肺纤维化中Fstl1调控间充质前体细胞向肌纤维母细胞分化的命运决定

特发性肺纤维化（IPF）是一种慢性发展致死性的肺疾病，其特征为肺组织中肌纤维母细胞大量积累和胶原等胞外基质过度沉积，导致肺组织破坏肺功能丧失，目前临床尚无有效的治疗方法，主要原因是对其发病机制尚不清楚。本课题在前期研究中首次发现基质蛋白Fstl1是新的内源促纤维化因子，在病理状态下表达上调的Fstl1与肌纤维母细胞积累正相关。本课题将利用Fstl1报告小鼠、Fstl1谱系删除小鼠和博莱霉素诱导的小鼠肺纤维化疾病模型，采用体内谱系追踪结合体外FACS分选等方法，首次验证Fstl1谱系间充质细胞是大量积累肌纤维母细胞的重要细胞来源；研究Fstl1参与间充质干细胞向myofibroblasts分化的命运决定作用；评估Fstl1是myofibroblast前体细胞的一种重要标记分子；筛选抗纤维化的天然药物活性小分子。研究结果进一步揭示肺纤维化的生理病理机制，并为其临床治疗提供新的潜在药物。

IPF is a chronic and progressive lung disease of unknown etiology that leads to loss of lung function. It is characterized by accumulation of myofibroblasts and unremitting matrix deposition. Currently, no medical therapies exist. We have previously shown that FSTL1 is a profibrotic factor that is up-regulated in lungs of patients with IPF, as well as in bleomycin-injured mice. The population of myofibroblasts during fibrogenesis seems to depend on the expression of Fstl1. In this study, we will use a combination of in vivo cell lineage tracing method and in vitro FACS analysis to identify the contribution of Fstl1-derived mesenchymal cells to the origins of myofibroblasts; to investigate the role of Fstl1 in regulating the differentiation of mesenchymal progenitor cell into myofibroblasts; to score Fstl1 as a specific marker of mesenchymal progenitor cells; to screen and identify anti-fibrotic candicates of nature medicin small moleculars. Our study will improve the understanding of the molecular mechanisms underlying lung ?brosis, and may offer a novel therapeutic strategy for the patients with progressive tissue fibrosis.