少突胶质细胞调控帕金森病发病及其分子机制研究

帕金森病（PD）是第二常见的神经退行性疾病，但其发病机制仍不清楚。最近研究表明少突胶质细胞与PD之间具有重要相关性，然而少突胶质细胞如何调节PD发病及其分子机制目前未知。我们的预实验结果表明GPR37特异性表达在少突胶质细胞中，在PD小鼠黑质区表达显著上调；敲除少突胶质细胞中GPR37能有效缓解PD小鼠的运动功能障碍和多巴胺能神经元缺失，提示少突胶质细胞中GPR37在PD发病过程中发挥重要作用。我们还发现GPR37内源性配体PSAP主要表达在多巴胺能神经元中。本项目将在前期工作基础上，运用分子与细胞生物学、钙成像、转基因小鼠和行为学等多种技术，研究：（1）PD前后GPR37与PSAP表达的时程变化与细胞定位；（2）GPR37与PSAP在PD发生和发展中的作用；（3）GPR37调节PD发病的下游信号及其分子机制。本研究将为PD提供新的分子机制和治疗靶点，并为开发新药提供理论基础与新策略。

Parkinson's disease (PD) is the second common neurodegenerative disease, but its pathogenesis is still unclear. Recent studies have shown that there is an important correlation between oligodendrocytes and PD. However, how oligodendrocytes regulate the pathogenesis of PD and its molecular mechanisms are unknown. Our preliminary data showed that G protein coupled receptor 37 (GPR37) was specifically expressed in oligodendrocytes and significantly up-regulated in substantia nigra of PD mice; conditional knockout of GPR37 in oligodendrocytes could effectively alleviate motor dysfunction and dopaminergic neuron loss in PD mice, suggesting that GPR37 in oligodendrocytes plays an important role in the pathogenesis of PD. We also found that the endogenous ligand of GPR37, PSAP, was mainly expressed in dopaminergic neurons. On the basis of previous work, this project will use molecular and cellular biology, calcium imaging, transgenic mice and behavioral techniques to study: (1) the time course and cellular localization of GPR37 and PSAP expression in substantia nigra-striatum before and after PD; (2) the role of GPR37 and PSAP in the occurrence and development of PD; (3) the downstream signaling and molecular mechanism of GPR37 involved in the pathogenesis of PD. The proposed study will provide new molecular mechanisms and therapeutic targets for PD, and provide theoretical basis and new strategies for the development of therapeutic drugs.