Sphingosine 1-phosphate receptors in vascular homeostasis and pathology

描述(由申请人提供)：1-磷酸鞘氨醇(S1P)通过其细胞表面G蛋白偶联受体调节血管通透性、炎症、血管生成和血管成熟。在过去的资金支持期间，我们发现载脂蛋白M(ApoM)是S1P与高密度脂蛋白结合所必需的，并且apom+高密度脂蛋白激活内皮细胞S1P1受体以诱导血管内稳态和抑制炎症反应。最近的发现也揭示了载脂蛋白+高密度脂蛋白在抑制淋巴生成方面的新功能。此外，我们发现S1P1受体是血管内皮细胞切应力感应的关键近端组件，并调节血管发育和内稳态。这一更新应用旨在进一步阐明这一基本的信号系统、血管和免疫系统。由于S1P受体调节剂目前在临床上用于治疗自身免疫性疾病，充分定义这一信号系统并了解其对心血管的影响是很重要的。这一建议的主要假设是，血浆中高密度脂蛋白结合的载脂蛋白/S1P复合体激活S1P受体，调节生理性血管发育和动态平衡以及免疫动态平衡。高密度脂蛋白/S1P对多种S1P受体的平衡激活对血管系统的正常健康起着至关重要的作用，如果调节失调，就会导致血管疾病。我们建议阐明apom+高密度脂蛋白将S1P递送到其内皮细胞上的受体并调节其生物学效应的机制。其次，将在小鼠和鱼类模型中检验apom+高密度脂蛋白通过S1P受体调节血管炎症的生理重要性。将进行培养内皮细胞的生化分析、斑马鱼的遗传功能丧失研究以及受体功能的遗传小鼠模型，以进一步确定关键的S1P途径组件。第三，我们将探索新的发现，apom+高密度脂蛋白信号通过S1P受体抑制淋巴生成。载脂蛋白+高密度脂蛋白/S1P调节免疫个体发育，而白蛋白/S1P介导免疫细胞转运的概念将得到严格的检验。将探索重组的载脂蛋白+高密度脂蛋白的治疗机会。由于S1P受体调节剂已经进入治疗时代，该项目的发现很可能具有快速翻译的潜力。

DESCRIPTION (provided by applicant): Sphingosine 1-phosphate (S1P) signals via its cell-surface G protein-coupled receptors to regulate vascular permeability, inflammation, angiogenesis and vascular maturation. In the past funding period, we found that apolipoprotein M (ApoM) is required for S1P to be associated with HDL and that ApoM+HDL activates the endothelial S1P1 receptor to induce vascular homeostasis and inhibit inflammatory responses. Recent findings also revealed a novel function of ApoM+HDL in the suppression of lymphopoiesis. In addition, we uncovered that the S1P1 receptor is a critical proximal component of shear stress sensing in the vascular endothelium and regulates vascular development and homeostasis. This renewal application aims to further elucidate this fundamental signaling system vascular and immune systems. Since S1P receptor modulators are now used in the clinic to treat autoimmune conditions, it is important to fully define this signaling system and to understand the cardiovascular implications. The overarching hypothesis of this proposal is that an HDL-bound ApoM/ S1P complex in plasma activates S1P receptors to regulate physiologic vascular development and homeostasis as well as immune homeostasis. The balanced activation of multiple S1P receptors by HDL/S1P plays a critical role in normal health of the vascular system and if dysregulated, leads to vascular disease. We propose to elucidate the mechanisms by which ApoM+HDL delivers S1P to its receptors on endothelial cells and regulates biological effects. Second, the physiological importance of ApoM+HDL to regulate vascular inflammation via S1P receptors will be examined in mouse and fish models. Biochemical analysis in cultured endothelial cells, genetic loss-of-function studies in zebrafish and genetic mouse models of receptor function will be conducted to further define the key S1P pathway components. Third, we will explore the novel finding that ApoM+HDL signaling via S1P receptors restrain lymphopoiesis. The concept that ApoM+HDL/S1P regulates immune ontogeny while albumin/S1P mediates immune cell trafficking will be tested rigorously. Therapeutic opportunities with reconstituted ApoM+HDL will be explored. Since S1P receptor modulators have entered the therapeutic era, the findings from this project are likely to have rapid translational potential.