The role of HDL-bound and unbound S1P in human and mouse atherosclerosis

HDL 结合和未结合的 S1P 在人和小鼠动脉粥样硬化中的作用

• 批准号: 39297953
• 负责人: Professor Dr. Bodo Levkau
• 金额: --
• 依托单位: Institut für Molekulare Medizin III
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2007
• 资助国家: 德国
• 起止时间: 2006-12-31 至 2013-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/39297953?language=en
• 关键词: role; HDL; bound; unbound; S1P

The most powerful atheroprotective factor are high-density lipoproteins (HDL). We have identified sphingosine-1-phosphate (S1P) as a constituent of human HDL and have attributed several of their pleiotropic functions to their S1P content. Specifically, we have characterized an important role for S1P and its receptor S1P3 in macrophage-driven inflammation in experimental atherosclerosis. In a clinical setting, we have identified HDL-bound and non-HDL-bound S1P as novel biomarkers for cardiovascular risk in coronary artery disease (CAD) and have provided evidence of an uptake defect of HDL from CAD patients for S1P. In this project, we will characterize how S1P impacts on the mechanisms governing monocyte/macrophage recruitment to atherosclerotic lesions and other inflammation sites. We will modulate endogenous S1P levels by S1P lyase inhibition and S1P-neutralizing antibodies and will explore the effects on inflammation and atherosclerosis. Focussing on the interplay between HDL and S1P, we will identify the molecular S1P acceptors inside HDL and their alleged alterations that cause the defective S1P uptake by HDL in CAD, and will explore ways to compensate it. Finally, we will perform prospective studies with CAD patients to test the applicability of HDL-bound and unbound S1P as predictors of cardiovascular risk and cardiac function after myocardial infarction. Our studies will elucidate the diagnostic and therapeutic ramifications of S1P in CAD and assess the potential of S1Pbased therapies for its clinical treatment.

最强大的动脉保护因子是高密度脂蛋白（HDL）。我们已经将鞘氨氨酸1-磷酸（S1P）确定为人类HDL的组成部分，并将其几种多效性功能归因于其S1P含量。具体而言，我们表征了S1P及其受体S13在实验性动脉粥样硬化中的炎症中的重要作用。在临床环境中，我们已经确定HDL结合和非HDL结合的S1P是冠状动脉疾病（CAD）心血管风险的新型生物标志物（CAD），并提供了S1P CAD患者HDL摄取HDL缺陷的证据。在这个项目中，我们将表征S1P如何影响控制动脉粥样硬化病变和其他炎症部位的单核细胞/巨噬细胞募集的机制。我们将通过S1P裂解酶抑制和S1P中和抗体来调节内源S1P水平，并将探索对炎症和动脉粥样硬化的影响。集中在HDL和S1P之间的相互作用上，我们将确定HDL内部的分子S1P受体及其所谓的改变，这些变化导致HDL在CAD中摄取有缺陷的S1P摄取，并将探索补偿它的方法。最后，我们将对CAD患者进行前瞻性研究，以测试HDL结合和未结合的S1P作为心肌梗死后心血管风险和心脏功能的预测指标。我们的研究将阐明S1P在CAD中的诊断和治疗后果，并评估S1PB疗法对其临床治疗的潜力。