GCN2-ATF4通路调控巨噬细胞-肌成纤维细胞转化在肺纤维化中的作用及分子机制研究

特发性肺纤维化（IPF）发病机制尚不清楚，目前研究认为肌成纤维细胞在肺纤维化发病中起关键性作用。有文献研究表明在肾纤维化的发病过程中，存在着巨噬细胞向肌成纤维细胞转化（MMT）的现象，但目前MMT在肺纤维化中的研究尚未见报道。我们前期研究发现博来霉素诱导的小鼠纤维化肺组织中存在着MMT的现象，提示MMT可能参与肺纤维化的发生。另有文献研究表明在黑色素瘤中，GCN2的缺失可通过抑制转录因子ATF4的表达影响肿瘤相关巨噬细胞的表型向促炎的M1型转变。本课题组前期研究发现特发性肺纤维化患者和博来霉素诱导的小鼠纤维化肺组织中GCN2和ATF4的表达水平均明显上调。因此本研究拟证实肺纤维化中的MMT现象，并从临床、动物、细胞水平探讨GCN2-ATF4通路调控MMT在肺纤维化中的作用，同时进一步在分子水平找到ATF4与下游靶基因的结合位点，为今后研发IPF治疗靶点提供理论依据。

Idiopathic pulmonary fibrosis (IPF) is a disease of unknown pathogenesis and myofibroblasts play a key role in the pathogenesis of pulmonary fibrosis. The studies indicated that in the pathogenesis of renal fibrosis, macrophages could differentiate into myofibroblasts within the injured kidney in a process termed macrophage-to-myofibroblast transition (MMT). However, there is no evidence about MMT in pulmonary fibrosis. Our previous study found that macrophages could differentiate into myofibroblasts in BLM-induced murine pulmonary fibrosis, suggesting that MMT may be also involved in the pathogenesis of pulmonary fibrosis. The study found that deletion of GCN2 drives a shift in the phenotype of tumor-associated macrophages toward to an M1 phenotype through inhibiting ATF4 expression in melanoma tumor. In our previous study, we found increased GCN2 and ATF4 expression in both lung tissue of patient with IPF and murine model of pulmonary fibrosis. We plan to investigate role of MMT in lung fibrosis and the effect of GCN2-ATF4 pathway regulating MMT in lung fibrosis by clinical study, animal experiment and cell culture experiment in vitro. We plan to further confirm the specific binding sites on which ATF4 regulate target genes to provide theory evidence for the targeting therapy of IPF.