神经损伤引起的轴突退化（即“沃勒变性”）是一个积极主动、在分子水平被高度调控的过程，但具体机制尚不清楚。申请人在最近的工作中发现，ESCRT（转运必需内吞体分选复合物）蛋白Vps4具有延缓受损神经退化的功能，且降低神经元中Vps4水平可以引起轴突中自噬小体的堆积和沃勒变性的发生。申请人在前期工作中创建了一个基于果蝇翼神经束的新型神经损伤活体动物模型。在本项目中，申请人计划运用这一果蝇模型结合DRG原代神经元培养、小鼠坐骨神经损伤模型等实验体系，系统化地研究Vps4蛋白神经保护功能的上游调节通路和下游作用机制，以此揭示调控神经轴突退化变性的关键基因和核心机制，为研发治疗神经损伤和轴突退化的新型药物提供理论基础和新方向。

Injury-induced axonal degeneration (termed as “Wallerian degeneration”) is an active process that is highly regulated at the molecular level. However, the underlying mechanism is still unclear. The applicant has discovered in the recent work that the ESCRT (Endosomal Sorting Complexes Required for Transport) protein Vps4 can prevent injured axons from degeneration. Moreover, downregulation of Vps4 in neurons causes the accumulation of autophagosomes in the axons, which triggers Wallerian degeneration. In the applicant’s earlier work, she has developed a novel animal model of axon injury based on the Drosophila wing nerve. In this proposal, the applicant plans to use this fly model combined with DRG primary neuron culture, the mouse sciatic nerve injury model and other experimental systems to systematically study the upstream regulatory pathways and downstream targets of Vps4, which will reveal key genes and core mechanisms that regulate Wallerian degeneration. By this study, the applicant hopes to provide the foundation and new direction for the development of novel drugs for the treatment of neural injury and axonal degeneration.