SUMO化PPARγ1与FOXO1相互作用正反馈调节高脂高糖应激诱导血管内皮胰岛素抵抗

PPARγ1和FOXO1均为体内重要的核转录因子且协同调控机体胰岛素的敏感性。我们近期的研究发现，ROS-IKK-PIAS1通路介导的PPARγ1K77SUMO化可通过稳定共阻遏蛋白(NcoR)，引起PPRE依赖的转录阻抑从而导致血管内皮胰岛素抵抗（IR）。但PPARγ1K77SUMO与FOXO1间交互作用是否及如何参与高脂高糖（HF/HG）应激所致血管内皮IR目前尚不清楚。本项目围绕“SUMO化PPARγ1与FOXO1相互作用正反馈调节HF/HG应激诱导血管内皮IR”这一关键科学问题，拟应用细胞/分子生物学和模型动物相结合的方法探讨PPARγ1SUMO化修饰及其与FOXO1交互作用在HF/HG应激诱导血管内皮IR的作用及机制。本研究为丰富和完善内皮IR信号网络调节机制，为代谢性疾病，癌症等重大疾病的防治提供潜在的分子靶点，也为新药开发提供依据。

PPARγ1 and FOXO1 which are important nuclear transcriptional factors cooperatively regulate systemic insulin sensitivity. Our recent data have shown that the sumoylation of PPARγ1 at K77 mediated by ROS-IKK-PIAS1 pathway participates in endothelial insulin resistance (IR) induced by hyperlipidemia and hyperglycemia (HF/HG) through stabilizing NcoR and repressing the PPRE-dependent transcription. The underlying mechanisms, nonetheless, remain to be identified. Therefore, the project will focus tightly on the key scientific issue whether and how crosstalk between SUMOylated PPARγ1 and FOXO1 exerts positive-feedback effects on vascular endothelial insulin resistance induced by hyperlipidemia and hyperglycemia.The study will be carried out using a combined approach of cell biology, molecular biology and animal model. The findings will enrich and better the regulation pathway of endothelial IR, and offer a novel target and preventional/therapeutic strategy for the related metabolic diseases and cancer.