研究肝再生的发生机制对肝脏损伤和肝功能衰竭的治疗具有重要意义。课题组前期研究发现，骨形态发生蛋白-7（BMP-7）具有促进损伤肝脏再生的作用。但其上游调控分子尚不清楚。我们前期采用生物信息学方法预测出同源盒基因A13（HOXA13）正向调控BMP-7。HOXA13在小鼠肝大切后肝再生中表达增加，而抑制HOXA13可使肝细胞增殖降低，说明HOXA13与BMP7能够一致性地促进肝再生。此次，拟首先在细胞水平（肝细胞系及原代肝细胞）和动物水平行功能获得性和缺失性实验，明确HOXA13与肝再生的关系。接着，通过荧光素酶、凝胶迁移、染色质免疫共沉淀以及功能挽救实验，明确HOXA13作为BMP-7的上游调控因子介导肝再生。最后，在急性肝衰竭小鼠模型中探索过表达HOXA13的治疗效应。本项目将揭示BMP-7的上游调控因子HOXA13在肝再生中的作用，并基于HOXA13开发出一个新的治疗急性肝衰竭的方法。

The study on liver regeneration has an important theoretical and clinical significance for the treatment of liver injury and liver failure. We previously reported that the peptide of bone morphogenetic protein-7 (BMP-7) could promote liver regeneration, though the upstream molecular mechanism remains unclarified. In our preliminary work, we used bioinformatics analysis to identify that the homeobox gene Hox A13 (HOXA13) might be a positive upstream regulator of BMP-7. Meanwhile, HOXA13 was found to be upregulated during liver regeneration in an animal model of hepatectomy, while inhibition of HOXA13 reduced proliferative rate. These data indicate that HOXA13 and BMP7 could consistently promote liver regeneration. In this project, we will first clarify the role of HOXA13 in liver regeneration through gain- and loss-of-function assays of HOXA13 in vitro (cell lines and primary culture of hepatocytes) and in vivo. Then, luciferase reporter assay, electrophoretic mobility shift assay, chromatin immunoprecipitation assay, as well as functional rescue assays will be performed to elucidate the molecular mechanism of HOXA13 as an upstream regulator of BMP7 in liver regeneration. Finally, the therapeutic effect of HOXA13 overexpression will be evaluated in an animal model of acute liver failure. Our project will reveal the role of HOXA13 as an upstream regulator of BMP7 in the control of liver regeneration. HOXA13 might be a novel therapeutic target in acute liver failure.