mGluR5通过PKC/ERK/c-Rel信号通路参与帕金森病异动症发生及治疗机制研究

项目名称： mGluR5通过PKC/ERK/c-Rel信号通路参与帕金森病异动症发生及治疗机制研究

项目编号： No.81471148

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 刘振国

作者单位： 上海交通大学

项目金额： 80万元

中文摘要： 帕金森病（PD）长期左旋多巴治疗产生运动并发症，其中异动症（LIDs）严重影响患者的生活质量，其发生机制尚不明确。非多巴胺能神经元参与了LIDs的发生。其中选择性阻断代谢型谷氨酸受体5（mGluR5）可产生抗异动症作用，然而对mGluR5参与LIDs发生以及治疗机制研究很少。我们前期研究发现LIDs大鼠纹状体细胞表面的mGluR5水平明显升高，胞内亚细胞分布的mGluR5向细胞表面重新分布，而PD大鼠虽然mGluR5升高，但不存在亚细胞分布改变，提示mGluR5在LIDs发生中的重要作用。本课题拟通过研究LIDs纹状体mGluR5/A2A、mGluR5/NMDA镶嵌复合体功能改变，以及mGluR5相关的PKC-ERK-c-Rel胞内信号通路变化，解释mGluR5拮抗剂治疗LIDs的机制，为mGluR5拮抗剂治疗运动并发症提供理论支持。

中文关键词： 帕金森病；异动症；代谢型谷氨酸受体5；信号通路；镶嵌复合物

英文摘要： Levodopa is the most effective and commonly prescribed treatment for Parkinson's disease (PD). Prolonged levodopa treatment is associated with development of levodopa-induced dyskinesias (LIDs), diminishing the patients' quality of life. The management of LIDs is an ongoing challenge in PD treatment. Since the neurobiological mechanisms of LIDs remain unclear, clinical pharmacologically intervention is restricted. Nondopaminergic receptors expressed by striatal MSNs are likely to play a direct role in the pathogenesis of LIDs. Therefore, these receptors are becoming the target of innovative pharmacological strategies aimed at counteracting the occurrence of LIDs in PD. Among these receptors, mGluR5 receives much concern. mGluR5 selective antagonist AFQ056 shows an antidyskinetic effect both on animal models and patients. Little is known about the concrete role of mGluR5 during the development of LIDs. Our previous study finds a proportional increase of total and membrane mGluR5 in striatum of PD rat, while in LIDs rat, mGluR5 on surface shows a sharp increment, indicating a modification of subcellular distribution. In this research, we will explore the interaction of mGluR5 and A2A,NMDA receptors in order to elucidate the role of mGluR5/A2A、mGluR5/NMDA receptor mosaic during the LIDs progressing and therapy. We also detect the alteration of intracellular signal molecule in basal ganglia to demonstrate that mGluR5 takes part in LIDs development and treatment via PKC-ERK-c-Rel signaling pathway. This study will further explain the mechanism of LIDs and provide theory evidences for mGluR5 modulator therapy for Parkinson's disease with dyskinesia.

英文关键词： Parkinson's disease;dyskinesia;mGluR5;signal pathway;receptor mosaic