脊髓损伤是目前临床面临的难题，损伤区显著的胶质细胞活化和瘢痕形成是阻碍轴突再生的重要原因，如何解除胶质瘢痕对轴突再生的抑制是脊髓损伤修复的关键问题。资料表明活化星形胶质和小胶质细胞是胶质瘢痕的主要来源，而Notch信号是胶质细胞功能的重要调节因子。我们前期研究发现巨噬细胞特异性Notch信号阻断能降低脊髓损伤后小胶质细胞M1极化和炎症反应、促进轴突生长和运动恢复，预实验结果发现活化星形胶质细胞给予Notch阻断剂可抑制TGF-beta、Smad2和CS56表达。我们推测Notch-TGF-beta/Smad信号可能是星形胶质化反应和瘢痕形成的重要调节途径。本项目拟构建条件性RBP-j敲除小鼠，通过脊髓损伤动物模型、细胞培养与抑制剂干预等方法，研究阐明Notch信号调节星形胶质细胞活化增殖、胶质瘢痕形成、轴突再生以及TGF-beta/Smad信号激活介导机制，为脊髓损伤治疗提供新的干预靶点。

The spinal cord injury is a severe debilitating trauma problem in the hospital currently. The remarkable gliosis and glial scar formation in injured area obstruct axonal regeneration obviously, and it remains a key question how to deal with inhibition of glial scar on axonal regeneration during the spinal cord injury and recovery. Evidence has shown that glial scar is mainly generated from activated astrocytes and microglial cells, and Notch signaling pathway may critically involve in glial functional activation. Our study has shown that myeloid-specific blockade of Notch signaling pathway by RBP-J knockout (RBP-j-KO) attenuates microglial M1 polarization and inflammation, promote axonal regeneration and improve motor function after spinal cord injury. Our preliminary experiment results further indicated that application of specific Notch signaling pathway inhibitor in the cultured astrocytes resulted in decease of TGF-beta, Smad2 and CS56 expression levels. We thus hypothesize that Notch-TGF-beta/Smad signaling may function as a key regulator in the astrogliosis and glial scar formation. In this project, astrocyte-specific blockage of Notch signaling by RBP-j-KO, the spinal cord injury animal model, cell culture of astrocytes and specific inhibitors will be applied to study roles of Notch signaling pathway in regulation of astrocytic activation or astrogliosis, glial scar formation, axonal regeneration, and possible TGF-beta/Smad signal mediating mechanism. It is hopefully expected to find or to provide a new manipulation target for the spinal cord injury.