NDRG2在细胞内质网应激及肝脂质代谢中的作用

项目名称： NDRG2在细胞内质网应激及肝脂质代谢中的作用

项目编号： No.31470803

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 生物物理、生化与生物分子学、生物力学与组织工程

项目作者： 药立波

作者单位： 中国人民解放军第四军医大学

项目金额： 80万元

中文摘要： 内质网应激（ERS）触发的未折叠蛋白反应（UPR）是真核细胞的一种适应性反应，主要经由IRE1、PERK和ATF6三个分支介导。目前尽管对上述各通路的信号传递和作用方式已有较多研究，但特定条件下UPR的调控及其对细胞功能的影响尚未完全阐明。NDRG2是我们首先报道的新抑癌基因和应激反应基因，前期研究显示在缺氧、脂毒性等多种应激条件下NDRG2参与细胞凋亡或存活；新近发现，NDRG2可与PERK相互作用，并且在内质网应激时参与肝细胞脂质代谢，但具体作用方式和功能效应仍待深入研究。基于此，本项目拟利用已有的Ndrg2-KO小鼠，结合细胞和分子水平研究，进一步确认NDRG2在ERS/UPR和肝脂质代谢中的作用；探索其上游调控机制；阐明NDRG2调节UPR及脂质代谢的分子机制；最后，解析NDRG2功能结构域在其中的作用。本项目从新的视角阐释NDRG2的生物学功能，并有助于丰富UPR调控机制的理论。

中文关键词： 内质网应激；脂质代谢；NDRG2

英文摘要： The unfolded protein response (UPR) trigered by endoplasmic reticulum stress (ERS) is an adaptive response in eukaryotic cells and is carried out mainly through IRE1, PERK and ATF6. Currently, although the signal transdution and the action mode of the above pathways have been extensively investigated, UPR regulation as well as its influence on cellular function have not been clarified completely. We firstly reported NDRG2 as a tumor suppressor gene and a stess-responsive gene. Our previous studies showed that NDRG2 is invovled in cell apoptosis or survival when the cells are challenged by various stress factors such as hypoxia and lipotoxicity. Most recently, we found that NDRG2 interacts with PERK and is involved in hepatic cell lipid metabolism during ERS, but the detailed mechanism as well as its effect on cellular function await an in-depth investigation. In this project, we plan to use Ndrg2-KO mouse model, along with molecular and cellular technique, to further determine the role of NDRG2 in ERS/UPR and hepatic lipid metabolism; to explore the upstream regulation of NDRG2; to clarify the underlying mechanism through which NDRG2 regulates ERS/UPR and lipid metabolism; finally to analyze the relevance of its domain in this process. This study will interprete the biological function of NDRG2 from a new aspect and will enrich the theroy about UPR regulation.

英文关键词： ER stress;lipid metabolism;NDRG2