核磷蛋白 Nucleophosmin（NPM）在肝硬化进程中的作用与分子机制研究

肝硬化是肝纤维化不断进展的结果，因机制研究缺乏突破，尚无较好的治疗手段。核仁磷酸化蛋白NPM是一个能在细胞核--胞质穿梭的增殖、分化与凋亡相关调控蛋白。前期工作发现NPM在肝炎-肝硬化进程中表达变化，而且NPM过表达或沉默显著影响了肝星状细胞的增殖和细胞外基质合成等肝纤维化的中心事件，提示NPM可能通过促进肝纤维化而参与肝硬化进程。目前尚无文献报道NPM与肝硬化的关系，NPM在肝硬化中的具体作用与机制有待深入揭示。本项目研究拟通过肝硬化动物模型和体外细胞实验，并结合临床样本，进行以下研究：① 肝纤维化-肝硬化发展过程中NPM蛋白表达、定位变化；② 体内及体外水平上， NPM表达与定位变化对肝硬化进程的影响；③ NPM相互作用蛋白网络的组成与变化，以及NPM对蛋白质表达谱和重要信号通路的影响。通过上述研究，阐明NPM在肝硬化发生发展中的作用与分子机制，并为新的诊疗方法和药物开发提供科学依据。

Cirrhosis is the result of the development of liver fibrosis and there is currently no better treatment due to the lack of breakthrough in mechanism research.NPM is a proliferation, differentiation and apoptosis related regulatory proteins which mainly locates in nucleolus and shuttles between nucleolus and cytoplasm. Our preliminary works have found that NPM expression pattern changes at different stages of liver cirrhosis. Furthermore, over-expression or knockdown of NPM affected the activation, proliferation and expression of extracellular matrix by hepatic stellate cells, which formed the centerpiece of hepatic fibrosis. Our discoveries indicate that NPM may promote the process of cirrhosis by affecting hepatic fibrosis, and so far they have not been reported. However, the specific role and mechanisms in the development of cirrhosis of the liver remain unclear. Based on previous discoveries, the present project will focus on the following researches: ①investigating the expression pattern and the nucleocytoplasmic shuttling of NPM at different stages of cirrhosis with the cirrhosis animal model, cell model and the samples of human liver cancer; ② examing the effects of the altered expression and localization of NPM on hepatitis-cirrhosis development both in vivo and in vitro; ③ studying the alteration of NPM interacting network, proteomic expression profile and signal pathways affected by NPM using targeted proteomics technology. The studies may clarify the role of NPM in molecular mechanisms invloved in hepatitis-cirrhosis development, and may provide scientific basis for the development of diagnostic methods, treatment strategy and new drug.