资料表明脑内胶质细胞活化是影响帕金森病（PD）进程的重要因素，但目前对于其活化增殖的关键调控机制尚不清楚。我们前期研究发现：星形胶质活化早而短暂、具有神经营养特性，小胶质活化晚而持久、产生神经毒性效应；Wnt信号作为调节细胞增殖分化的主要因子、定位表达于活化胶质细胞。我们推测：Wnt/β-catenin信号可能具有调控胶质细胞活化增殖、多巴胺稳态和PD疾病进程的重要作用。本项目拟通过：1）采用Wnt报告基因鼠PD模型，分析Wnt/β-catenin激活与星形胶质、小胶质细胞活化的关系；2）应用细胞共培养，明确激活Wnt信号促进星形胶质活化、营养因子合成和神经保护作用，阻断Wnt信号对小胶质活化、炎症因子分泌和神经毒性的抑制作用；3）运用体内干预实验，探讨早期激活/晚期抑制胶质细胞Wnt信号的神经保护、多巴胺稳态和疾病治疗效果，阐明胶质细胞活化的Wnt信号调控机制及PD干预治疗新靶点价值。

Accumulating evidences have shown that brain glial cell activation might act as a critical factor in the pathological progression of Parkinson's disease (PD). Currently,however,the critical controlling mechanism underling glial activation and proliferation remains unclear. Our preliminary observations have shown that the activated astrocytes appeared early,maintained shorter time and exhibited neuroprotective role, while the reactive microglial cells occurred later, maintained longer peroid and showed neurotoxic effect. While Wnt signaling pathway actively functions in cell division and differentiation, cellular localization and expression has been detected in the activated glial cells under PD condition. We thus hypothesize that Wnt/β-catenin signaling pathway may play an important role in dopaminergic system balance and disease progression by regualtion of the glial activation and cell proliferation. In this project, we shall perform these following experiments: 1)Dynamic relationship of Wnt/β-catenin signaling activation with astrocytic and microglial cell reaction in PD model prepared from TOPgal (Wnt reporter) mice; 2)Promotion effect of Wnt signaling to trigger astrocytic activation , neurotrophic factor production and neuroprotection, and effect of Wnt signaling blocker to inhibit microglial reaction, inflammatory cytokine generation and neurotoxicity by in vitro co-culture system; 3)Neuroprotective and therapeutic effects of Wnt signaling and glial activation intervention by in vivo animal model study. It is expected that Wnt signaling mechanism underling glial cell activation and potential application for therapeutic intervention target in PD will be elucidated in this study.