动物肝脏发育和稳态维持受遗传和非遗传因素的影响，稳态失衡导致肝病发生。肝纤维化是慢性肝病一种，主要表现为肝星状上皮细胞过度增殖导致肝细胞变性、坏死和纤维增生，分子机制不明。Ufm1泛素化样修饰(Ufmylation)是一新型蛋白修饰系统，2015年我们首次发现该系统E3连接酶--Ufl1及下游Ufbp1基因敲除后，动物胚胎期死亡及肝脏发育异常。为了进一步研究Ufl1对肝脏的影响，我们又繁育了Ufl1和Ufbp1的Alb-Cre肝细胞定向敲除小鼠，8周龄时出现原发性肝纤维化表型。本课题拟利用该定向敲除小鼠，研究不同发育阶段的肝脏表型；原代培养肝细胞，通过iTRAQ筛选与肝脏纤维化表型相关的信号通路及候选基因；体外利用原代肝细胞和HepG2细胞，体内利用定向基因敲除小鼠研究信号通路活化情况，阐明Ufl1缺失调控肝脏发育和原发性肝纤维化发生的分子机制。最终为肝脏发育、稳态及肝病研究提供理论依据。

Genetic and non-genetic factors contribute to liver development and homeostasis, loss of homeostasis induces hepatic disease. Liver fibrosis is one of chronic diseases. Hepatic stellate cell (HSC) is the key effector. Excessive proliferation of HSC leads to the deposition of extracellular matrix (ECM), degeneration and apoptosis of hepatic cells. Little is known about the truth. The Ufm1 conjugation system is a novel ubiquitin-like modification system, and its biological functions are emerging. Recently, we have successfully established the knockout mice of Ufl1 and Ufbp1, two key components of this system. Our published works demonstrated Ufl1or Ufbp1 deficiency led to lethality of embryo and defect of fetal liver. To explore their role in liver, we generate Ufl1 and Ufbp1Δ/Δhep: Alb-Cre (hepatocyte specific) knockout mice. The primary liver fibrosis occured in Ufl1 and Ufbp1Δ/Δhep mice at eight weeks. In this project, we will study the liver phenotypes of transgenic animals at different stages. iTRAQ was used to screen candidate pathway and signals in primary hepatocyte. We will further elucidate the function and mechanism of Ufl1/Ufbp1-mediated regulation of liver fibrosis in vivo and vitro, using transgenic mice, animal model of experimental disease, primary hepatocytes and HepG2 cells. Eventually, this study will throw a new light on the liver development, homeostasis and disease.