组蛋白和DNA甲基化相互作用调控内质网应激通路介导同型半胱氨酸致肝脏脂代谢紊乱的分子机制

项目名称： 组蛋白和DNA甲基化相互作用调控内质网应激通路介导同型半胱氨酸致肝脏脂代谢紊乱的分子机制

项目编号： No.81460121

项目类型： 地区科学基金项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 金少举

作者单位： 宁夏医科大学

项目金额： 47万元

中文摘要： 同型半胱氨酸(Hcy)并不直接参与脂质代谢，何以能显著扰乱肝脏脂质转运平衡引起血脂异常尚未清楚。肝脏作为内源性脂代谢的主要场所，易发生内质网应激(ERS)，且前期发现Hcy可引起肝细胞功能障碍致脂代谢紊乱，并DNA甲基化是Hcy致病重要机制，同时组蛋白甲基化是协同DNA甲基化编码遗传信息的重要调控方式，但组蛋白和DNA甲基化在Hcy经ERS致脂代谢紊乱的机制未见报道。本项目拟以ERS通路基因为靶基因，CHIP检测H3K9me3及其位点相关的ERS通路基因的变化，明确其在脂代谢紊乱中的作用；构建组蛋白甲基化酶(HMT)和去甲基化酶(UTX)载体及拮抗剂干预，逆转H3K9甲基化，通过双向干预组蛋白和DNA甲基化模式的平衡，探讨H3K9和DNA甲基化相互作用及对关键靶基因的调控机制，研究其对肝细胞生物学活性和ERS通路的影响，揭示Hcy致病的表观遗传学机制，确定关键靶点，为靶向治疗提供实验依据。

中文关键词： 同型半胱氨酸；内质网应激；组蛋白甲基化；DNA甲基化；脂代谢紊乱

英文摘要： How could homocysteine (Hcy) disrupt the balance of lipid transport in liver and cause atherosclerosis (As) while Hcy is not involved in lipid metabolism directly is not yet clear. The liver，the place of endogenous lipid metabolism ，is to be more prone to endoplasmic reticulum stress. Our previous study found Hcy could lead to liver cell dysfunction-induced lipid metabolism disorders, and DNA methylation is an important mechanism of Homocysteine-induced AS, and histone methylation is an important regulation way of encoding genetic information cooperated with DNA methylation. But the role of histone methylation and DNA methylation in Hcy-induced lipid metabolism disorder via ERS has not been reported. This project intends to target for ERS pathway gene, CHIP is used to detect the changes of H3K9me3 of ERS pathways related genes to determine its role of lipid metabolism disorder. Constructing carriers of histone methyltransferases(HMT) and demethylase(UTX)and intervent with antagonists to reverse H3K9 methylation. Interfere the balance of DNA methylation and histone methylation pattern bilaterally to explore the mechanism of interaction between DNA methylation and H3K9 methylation and the regulation of target genes, to study the effect of interaction for biological activities of liver cells and ERS pathways, to reveal epigenetic mechanisms of pathogenicity of Hcy and determine the key targets, to provide experimental basis for the therapy of As.

英文关键词： Homocysteine;Endoplasmic Reticulum Stress;Histone methylation;DNA methylation;Lipid metabolism disorder