壳聚糖神经移植物降解产物壳寡糖调控周围神经髓鞘形成的作用研究

Repair of long distance peripheral nerve defects is still a big challenge in clinics. The artificial nerve grafts have been effectively bridged peripheral nerve defects with satisfactory functional reconstruction. Numerous studies showed that, the chitosan constructed nerve grafts not only provide a good channel for nerve regeneration; its degradation products, chitooligosaccharides (COS), can also promote facilitate nerve repair by improving axon growth, Schwann cell (SCs) proliferation and regeneration microenvironments. Myelination is pivotal for the proper physiological functions of the peripheral nerve system, and its formation is an important marker of peripheral nerve repair accomplishment. Our previous study showed that the chitosan constructed nerve grafts facilitate myelin formation. Moreover, COS stimulate myelin gene expression in the cultured Schwann cells. Consistently with this observation, COS enhance myelin formation in a SC-axon co-cultured model. Together, these evidences suggest that chitosan degradation products--COS may plan an important role in the peripheral myelination processess. To address this hypothesis, a series of experiments will be carried out as described below. Firstly, we will confirm the effects of COS on myelination both in cell and animal models. Secondly, microarray sequencing and bioinformatic analysis will be used to identify the involved signaling pathways targeted by COS, by which myelin formation was stimulated. Thirdly, we plan to reveal how COS regulates the interaction between axons and SCs and thus to promote myelination. Taken together, our study will further expand the function and application of chitosan nerve grafts and their degradation products COS, and provide a theoretical basis for clinical application.

周围神经长距离损伤后的修复仍是医学一大难题。神经移植物桥接是临床治疗周围神经缺损的有效措施，研究发现壳聚糖神经移植物不仅为神经再生提供了良好通道，其降解产物壳寡糖还可以促进轴突生长、施万细胞增殖以及改善再生微环境。髓鞘是神经生理功能重要执行者，其形成是周围神经损伤恢复的关键标志。我们前期研究发现，壳聚糖移植物有利于髓鞘形成；并且，基因检测发现壳寡糖可促进施万细胞髓鞘形成相关基因的表达，体外共培养成髓鞘模型表明壳寡糖可促进髓鞘形成。据此，我们推测壳聚糖降解产物壳寡糖具有促进施万细胞形成髓鞘的生理功能。本项目拟从细胞及动物活体水平研究壳寡糖对髓鞘形成的效应和功能影响；采用芯片测序及生物信息学方法分析壳寡糖介导的、促进髓鞘形成的信号通路，研究壳寡糖如何调控施万细胞与轴突之间的相互作用，促进髓鞘形成的分子机制。该项目将进一步拓展壳聚糖神经移植物和降解产物壳寡糖的功能及应用，为临床应用提供理论基础。

周围神经长距离损伤后的修复仍是医学一大难题。神经移植物桥接是临床治疗周围神经缺损的有效措施，研究发现壳聚糖神经移植物不仅为神经再生提供了良好通道，其降解产物壳寡糖还可以促进轴突生长、施万细胞增殖以及改善再生微环境。髓鞘是神经生理功能重要执行者，其形成是周围神经损伤恢复的关键标志。我们前期研究发现，壳聚糖移植物有利于髓鞘形成；并且，基因检测发现壳寡糖可促进施万细胞髓鞘形成相关基因的表达，体外共培养成髓鞘模型表明壳寡糖可促进髓鞘形成。这提示我们壳聚糖降解产物壳寡糖具有促进施万细胞形成髓鞘的生理功能。我们的项目按照项目申报书的研究内容，从细胞及动物活体水平研究壳寡糖对髓鞘形成的效应和功能影响；采用芯片测序及生物信息学方法分析壳寡糖介导的、促髓鞘形成的信号通路；研究壳寡糖如何调控施万细胞与轴突之间的相互作用，促进髓鞘形成的分子机制。该研究的开展将进一步阐明神经再生的功能和作用机制，有助于为神经移植物及壳寡糖的临床应用提供新的理论支撑。研究超额完成了项目既定指标，共发表标注项目号的SCI论文5篇，申请发明专利1项，并指导2名参与该项目的硕士研究生以及1名博士研究生顺利完成学业。