Septin7下调导致髓鞘病变的分子机制及MK5干预评价

髓鞘病变常见于多种中枢神经系统疾病，与细胞骨架关系密切。septins支架是由其亚家族成员构成的异源多聚体，其中Septin7(Sept7）可通过与细胞外信号调节激酶3（ERK3）结合，激活MAPK活化蛋白激酶5（MK5）进而形成septins支架的核心部分。Sept7在老化动物和髓鞘病变中表达下调，但其具体作用及机制不清。我们前期研究发现Sept7在髓鞘蛋白提取物中表达，并与髓鞘形成和再生关系密切；被敲减后，可导致OPC增殖、分化障碍，成熟髓鞘发生外折、内舌肿胀、致密部松散等病理改变，以及损伤后髓鞘病变加重等；说明Sept7在髓鞘的形成、维持和再生中均具有重要作用。本项目拟在此基础上研究Sept7：1.影响OPC增殖、迁移与分化的作用机制；2.在髓鞘形成、维持与再生中的作用及机制；3.评价调控ERK3/MK5通路对Sept7敲减所致髓鞘病变的干预效应。为髓鞘病变机制研究与治疗提供新思路。

Myelin sheath lesions are common incident in various central nervous system diseases and are closely related to the cytoskeleton. The septins scaffold is the heteromultimer that is composed of its subfamily members. Septin7 (Sept7), which is the unique member of septin 7 subfamily, can bind to extracellular regulated protein kinases 3 (ERK3) to activate MAPK-activated protein kinase 5 (MK5) to form the core of septins scaffold. Sept7 was found being down-regulated in aging animals and myelin lesions, but its specific role and mechanism are unclear. Our previous study found that Sept7 is expressed in myelin sheath protein extracts and is closely related to myelination and remyelination; after being knocked down, it can lead to OPC proliferation and differentiation disorders; mature myelin sheaths out-folding, swelling of the inner tongue, and pathological changes in dense parts, such as loosening; and aggravation of myelin sheath lesions after injury. These findings indicate that Sept7 plays an important role in the formation, maintenance and regeneration of myelin sheath. Based on previous study, this project intends to study: 1. The mechanism of Sept7 affecting the proliferation, migration and differentiation of OPC; 2. The role and mechanism of Sept7 in myelination, maintenance and remyeliantion. 3. To evaluate the intervention effect of regulating ERK3 / MK5 pathway on myelin lesions caused by down-regulated Sept7 expression, aiming to provide new ideas for the treatment of myelin-related diseases.