Sphingosine 1-phosphate receptors in vascular homeostasis and pathology

描述（由申请人提供）：鞘氨醇1-磷酸（S1 P）通过其细胞表面G蛋白偶联受体发出信号，以调节血管通透性、炎症、血管生成和血管成熟。在过去的资助期间，我们发现载脂蛋白M（ApoM）是S1 P与HDL相关所必需的，ApoM+HDL激活内皮S1 P1受体以诱导血管稳态并抑制炎症反应。最近的研究结果还揭示了ApoM+HDL在抑制淋巴细胞生成中的新功能。此外，我们发现S1 P1受体是血管内皮中剪切应力感知的关键近端组分，并调节血管发育和稳态。这一更新申请旨在进一步阐明这一基本信号系统血管和免疫系统。由于S1 P受体调节剂现在用于临床治疗自身免疫性疾病，因此充分定义这种信号传导系统并了解心血管影响非常重要。该提议的总体假设是血浆中HDL结合的ApoM/S1 P复合物激活S1 P受体以调节生理血管发育和稳态以及免疫稳态。HDL/S1 P对多种S1 P受体的平衡激活在血管系统的正常健康中起着关键作用，如果失调，会导致血管疾病。 我们建议阐明ApoM+HDL将S1 P传递到内皮细胞上的受体并调节生物学效应的机制。其次，将在小鼠和鱼类模型中检查ApoM+HDL通过S1 P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和受体功能的遗传小鼠模型，以进一步确定关键的S1 P通路组分。第三，我们将探索ApoM+HDL信号通过S1 P受体抑制淋巴细胞生成的新发现。ApoM+HDL/S1 P调节免疫个体发生而白蛋白/S1 P介导免疫细胞运输的概念将被严格测试。将探索重组ApoM+HDL的治疗机会。 由于S1 P受体调节剂已进入治疗时代，因此该项目的发现可能具有快速转化的潜力。

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.