HSPA12B对I-kappa B alpha及NF-kappa B p50调节在小胶质细胞极化中的作用及意义

Microglia play an important role in the inflammatory response in the central never system. In this project, we intend to study the effect of interaction between HSPA12B and I-κBα or NF-κBp50 in NF-κB signaling transduction, and its role in microglia immunological phenotype polarization and inflammatory response of central never system. We will first investigate whether HSPA12B form complexes with I-κBα and NF-κBp50 in vitro and in vivo. Secondly, we will analysis the impact of the complex formation in NF-κB signaling transduction during microglia activation, and look for its regulation of molecular mechanism. Based on these, we will analysis of the role the complex formation in microglia immunological phenotype polarization and neuronal damage. Finally, we will turgidly affect the HSPA12B and I-κBα or NF-κB p50 combination, and analysis its impact of the inflammatory response in the CNS. The project will clarify the molecular mechanisms of the dysfunction of microglia, and provide a theoretical basis for new drug design and therapeutic targets, looking for the treatment of CNS disorders.

小胶质细胞在CNS的炎症反应中发挥重要作用，本课题拟研究HSPA12B与I-κBα及NF-κBp50结合对NF-κB信号转导激活的调节在小胶质细胞免疫学表型极化及神经系统炎症反应中的作用。拟首先在体内外分析HSPA12B是否能与I-κBα及NF-κBp50结合形成复合物；接着分析上述复合物的形成对小胶质细胞NF-κB信号转导激活的影响，并寻找其调节的分子机制；在此基础上，分析HSPA12B对NF-κB信号转导激活的调节在小胶质细胞免疫学表型极化中的作用及其对神经元损伤的影响；最后在CNS动物模型中靶向干预HSPA12B与I-κBα及NF-κBp50的结合，分析其对CNS炎症反应的影响。项目的研究将为阐明小胶质细胞功能异常机制提供理论基础，为CNS疾病的治疗提供新的药物设计和治疗靶点。

小胶质细胞在中枢神经系统CNS的炎症反应中发挥重要作用，本课题研究HSPA12B与I-κBα及NF-κBp50结合对NF-κB信号转导激活的调节在小胶质细胞激活及神经系统炎症反应中的作用。研究发现HSPA12B能与I-κBα及NF-κBp50结合形成复合物，通过调节I-κBα的泛素化降解及NF-κBp50与NF-κBp65的结合及细胞核转位，抑制NF-κB信号转导的激活。HSPA12B抑制NF-κB信号转导激活可抑制小胶质细胞的炎症激活及其诱导的神经元损伤。在CNS动物模型中靶向干预HSPA12B与I-κBα及NF-κBp50的结合可抑制CNS炎症反应。项目的研究结果为阐明小胶质细胞激活的分子机制提供理论基础，为CNS疾病的治疗提供新的药物设计和治疗靶点。项目研究结果发表论文5篇；项目资助参加国内外学术会议4人次，培养研究8名。