内皮细胞FOXO1的功能和表观调控机制

Atherosclerosis (AS) is a local chronic inflammatory disease of arteries caused by systemic risk factors such as hypercholesterolemia (HC). This heterogeneous disease originates and develops preferentially at sites of curvature, branching, and bifurcation in arteries where complex hemodynamic disturbed flow (DF) is prominent. In contrast, undisturbed flow (UF) region is athero-protected. DF in athero-susceptible regions induces changes in endothelial phenotype including pro-inflammatory signaling pathways. Forkhead box protein O1（FOXO1）is a pro-inflammatory transcription factor that regulate both lipid metabolism and hemodynamic response. Our preliminary data showed that regulation of FOXO1 by HC was associated with epigenetic co-repressor complex SIN3A. Therefore, I propose to study these aims: 1. The roles of FOXO1 in the hemodynamic flow and HC regulation of the endothelial functions and the downstream target of FOXO1. 2. Epigenetic regulation of FOXO1 by hemodynamic flow and HC. 3. Development of DNA sequence specific epigenetic molecular tool based on the principle of CRISPR system. Achievement of the aims will reveal the roles of FOXO1 in DF/ HC-induced endothelial dysfunction during AS, address SIN3A epigenetic regulation of FOXO1 and develop epiCRISPR epigenetic tool in editing FOXO1 promoter.

血流和高胆固醇（HC）共同决定动脉粥样硬化（AS）的发生。AS首先在动脉血管的紊流DF区域出现病变,HC加速AS过程；相对的，AS一般不发生在非紊流UF区域。DF和HC能够诱发炎症反应。FOXO1是调控脂类代谢的重要转录因子，同时血流也可以调节FOXO1的表达。课题组的前期工作发现HC调控的FOXO1与表观遗传抑制复合体SIN3A相关，因此本项目将研究：1.血流和HC共同调控的内皮细胞FOXO1的功能，以及FOXO1转录因子所调控的下游基因。2.血流和高胆固醇的对FOXO1的表观调控SIN3A分子机理。3.开发基因序列特异性的epiCRISPR表观分子工具修饰FOXO1的基因启动子。完成本项目将揭示AS在发生过程中内皮细胞病变的分子信号和表观机制，验证SIN3A表观遗传抑制复合体对FOXO1的调控作用，开发新的分子工具epiCRISPR为治疗AS提供新的理论参考。

血流和高胆固醇共同决定动脉粥样硬化的发生。动脉粥样硬化首先在动脉血管的紊流区域出现病变, 高胆固醇加速动脉粥样硬化过程；相对的，动脉粥样硬化一般不发生在非紊流区域。紊流和高胆固醇能够诱发炎症反应。FOXO1是调控脂类代谢的重要转录因子，同时血流也可以调节FOXO1的表达。课题组的前期工作发现HC调控的FOXO1与表观遗传抑制复合体SIN3A相关，因此我们在本项目中研究了：1.血流和HC共同调控的内皮细胞FOXO1的功能，以及FOXO1转录因子所调控的下游基因。2.血流和高胆固醇的对FOXO1的表观调控SIN3A分子机理。本项目揭示动脉粥样硬化在发生过程中内皮细胞病变的分子信号和表观机制，验证SIN3A表观遗传抑制复合体对FOXO1的调控作用，为治疗动脉粥样硬化提供新的思路。