代谢型谷氨酸受体5在帕金森病对肝癌影响中的作用及其机制的研究

Epidemiological studies have found the correlation between neurodegenerative disease and tumor, especially Parkinson's disease (PD) and tumor, suggesting that common pathogenesis may exist in the both diseases. Clarifying the common target site may help to understand the process of the two diseases and further to treat them. Our preliminary results have shown that inhibition of metabotropic glutamate receptor 5（mGluR5） alleviates PD and suppresses liver cancer, moreover, the growth and migration of liver cancer cells are inhibited by conditional medium culturing dopaminergic neurons, which indicates there is correlation between the two diseases and mGluR5 may be the key molecular linking the two diseases. The aim of this study is to investigate the effects of mGluR5 during the regulation of PD to liver cancer and explore the underlying mechanism. The importance of our proposed work is that it would not only clarify the common target point between the two diseases, but also provide improved guidance for understanding the pathogenesis of tumor. In addition, this study will remind us that there is correlation between neurodegenerative disease with tumor and we should consider fully the disease itself and its corresponding before treat them.

临床流行病调查发现，老年神经退行性疾病与肿瘤之间存在相关性，尤其是帕金森病与肿瘤的发生，提示这两种疾病之间可能存相关的发病机制，寻找其共同靶位点有助于理解这两种疾病的发生和治疗。文献及本实验室前期研究结果显示，抑制代谢型谷氨酸受体5（Metabotropic glutamate receptor 5，mGluR5）可缓解帕金森病并有抑制肝癌的作用；多巴胺能神经元能够影响肝癌细胞的生长、迁移等功能，提示帕金森病与肝癌间存在相关性，并且mGluR5可能是联系这两种疾病的靶分子。本课题将在此基础上深入探讨mGluR5在帕金森病影响肝癌中的作用及其机制。本课题有助于阐明帕金森病与肝癌相互关系及其作用的共同靶位点，为探讨肿瘤的发病提供疾病之间联系的新思路。另外，此研究还将提示，神经系统退行性疾病与肿瘤发生存在内在相关性，在设计治疗方案时应全面考虑疾病本身及相关疾病情况。

流行病学研究发现，帕金森病与肿瘤之间存在相关性，提示这两种疾病之间可能存在相关的发病机制，寻找二者共同靶位点有助于理解这两种疾病的发生和发展，并为治疗提供新的思路。本课题采用6-OHDA和鱼藤酮建造两种帕金森病细胞和动物模型，并在上述动物模型基础上分别采用DEN诱导原发性肝癌，注射LLC-WRC256细胞诱导移植型肝癌。通过比较实验组与对照组组织细胞存活、凋亡、浸润和转移的差异，发现帕金森病能够抑制肝癌细胞存活，降低其浸润和转移的能力，并促进肝癌细胞的凋亡；在上述过程中mGluR5的表达发生变化，过表达或敲减mGluR5，激活或抑制mGluR5能够影响帕金森病对肝癌的调节作用；通过研究mGluR5介导的信号通路以及谷氨酸的释放量等在模型组与对照组间的差异，发现在帕金森病影响肝癌的过程中，mGluR5通过其介导的MAPK和Akt信号通路，并调节谷氨酸的释放发挥其调控作用。本课题明确了帕金森病对肝癌发生发展的影响；阐明了mGluR5在帕金森病影响肝癌中的作用；揭示了mGluR5在帕金森病影响肝癌过程中的机制。本研究为预防和治疗帕金森病及肝癌提供理论依据和实验支持。