SSeCKS对PKCζ-TAK1信号转导的激活在星形胶质细胞炎性活化中的作用

The inflammation response is one of the primary pathogenesis in central nervous system (CNS) diseases and age-related degeneration. The activation of astrocyte plays an important role in this process. Previous studies have shown that the expression of SSeCKS increased in astrocyte activation and interacted with PKCζ and TAK1.In view of this,we will firstly prove that SSeCKS binds with PKCζ and TAK1 to form a ternary complex in astrocyte,which promote the PKCζ-TAK1 and NF-κB signal transduction and take part in the chronic inflammation response in CNS. And after that,via affecting the formation of the complex in cells,the role which the complex plays in astrocyte activation and the potential effect of the intervention will be measured.At last,we aim to detect the role of PKCζ-SSeCKS-TAK1 in CNS inflammation disease models by affecting its formation in astrocyte.All the data may further clarify the regulatory mechanism and pathological significance involved in the chronic inflammation activation of astrocyte, and provide a new target for prevention and treatment of CNS degeneration .

炎症反应是中枢神经系统疾病及衰老退变主要发病机制之一，其中星形胶质细胞的炎症通路激活在其发生发展中至关重要。课题组前期研究发现星形胶质细胞炎性活化过程中SSeCKS表达增加，并且SSeCKS能与PKCζ及TAK1相互作用。鉴于此，本项目拟证明：星形胶质细胞中SSeCKS能与PKCζ及TAK1结合，形成三元复合物后能促进PKCζ-TAK1信号转导及下游NF-κB的激活，参与中枢神经系统慢性炎症反应，导致神经元损伤；并拟在细胞水平干预三种蛋白质的相互作用，分析其对星形胶质细胞激活的影响及可能意义；在中枢神经系统炎症性疾病模型中，靶向干预星形胶质细胞中SSeCKS及其复合物的形成和功能调节，以探讨其对神经系统疾病预后的影响；籍以进一步阐明中枢神经系统慢性炎症反应中星形胶质细胞炎性活化的激活调节机制及病理意义，为中枢神经系统衰老退变的防治提供新思路和新靶点。

炎症反应在中枢神经系衰老退变过程中有重要作用，在这过程中星形胶质细胞的激活至关重要。本项目基于前期研究发现SSeCKS能调节星形胶质细胞的炎性活化过程及PKCζ-TAK1信号转导，深入的研究星形胶质细胞中SSeCKS与TAK1结合对PKC调节的TAK1激活及其在细胞激活中的作用。研究结果发现SSeCKS可与TAK1结合形成复合物，且SSeCKS可调节PKC介导的TAK1的激活，深入的研究还发现SSeCKS调节的PKC介导TAK1的激活可促进星形胶质细胞的激活及神经炎症反应。此外课题最还对HSPA12B调节的SSeCKS磷酸化及其在星形胶质细胞中的作用展开研究。研究结果可进一步阐明中枢神经系统慢性炎症反应中星形胶质细胞炎性活化的激活调节机制及病理意义，并为中枢衰老退行性疾病的防治提供新方法。项目实施期间共发表SCI期刊收录论文8篇，培养研究生6名，参加国内外学术会议4次。