A20对NF-κB激活及ATF-2介导的基因转录调节在小胶质细胞极化中的作用

Microglia polarization played an important role in development of central nervous system inflammation. A20 inhibited the inflammatory reaction via regulated NF- kappa B activation. In previous study, we have found that A20 can combine with ATF-2, and form a complexes. So we put forward that A20 inhabited microglia polarization and central nervous system inflammation inflammation via regulated NF-κB activation and ATF-2 mediated gene transcription. In following study, we will firstly define the role of A20 in microglia polarization. And then we will analyze the role of A20 regulated NF- kappa B signaling in microglia polarization; In further, we will prove that A20 may bind with ATF-2 and affected its mediated gene transcription. Based on this, we will analysis A20 regulated ATF-2 gene transcription in microglia activation. At last, we will analysis the effect of A20 regulated NF-κB activation and ATF-2 mediated gene transcription in microglia polarization and its mediated central never system inflammation in inflammatory model in central nervous system inflammation. Our study results can provide theoretical basis for clarifying the mechanism of microglia abnormal activation, and provide the drug design and therapeutic target for the treatment of central nervous system diseases.

小胶质细胞极化在中枢神经系统（CNS）炎症反应中发挥重要作用，A20可通过调节NF-κB激活抑制炎症反应，课题组前期研究发现A20可与ATF-2结合形成复合物，据此提出A20可通过调节NF-κB激活及ATF-2介导的基因转录，参与小胶质细胞极化及CNS炎症反应，课题组拟首先明确A20在小胶质细胞极化中的作用，并分析A20对NF-κB信号转导的调节在小胶质细胞极化中的作用；接着证明A20与ATF-2结合对ATF-2介导的基因转录的影响；在此基础上分析A20对ATF-2的调节介导在小胶质细胞极化中的作用；最后在CNS炎症模型中分析干预A20调节的NF-κB信号转导及ATF-2介导的基因转录对小胶质细胞激活及神经功能的影响。本项目研究结果为阐明小胶质细胞异常激活的机制提供理论基础，为CNS疾病的治疗提供新的药物设计和治疗靶点。

小胶质细胞极化在中枢神经系统（CNS）炎症反应中发挥重要作用，A20可通过调节NF-κB激活抑制炎症反应，本项目在前期研究的基础上，探讨A20调节NF-κB激活及ATF-2介导的基因转录的机制，分析其参与小胶质细胞激活及CNS炎症反应作用。项目首先明确A20在小胶质细胞激活中的作用；探讨A20与TAK1结合对NF-κB信号转导的调节在小胶质细胞激活中的作用；接着研究A20与ATF-2结合调节ATF-2介导的基因转录在小胶质细胞激活中的作用；还在CNS炎症模型中分析A20调节TAK1介导的NF-κB信号转导及ATF-2介导的基因转录对小胶质细胞激活及神经功能的影响。研究结果显示A20可抑制小胶质细胞激活介导的炎症反应。一方面，A20可通过与TAK1结合，抑制NF-κB激活；另一方面，A20可以与ATF-2结合，通过抑制ATF-2磷酸化修饰，促进ATF-2的泛素化降解，从而抑制ATF-2 介导的炎症基因的表达。本项目研究结果为阐明小胶质细胞异常激活的机制提供理论基础，为CNS疾病的治疗提供新的药物设计和治疗靶点。