肝纤维化是慢性肝病进展至终末期的核心环节，临床缺乏早期无创性诊断和有效治疗靶点。前期研究发现肝硬化患者血清和肝组织中LECT2的含量显著升高，LECT2敲除小鼠能减缓CCL4诱导的肝纤维化；机制研究表明LECT2不表达于肝星状细胞和巨噬细胞，而在血管内皮细胞及其周围肝细胞中高表达，并能结合内皮细胞膜受体Tie1。据此，我们推测：LECT2可结合肝窦内皮细胞膜受体Tie1，通过调控血管生成进而促进肝纤维化。本课题拟体内过表达LECT2验证其促进肝纤维化的作用和对血管生成的影响；体外运用GST pull-down实验证实LECT2直接结合Tie1，并通过细胞侵袭实验和小管形成实验探索LECT2结合Tie1调控血管生成的机制；最后以LECT2为靶点进行治疗性探索。课题的实施将阐明LECT2结合Tie1调控血管生成进而促进肝纤维化的分子机制，为探索LECT2作为新的肝纤维化治疗靶点提供理论依据。

Liver fibrosis is the key step of the progression of chronic liver disease to the end stage, which lacks early non-invasive diagnosis and effective therapeutic target. Our previous work found that the level of LECT2 in serum and liver tissue of patients with cirrhosis is significantly increased. Loss of LECT2 alleviate the degree of fibrosis in mice induced by CCL4. Interestingly, we also found that LECT2 is not expressed in hepatic stellate cells and macrophages, but highly expressed in vascular endothelial cells and surrounding hepatocytes, which binding to endothelial cell membrane receptor Tie1. Based on the above findings, we speculate that LECT2 could combine with Tie1 and promote liver fibrosis by regulating angiogenesis. To test this hypothesis, we first confirm the role of LECT2 in promoting liver fibrosis and influencing angiogenesis by over-expressing LECT2 in vivo. Secondly, we plan to use in vitro experiments to confirm the direct binding of LECT2 to Tie1 by GST pull-down method, and explore the mechanism of LECT2 binding to Tie1 to regulate angiogenesis by transwell and tube formation assay. Last, based on the above findings, LECT2 will be used as a target for therapeutic exploration. This proposal may clarify the molecular mechanism of LECT2 combined with Tie1 in regulating angiogenesis and promoting liver fibrosis. This project also may provide some evidence to developing a new therapeutic strategy in liver fibrosis through targeting LECT2.