TGF-β介导的肝星状细胞微丝骨架重排的分子机制研究及其在预防肝纤维化过程中的应用

TGF-β signaling pathway drives fibrogenesis after tissue injury in many organs. During the progression of liver fibrosis, TGF-β signaling activates hepatic stellate cell (HSC) and transforms it into fibroblast-like cell, and in turn induces fibrogenesis. The canonical TGF-β signaling pathway involves Smad-dependent transcriptional regulation, which is a slow process. Interestingly, our previous findings showed that short exposure of TGF-β significantly enhanced the migration of HSC and induced the formation of stress fiber. These phonotypical changes are not dependent on canonical TGF-β pathway; instead, it triggers the activation of RhoA and hence induces actin cytoskeletal rearrangement. During epithelial-mechychamal transition, TGF-β rapidly activates mTOR pathway, which is necessary for RhoA activation. Here, we will study how TGF-β-mTOR signaling axis activates RhoA in HSC during liver fibrosis, and we will evaluate the application of small inhibitors of mTOR, such as Rapamycin and Resveratrol, in liver fibrosis prevention. We propose signaling transduction along the axis of TGF-β-mTOR-RhoA is an important step of liver fibrosis initiation. The accomplishment of this proposal will shed new light on liver fibrosis prevention.

转化生长因子TGF-β信号通路主导着组织纤维化的起始和形成。在肝纤维化过程中，TGF-β通过激活肝星状细胞形成成纤维细胞，参与了纤维化的形成。经典的TGF-β通路作用于蛋白的转录调控，其效力一般发生在1天或数天后。然而我们先前的研究发现短时间TGF-β处理即可显著增强肝星状细胞的迁移及形成应力纤维的能力。TGF-β的这一活性不是作用于转录水平，而是通过激活RhoA通路引起肝星状细胞微丝骨架重排。在上皮细胞向间叶细胞转变时，TGF-β信号通路能快速激活mTOR并上调RhoA活性。本研究将探讨TGF-β－mTOR信号轴在肝星状细胞中如何激活RhoA，并评估mTOR通路的小分子抑制剂Rapamycin以及Resveratrol（红酒活性成分）对肝纤维化的抑制效果。我们提出TGF-β－mTOR－RhoA通路是起始肝纤维化的重要一环，该项目的完成将为肝纤维化的预防提供新思路与新方法。