M3受体调控LncRNA-Gm2199-miR-212/217-ERK改善慢性肝损伤作用的分子机制

由各种原因导致的慢性肝损伤在我国呈现发病率高、治疗周期长且疗效不显著的特点。因此寻找治疗新靶点具有重要意义。促进肝细胞增殖、抑制其凋亡是防治慢性肝损伤的关键。M3受体广泛表达于肝脏，激动M3受体可改善慢性肝损伤，且ERK是M3受体下游重要信号分子并参与细胞增殖。我们研究发现LncRNA-Gm2199通过激活ERK信号通路促进肝细胞增殖、减轻肝损伤。通过生物信息学预测Gm2199调控miR-212/217，且ERK是miR-212/217的靶点。更为关键的是，预实验显示M3受体可调控Gm2199的表达。我们据此推测：激活M3受体通过Gm2199调控miR-212/217，进而上调ERK促进肝细胞增殖抑制肝损伤。本项目拟在CCl4肝损伤模型和M3转基因敲除模型鼠基础上，阐明激活M3受体对慢性肝损伤的改善作用及详细机制。本项目对防治慢性肝损伤具有重要的理论意义及应用价值。

Chronic liver injury (CLI) is a serious disease and at present little information is available on both its pathogenesis and pharmacological treatment. It is of great significance to focus on the new targets to the treatment of CLI. Combing promoting liver cell proliferation and inhibiting the apoptosis together is a key strategy to the treatment of CLI. We used bioinformatics technology to predict the relationship between the lncRNA-Gm2199 and ERK, and also to predict that ERK is the potential target of miR-212/217. M3 receptor is widely expressed in the liver, and our preliminary study confirmed that M3 receptor reversed chronic liver injury. ERK, an important signaling molecule of the downstream of M3 receptor, participates in cell proliferation, suggesting that Gm2199-ERK pathway may be involved in the process which M3 receptor reversed liver injury. Therefore, we hypothesize that activation of M3 receptor regulates expression of miR-212/217 through upregulation of Gm2199, which activates the ERK signaling pathway to promote hepatocyte proliferation and inhibit chronic liver injury. This providis a reference for prevention and treatment of chronic liver injury.