铜在脑组织的沉积是肝豆状核变性（Wilson's disease, WD）患者出现神经症状的主要原因，其转运和清除机制不明。本课题组前期发现WD动物模型toxic milk（tx）小鼠予青霉胺驱铜后脑间质液游离铜升高，预实验发现阻断小鼠脑淋巴引流可引起脑间质液游离铜升高，并发现tx小鼠的glymphatic系统功能受损。因此，我们推测脑铜可经glymphatic系统清除，WD脑铜沉积可损害glymphatic系统功能而影响脑铜清除。我们拟以tx小鼠为WD模型，结合双光子活体成像、微透析等技术明确tx小鼠存在glymphatic系统功能损害并导致脑铜清除障碍，并探讨星型胶质细胞铜沉积在tx小鼠glymphatic系统功能损害导致脑铜清除障碍中的作用和相关机制。本项目的完成有助于进一步阐明WD脑铜清除的相关机制，并为改善脑型WD患者治疗现状提供新的治疗靶点。

The deposition of copper in brain tissue is the main cause of neurological symptoms in patients with hepatolenticular degeneration (Wilson’s disease, WD), and its transport and clearance mechanisms are unknown. We recently found that the free copper concentrations in toxic milk(tx) mice brain tissue significantly elevated during penicillamine treatment. The pilot experiments revealed copper clearance through brain lymphatic drainage pathway, as well as the impaired glymphatic system, in tx mice. Thus, we speculate that copper can be cleared by glymphatic system, and WD copper deposition may damage glymphatic system function and affect brain copper clearance. We plan to use tx mice as WD model, combine with two-photon imaging, microdialysis and other techniques to comfirm that tx mouse glymphatic system damage leads to the brain copper removal disorder. And we plan to investigate the role of copper deposition of astrocytes in the damage brain copper clearing function of tx mouse glymphatic system. The completion of this project will help to elucidate the mechanism of brain copper clearance, and provide a new target for improving the treatment of brain WD patients.