新近研究提示，肝星状细胞（HSC）并非如已往认为的那样，只是肝纤维化的被动参与者，它通过TLR4通路主动参与炎症，进而调控炎症与肝纤维化的级联反应。前期工作发现，miR-192通过靶向Rictor参与mTORC2通路调控，预实验结果显示在LPS-TLR4激活的HSC中miR-192表达下调，过表达miR-192可引起mTORC2和TLR4信号改变。据此我们提出科学假设：miR-192-Rictor/mTORC2参与TLR4信号调控，在炎症和肝纤维化的级联反应中发挥重要作用。本课题拟在前期工作基础上，进一步探讨miR-192在HSC炎症和纤维化级联反应中的作用，重点验证miR-192-Rictor/mTORC2-TLR4信号通路，并应用已建立的内含子miRNA表达技术，实现对HSC特异性的miR-192表达，以期为小分子物质miR-192成为有效而特异的纤维化干预靶点提供理论依据和应用前景。

Even quiescent hepatic stellate cells (HSCs) express high levels of TLR4 and are highly responsive to LPS treatment, suggesting that HSCs is not passively involved in inflammation, but positively act as sentinels that promote inflammatory and thus fibrogenic responses after increased hepatic exposure to TLR4 agonists such as LPS. In previous work, we found that miR-192 may directly target Rictor, implicated in mTORC2 signaling pathway. In HSCs which was activated by LPS-TLR4 signals, the downregulation of miR-192 was observed significantly, and restoration of miR-192 in activated-HSCs may lead to alterations of both mTORC2 and TLR4 signaling spontaneously. Hence, we present a hypothesis that miR-192-Rictor/mTORC2 participates in the modulation of TLR4 signaling pathway, and plays a pivotal role in the cascade effects of inflammation and fibrogenesis. In this project, we will further investigate the role of miR-192 in the cascade effects of inflammation and fibrogenesis in terms of biological function of HSCs, verify the signaling pathway of miR-192-Rictor/mTORC2-TLR4 in HSCs, and utilize our established technique e.g. artificial intron-derived microRNAs (Id-miRNA) expression system to realize the activated-HSC-cell-specific gene silencing. Our project would guarantee further investments to develop miR-192 as an effective molecule for intervening therapy of liver fibrosis.