PD-L1对小鼠脊髓损伤后星形胶质细胞反应性增生和胶质瘢痕形成的负性调控机制研究

脊髓损伤（SCI）后星形胶质细胞反应性增生（RA），并通过正反馈环路加重反应形成胶质瘢痕(GC)，严重抑制轴突再生。但目前尚不清楚是否存在内源性负调控信号通路调控RA和GC的发生与发展。PD-L1是一种负调控分子，前期SCI的研究中发现：PD-L1在星形胶质细胞中表达显著上调；高表达PD-L1小鼠SCI后的GC明显轻于野生型小鼠，同时细胞迁移能力明显弱于敲除PD-L1的细胞。这些结果强烈提示：PD-L1可能参与RA的调控。我们推测：SCI后，活化的星形胶质细胞可能通过其表面高表达PD-L1以及与PD-1和/或CD80的相互作用，传递负调控信号，内源性的调控RA及GC的形成，促进SCI的修复。本课题拟采用多种基因修饰小鼠，通过在体和离体实验，阐明PD-L1在SCI导致的RA及GC形成过程中的作用机制及可能的信号通路，探讨RA和GC的内源性负调控机制，为今后SCI的治疗提供新靶点及理论依据。

Reactive astrogliosis (RA) evolves as time elapses and finally results in the formation of glial scar (GA) by a series of positive feedback after spinal cord injury (SCI), which inhibits the axon regeneration. Currently, however, whether the negative signaling pathway is involved in the controlling of the process of RA and GC remains unclear. Our preliminary observations have shown that PD-L1, as a negative regulatory molecular, shows upregulated expression in astrocytes after spinal cord injury. The degree of GA formation in PD-L1high mice is less than that in wild type mice. While the ability of migration in cultured astrocytes from PD-L1high mice is weaker than that from wild type mice. These evidences strongly suggest that the involvement of PD-L1 in the regulation of RA. We hypothesize that activated astrocytes may negatively control the process of RA and GC by the upregulating expression of PD-L1 and binding to PD-1 or/and CD80 to promote the recovery of spinal cord injury. In this project, we shall perform in vivo and in vitro experiments, using many kinds of gene mice, to testify roles of PD-L1 in the regulation of RA and GC in the model of spinal cord injury. It is expected that the underlying mechanism for negatively controlling RA and GC and new targets for the repair of SCI will be elucidated.