Curcumin调控活化型HSC衰老在抗肝纤维化中的作用及分子机理研究

肝星状细胞（HSC）活化是肝纤维化（HF）发生的核心环节。既往国内外抗HF研究多聚焦于抑制HSC活化和增殖及促进其凋亡，忽略了活化型HSC衰老及相关机制在其中扮演的重要角色。我们前期工作表明，姜黄素（Cur）可有效抑制HSC活化发挥抗HF作用并明确PPARγ为其作用靶标。本项目创新性地提出调控活化型HSC衰老可能是Cur抗HF的新机制。为此，本研究拟利用CCl4与胆管结扎HF模型，首先明确Cur对HF的抑制作用与活化型HSC衰老之间相关；然后利用活化型HSC衰老体外模型和p53-/-小鼠，研究Cur对HSC细胞周期、端粒酶系统、p53和PPARγ分子的影响，阐明Cur激活PPARγ调控p53基因从而影响活化型HSC衰老的机制；最后研究Cur对NK细胞清除衰老HSC的影响；以此从新的视角阐明Cur抗HF的作用机制，预期研究成果可望为药物防治HF提供新策略和新靶点。

Activation of HSC is the central event in hepatic fibrosis. Previous studies mainly focus on inhibition of HSC activation and induction of HSC apoptosis. Senescence of activated HSC and the related molecular mechanisms are rarely investigated. Our previous studies showed that curcumin could potently inhibit HSC activation to exert its antifibrotic effects by targeting PPARγ. We herein creationally put forward that curcumin has effects on senescence of activated HSC associated with PPARγ regulation of p53 signaling pathways. Curcumin also affects the interactions between NK cells and senescent HSC. To test these hypotheses, we first use rat liver fibrosis model induced by CCl4 and BDL to investigate the correlation between the antifibrotic effects and senescence of activated HSC. Then we use HSC culture system and p53-/- mice to further study the curcumin effects on cell cycle, telomerase system, p53 and PPARγ signal transductions. Based on the establishment of the critical role of p53 in curcumin intervention of senescence of activated HSC, we attempt to elucidate the molecular mechanisms of drug action, which may be associated with PPARγ/p53 regulation system. Finally, we investigate whether curcumin can affect the clearance of activated HSC by NK cells. Through these studies, we can interpret the actions of curcumin on HSC senescence and elucidate the underlying molecular mechanisms. These studies provide basis for developing curcumin as promising antifibrotic agent for clinical application.