组织纤维化是一个全球性的健康问题，其细胞外基质的积累主要来源于肌成纤维细胞，肝星状细胞（HSC）是肝纤维化中肌成纤维细胞的主要来源。许多研究表明在纤维化进展过程存在脂成纤维细胞表型向肌成纤维细胞转换，而纤维化消退过程存在其反过程。Fstl1是可被TGFβ1诱导的胞外小分子糖蛋白，我们前期工作证明Fstl1在肝纤维化进展中表达增高，和αSMA共定位于活化HSC，并在HSC去分化中表达下调。为深入研究Fstl1在肝纤维化HSC细胞命运决定中的作用，本课题拟通过HSC细胞模型及CCl4诱导的小鼠肝纤维化模型，利用Fstl1-creER等多种小鼠品系进行Fstl1细胞谱系示踪，基因消除和条件性敲除研究，并进一步探讨Fstl1在脂成纤维细胞和肌成纤维细胞双向转换过程中如何调节TGF-β1和PPARγ相关信号通路。该研究结果将提升学界对纤维化形成机制的认识，也为纤维化的临床诊治提供新靶点和新方法。

Tissue fibrosis is a serious health problem worldwide. Myofibroblasts are the major source of extracellular matrix that accumulate during tissue fibrosis, and hepatic stellate cells (HSCs) are believed to be the major source of myofibroblasts in the liver. Many studies demonstrate a lipogenic-to-myogenic switch in fibroblastic phenotype during fibrosis formation. Conversely, there is a myogenic-to-lipogenic switch during fibrosis resolution.This proposal is motivated by previous work from the evidence that Fstl1, a small secreted glycoprotein, induced by TGF-β1, is increased in liver fibrosis and co-localized with αSMA in activated HSCs, and from evidence that Fstl1 expression is decreased during HSCs dedifferentiation. We propose that Fstl1 signaling plays an important role in HSCs fate determination during fibrosis formation and resolution. We are going to use Fstl1-creER knockin, reporter, and knockout mouse lines to perform lineage-trace, gene ablation and conditional knockout studies. Moreover, we are going to study how Fstl1 regulates TGF-β1 and PPARγ signaling in two way conversion of myofibroblasts and lipofibroblast. Large impact on public health is anticipated upon completion of this study as the new gene targets will be identified to establish effective and safe strategies for the prevention and therapy for liver fibrosis.