星形胶质细胞炎症激活在多发性硬化（MS）的发病中有重要作用。课题组前期的研究发现SSeCKS促进星形胶质细胞的激活参与MS的发生发展，但是调节机制不清楚。预实验发现内质网应激（ERS）的标记GRP78能促进SSSeCKS磷酸化修饰；SSeCKS可增强OGT的酶活性促进NF-κB信号转导。据此我们提出在MS中，SSeCKS可通过与GRP78及OGT结合，衔接ERS和蛋白质的O-GlcNc修饰，促进NF-κB信号转导及星形胶质细胞的炎症激活的科学假说。本项目拟在实验性变态反应性脊髓炎（EAE）模型及星形胶质细胞激活模型中探讨GRP78对SSeCKS磷酸化及SSeCKS对OGT的酶活性调节作用及其机制，分析上述调节对NF-κB信号转导及星形胶质细胞激活的影响，明确SSeCKS衔接的内质网应激及蛋白质O-GlcNAc修饰与MS的关系。研究结果可为阐明MS的分子机制，寻找新的治疗方法提供依据。

The inflammatory activation of astrocytes play an important role in the pathogenesis of multiple sclerosis (MS). Previous research by our research team have found that Src-suppressed C kinase substrate (SSeCKS) promotes the activation of astrocytes, which was involved in the development of MS. But until now, the regulatory mechanism of SSeCKS in astrocyte is unclear. Our pre-experiment have found that GRP78, the endoplasmic reticulum stress (ERS) marker glucose regulated protein 78 kD (GRP78) can promote SSSeCKS phosphorylation modification; SSeCKS can regulate N-acetylglucosamine transferase (OGT) enzyme activity and promote nuclear actor kappa B (NF-κB) signal transduction. Based on this, we propose that in MS, SSeCKS can promote the NF-κB signal transduction and the inflammatory activation of astrocytes by binding to GRP78 and OGT, which linked the ERS and protein O-GlcNc modification. In this project, we will construct the experimental allergic myelitis (EAE) animal model and astrocyte activation model, and then investigate the regulation of GSP78 on SSeCKS phosphorylation, SSeCKS on OGT enzyme activity. Based on that, we will investigate the effects of these interaction on the NF-κB signal transduction and astrocyte activation. At last, we will study the relationship between SSeCKS connected ERS and protein O-GlcNAc modification and MS develoment. These results can provide a basis for elucidating the molecular mechanisms of MS and finding new treatments for MS.