基于LncRNA-MEG3调控FoxO1介导的MN-s细胞自噬探讨肝豆灵改善Wilson病神经元损伤的作用机制

Wilson病（WD）是一种铜代谢障碍的常染色体隐性遗传疾病；研究发现，WD患者存在广泛的神经元数目的减少或丢失。临床研究证实肝豆灵可显著改善WD神经功能，其机制尚不明确。前期实验发现，自噬在WD神经元损伤中作用重大，而抑制自噬可显著改善其神经元的损伤。FoxO1为LncRNA-MEG3的靶基因，参与调控自噬的起始阶段。而LncRNA-MEG3在TX小鼠脑神经元中呈差异性表达。基于以上研究，申请人提出：“肝豆灵调控LncRNA-MEG3及靶基因FoxO1，抑制神经元自噬，改善WD神经元损伤”的假说。本项目以TX小鼠及原代MN-s细胞为模型，LncRNA-MEG3及调控的靶基因FoxO1为切入点，细胞自噬为靶点，肝豆灵为干预手段，并运用体内体外相结合方式，从“LncRNA-MEG3→FoxO1→自噬”三个环节探讨肝豆灵治疗WD的神经保护机制，为深化其发病机制和中医药效应研究提供科学依据。

Wilson disease is a chronic progressive copper metabolic disorder, and the number of neurons was found to decrease obviously in their bodies. The gandouling tablets can significantly improve the neurological function for WD patients in treatment of WD, but the exact mechanism is not yet clear. Moreover, the relative expression of LncRNA-MEG3 in the model of TX mouse displayed a remarkable decrease, and autophagy has been reported to involve in the development of WD. Our previous studies have found that gandouling can significantly reduce and inhibit the excessive in the hippocampal neuron. In addition, studies on the network gene database also show that FoxO1, as the targets of gene of LncRNA-MEG3, are closely related to autophagy pathway. Therefore, we propose a hypothesis that the gandouling tablets can regulate the level of LncRNA-MEG3, and the expression of target gene FoxO1, inhibit neuronal autophagy, thereby improving neurological impairment in WD patients. In this study, to explore the neuroprotective mechanism of gandouling, we adopt the TX mice model, LncRNA-MEG3 and target gene FoxO1 as the starting point, autophagy as study targeting, gandouling as durg intervention, expecting to provide new scientific evidence for the efficacy mechanism of gandouling in treatment of Wilson disease.