ELF,肝硬化中肝干细胞分化再生肝细胞的关键调控分子

Clinical studies have demonstrated that liver function is a .crucial factor in assessing the prognosis of liver cirrhosis, which is associated.with liver regeneration upon chronic liver injury. Regenerative hepatocytes are.derived from the activation and differentiation of liver progenitor cells (LPC) in.liver cirrhosis. Therefore, it is important to explore the mechanism underlying the.activation and differentiation of LPC in improving the prognosis of liver cirrhosis. No available research has not been reported in this field until now. ELF is an adaptor in TGFβ/Smad signaling through controlling subcellular localization and nuclear tranlocation of Smad 3/4. Our previous studied demonstrated ELF played a key role in HSC activation and collagen deposition, and it was involved in hepatocytes regeneration. Base on this, a transgenic mouse model was established in which liver specific ELF expression was controlled by Tet system and liver specific promoter, and the role of ELF in activation and differentiation of LPC in liver cirrhosis was explored using above mice.Then lentivirus expressing siRNA against ELF was constucted and infected into liver progenitor cells, the effect of ELF siRNA on biological character of liver progenitos cells was analyzed. Liver progenitor cells will be infected with ELF siRNA transduced into mice of liver cirrhosis,and the therapeutic effect was evaluated. These studies demonstrated the crucial role of ELF in the activation and differentiation of liver progenitor cells,therefore，it will provide theoretical principle for improving the prognosis of the liver cirrhosis.

研究证实决定肝硬化预后的关键因素是肝功能代偿程度，其与肝脏慢性损伤后肝细胞再生密切相关，肝硬化时再生的肝细胞来源于肝干细胞的激活和分化，了解肝干细胞的调控机制对改善肝硬化的预后有着重要的意义，目前此方面研究基本属于空白；ELF.（Embryonic liver fodrin ) ，TGFβ/Smad 信号通路中的转接分子，参与Smad3/4 的分布.和核内转运。本申请者以往的研究证实，ELF 不仅在肝星状细胞活化和胶原沉积中发挥重要.作用；而且参与肝硬化中肝细胞的再生；因此本研究将以此为基础，制备靶向可控小鼠模型，论证ELF参与肝硬化中肝干细胞分化和激活；并制备表达ELF siRNA 的慢病毒，感染肝干细胞，分析其对肝干细胞生物学活性的影响；再将其移植肝硬化小鼠体内，检测其疗效，从而在细胞和整体水平揭示ELF 在肝干细胞分化调控中的作用机制，为改善肝硬化的预后奠定坚实的理论基础。

肝硬化时再生的肝细胞来源于肝干细胞的激活和分化，了解肝干细胞的调控机制对改善肝硬化的预后有着重要的意义，ELF（Embryonic liver fodrin ,也称为β血影蛋白) ，TGFβ/Smad信号通路中的转接分子；我们前期研究证实，其参与肝硬化中肝细胞的再生；因此本研究将以此为基础，探索ELF参与肝干细胞分化调控的作用及其机制。首先在动物模型和患者标本上证实ELF与肝脏分化密切相关，然后通过细胞和整体水平实验揭示ELF 在肝干细胞诱导分化调控中的关键作用，最后通过TGFβ/ Smad-ELF-βCatenin揭示ELF参与肝干细胞分化调控的机制，进而为将来利用ELF改善肝硬化的预后奠定坚实的理论基础。. 此外我们开展了一些临床研究，证实增强CT和MRI为吡咯烷生物碱诱导的肝窦阻塞综合征的诊断提供无创有效的手段；证实肿瘤标记物在良恶性腹水鉴别诊断中的价值，为恶性腹水的诊断提供良好补充；简化标准适用于中国人的重叠综合征（原发性胆汁性肝硬化和自身免疫性肝炎）的诊断。