1-磷酸鞘氨醇受体信号通路在氧化应激致内皮细胞损伤中的作用与机制

项目名称： 1-磷酸鞘氨醇受体信号通路在氧化应激致内皮细胞损伤中的作用与机制

项目编号： No.81470593

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 闾宏伟

作者单位： 中南大学

项目金额： 68万元

中文摘要： 内皮损伤是血管疾病发生的起始环节，而氧化应激是导致血管内皮损伤的主要因素之一；血液中1-磷酸鞘氨醇（S1P）可通过内皮细胞表面的1-磷酸鞘氨醇受体（S1PR）介导，激活细胞内不同信号通路而产生广泛的生物学效应。我们前期的研究通过分析内皮细胞S1PR表达与高糖诱导内皮细胞氧化应激损伤的关系；结果发现氧化应激致内皮细胞损伤过程中S1PR1表达显著降低和S1PR2表达明显升高，推测S1PR信号通路可能参与氧化应激致内皮细胞的损伤作用。因此，本项目拟采用氧化应激的内皮细胞模型、糖尿病和高脂血症小鼠模型，通过调控S1PR1/S1PR2的表达，分析对内皮细胞的功能变化；以及通过激活或阻断氧化应激致内皮细胞损伤过程中S1PR下游信号通路中的相应靶分子，评价其对内皮细胞的功能影响；以探讨S1PR信号通路在氧化应激致内皮细胞损伤中的作用与机制，为预防和治疗氧化应激所致血管疾病提供侯选靶标和理论依据。

中文关键词： 血管内皮细胞；氧化应激；1-磷酸鞘氨醇受体；信号通路

英文摘要： Vascular endothelial injury is positively correlated with the morbidity and mortality of cardiovascular disease. Oxidative stress is one of the main factors resulting in endothelial cell dysfunction and vascular endothelial injury. Previous studies have shown that sphingosine-1-phosphate (S1P) regulates an array of biological activities in endothelial cells mediated by sphingosine-1-phosphate receptors (S1PRs). Our studies have shown that the imbalance of S1PR1/S1PR2 expression in endothelia cells with high glucose treatment was associated with endothelia dysfunction. Therefore, based on the previous study, our aims of this project are: 1. to further determine the relationship between changes of S1PR1/S1PR2 expression and its signaling pathways downstream in endothelial cells, and the endothelia dysfunction during the oxidative stress process. 2. to observe the effect of an imbalance of S1PR1/S1PR2 receptor on endothelia function by up-regulating S1PR1 receptor and blocking S1P2 receptor in endothelial cells during the oxidative stress process, thus revealing whether an imbalance of S1PR1/S1PR2 pathway mediates endothelia cell impairment. 3. to evaluate the effect of S1PR1/S1PR2 receptor signaling pathway on endothelia function by blocking some signal molecules correspondingly in endothelia cells during the oxidative stress process, thus clarifying the role of an imbalance of S1PR1/S1PR2 signaling in endothelia dysfunction induced by oxidative stress and its mechanism. Therefore, understanding the molecular mechanisms of vascular endothelial cell dysfunction and endothelial injury induced by oxidative stress will be helpful in both prevention and treatment of cardiovascular disease.

英文关键词： Endothelial cell;oxidative stress;Sphingosine 1-Phosphate receptor;Signaling pathway