特异性lncRNA调控SDE2SUMO化修饰在同型半胱氨酸致动脉粥样硬化中的机制研究

巨噬细胞源性泡沫细胞形成是同型半胱氨酸(Hcy)引起动脉粥样硬化(As)的重要环节，但机制未清。RNA剪接可以产生带有编码信息功能的mRNA，是真核细胞基因表达的重要生物过程。lncRNA作为一种新的调控因子，可通过影响mRNA转录后调控参与细胞的调节。预实验结果提示SUMO化修饰调控pre-mRNA剪接参与了Hcy介导泡沫细胞形成，故本课题拟筛选和确定lncRNASHCBP1是Hcy促进泡沫细胞的形成特异性lncRNA，并阐明其功能性靶基因DDIT4的作用；明确SDE2调控pre-mRNA剪接是Hcy引起DDIT4表达下调的重要机制；质谱分析SDE2赖氨酸SUMO化修饰的变化，并采用阻断为主的策略确定SENP1为关键调控因子；探寻lncRNASHCBP1介导SDE2赖氨酸位点K132、323、405和450 SUMO化修饰的作用，明确关键位点，为防治As提供理论依据。

The formation of macrophage-derived foam cell is an important part of atherosclerosis (As) caused by homocysteine (Hcy), but the mechanism is unclear. RNA splicing produce mRNA with the function of coding information, which is an important biological process for eukaryotic cell gene expression. As a new regulatory factor, lncRNA can participate in the regulation of cells by affecting post-transcriptional regulation of mRNA. Previous results suggest that the SUMOylation modification modulates pre-mRNA splicing and participates in Hcy-mediated foam cells. Therefore, this project intends to screen and determine that lncRNASHCBP1 is a specific lncRNA of Hcy-promoted the formation of foam cells, and clarify the role of its functional target gene DDIT4. Clarify SDE2 regulates pre-mRNA splicing is an important mechanism of Hcy-induced down-regulation of DDIT4 expression. Mass spectrometry was used to analyze the changes of SDE2 lysine SUMO modification, and block-based strategy was used to determine SENP1 as the key regulatory factors. To explore the role of lncRNASHCBP1 in mediating SDE2 lysine sites K132, 323, 405, and 450 of SUMO modification, clarify key sites, and provide a theoretical basis for the prevention of As.