WDR76经ZHX2/NF-Y途径抑制ABCA1表达促动脉粥样硬化

色氨酸-天冬氨酸重复序列蛋白76（WDR76）是一种肥胖相关蛋白，参与脂质代谢，但在动脉粥样硬化（AS）中的作用及机制尚未阐明。ABCA1介导胆固醇流出发挥抗AS作用。预实验发现WDR76增加AS斑块面积，并下调泡沫细胞ABCA1表达。结合生物信息学分析，我们提出科学假说：“WDR76通过ZHX2/NF-Y途径抑制ABCA1表达，减少脂质蓄积，促As”。项目拟在巨噬细胞源性泡沫细胞过表达或沉默WDR76、ZHX2，检测ZHX2、NF-Y和ABCA1表达，NF-Y与ABCA1结合，胆固醇流出和脂质蓄积，阐明WDR76经ZHX2/NF-Y调控ABCA1的分子机制；在apoE-/-小鼠沉默或过表达WDR76，观察ZHX2、NF-Y和ABCA1表达，NF-Y与ABCA1结合，血脂水平和AS斑块面积，明确WDR76促AS作用。项目的完成将明确WDR76促AS及其分子机制，为AS防治提供理论依据。

Tryptophan-aspartate repeat protein 76 (WDR76) is an obesity-related protein and is involved in lipid metabolism, however, the role and underlying mechanisms of WDR76 in the process of atherosclerosis (AS) is unclear. ABCA1 inhibits atherosclerosis by promoting cholesterol efflux. Pre-experiments found that WDR76 promoted the formation of atherosclerotic plaque, and significantly inhibited ABCA1 expression in THP-1 macrophage derived foam cells. Combined with Bioinformatics predictions, we presume that: "WDR76 down-regulates ABCA1 expression through the ZHX2/NF-Y pathway, inhibits cholesterol efflux and promotes AS." To test this hypothesis, The project intends to overexpress or silence WDR76, ZHX2 in macrophage-derived foam cells, detect the expression of ZHX2, NF-Y and ABCA1, NF-Y binds to ABCA1, cholesterol efflux and lipid accumulation, thereby exploring the effect of WDR76 on ABCA1 expression and the involved mechanism. ApoE-/- mice transfected with shZHX2 or WDR76, observe the expression of ZHX2, NF-Y and ABCA1, the interaction between NF-Y and ABCA1, blood lipid level and AS plaque area, thereby revealing the role and mechanism of WDR76 in AS development. The completion of the project will clarify the WDR76 promotion of AS and its molecular mechanism, and provide a theoretical basis for the prevention and treatment of AS.