基于梣酮发现的FOLR2-TGF-βRII 相互作用维持肝星状细胞持续活化的新机制及其靶标属性

肝星状细胞（HSCs）的持续活化是肝纤维化进程的关键环节，但维持其持续活化的机制仍不清楚。我们借助小分子梣酮的抗肝纤维化活性发现了其靶蛋白叶酸（FA）受体2（FOLR2）并证明HSCs活化过程中存在FOLR2-TGF-βRII互作。本项目拟确证FA-FOLR2信号能促进TGF-β-Smad信号的从头活化；探讨从头活化的机制，包括TGF-βR重回细胞膜再次启动TGF-β-Smad信号的促进机制；阐明FOLR2-TGF-βRII互作及可供小分子干预的结构基础；通过遗传操纵改变互作双方并比较FA、梣酮、甲氨蝶呤及TGF-βR抑制剂对互作、细胞功能和肝纤维化的影响，阐明其靶标属性；最后，设计合成靶向FOLR2-TGF-βRII互作的化合物并探讨抗肝纤维化作用。本研究基于小分子的独特活性，创新性地从HSCs持续活化角度发现并确证肝纤维化的新型靶标，研究设计独辟蹊径，可望引领肝纤维化研究的学科前沿。

The sustained activation of hepatic stellate cells (HSCs) is the key event in the pathogenesis of liver fibrosis. However, there remains unknown underlying the mechanisms of the sustaining. Our previous studies have found the binding protein folate receptor 2 (FOLR2) of fraxinellone with an anti-fibrotic activity and the FOLR2-TGF-βRII interaction in HSCs activation. In this study, we will make an effort to confirm that folic acid-stimulated FOLR2 signal may promote the de novo activation of TGF-β-Smad signal; to investigate the underlying mechanism including the promotion of the TGF-βR recycling to membrane for re-eliciting the TGF-β-Smad signal; to elucidate the structural basis of FOLR2-TGF-βRII interaction, which can be used for small molecule intervention; to examine the drug target property of FOLR2-TGF-βRII interaction by genetic control and by comparing the effects of folate, fraxinellone, methotrexate and TGF-βR inhibitors on the interaction, HSCs function and liver fibrosis; and finally to design and synthesize various compounds to target FOLR2-TGF-βRII interaction and examine their anti-fibrotic activities. This study is designed to discover and validate the new target against liver fibrosis, which is based on the unique activity of a small molecule and performed from the aspect of sustained HSCs activation in a unique pattern. The achievements may be helpful to pave a new way to the treatment of liver fibrosis.