肝迷走神经靶向m3AchR调控肝泡型包虫病肝细胞增殖的分子机制及其临床意义

肝泡型包虫病（AE）新疆高发，危害严重，自体肝移植术式是终末期AE患者最后的救治手段，但部分AE患者因残存功能肝体积不足而失去了手术机会。我们前期研究发现受迷走神经调控的毒蕈碱乙酰胆碱受体m3（m3AchR）高表达和ERK信号通路活化与AE患者肝细胞增殖呈正相关，提出“m3AchR介导肝迷走神经促AE肝细胞增殖”这一科学假说。本项目拟研究：1.采用泡球蚴感染小鼠和AE临床病例标本方法，明确肝神经、m3AchR表达和AE肝细胞增殖的相关性及临床意义；2.利用肝细胞特异性敲除m3AchR转基因小鼠等、腺相关病毒转染、激动剂/拮抗剂干预等方法，干预m3AchR，明确m3AchR促AE肝细胞增殖的功能；3.进一步通过肝迷走神经切除术等，揭示m3AchR介导了肝迷走神经调控AE肝细胞增殖的分子机制。本研究结果将丰富m3AchR在寄生虫感染所致肝再生中的作用及其机制，为研发新的包虫病治疗方法奠定基础。

Alveolar echinococcosis (AE) is a severe disease and highly endemic in Xinjiang. Ex vivo liver resection combined with autotransplantation (ELRA) is the last choice for end-stage AE patients. But some patients could not be treated by ELRA, because their residual functional liver volume was not insufficient. In our previously study, we found that the high expression of muscarinic acetylcholine receptor m3 (m3AchR), which was regulated by the vagus nerve, and the activation of the ERK signaling pathway were positively correlated with the proliferation of hepatocyte in AE patients and mice. Therefore, we proposed the scientific hypothesis that "m3AchR/ERK pathway mediates the function of liver vagus nerve to promote the proliferation of hepatocyte in AE". In this work we intends to investigate: 1. The correlation and clinical significance between the number of hepatic nerve, the expression of m3AchR and the proliferation of AE hepatocytes were determined by alveolar echinococcosis mice model and AE clinical case. 2. The specific knockout of m3AchR transgenic mice, adeno-associated virus transfection, agonist/antagonist intervention and other methods were used to intervene m3AchR and clarify the role of m3AchR in promoting the proliferation of AE liver cells. 3. Further, the molecular mechanism of m3AchR mediating hepatic vagus to regulate the proliferation of AE hepatocytes was revealed by hepatovagus resection. This work would enrich the role and mechanism of m3AchR/ERK signaling pathway in liver regeneration caused by parasitic infection, and lay a foundation for the development of new treatment methods for hydatid disease.