增高；最近的研究发现NDRG2可能与神经系统中的谷氨酸代谢有关；而我们的实验也发现，在星形胶质细胞培养过程中，LPS可以导致NDRG2表达增高以及突触间谷氨酸重吸收减少，给予JAK/STAT通路的拮抗剂可以促进谷氨酸的重吸收。上述结果提示，NDRG2可能通过JAK/STAT通路调控谷氨酸转运体而参与NP慢性化过程。本项目综合利用动物行为学、形态学、分子生物学、细胞生物学和神经生物学等方法，通过离体星形胶质细胞培养和NP模型，构建NDRG2基因干扰及基因过表达大鼠模型以及腺病毒转染技术深入研究NDRG2对NP慢性化的调控作用及机制，为其防治提供新策略。