Molecular Pharmacology of Sphingosine 1-Phosphate

描述（由申请人提供）：鞘氨醇1-磷酸（S1 P）是一种生物活性脂质，由于S1 P储存在红细胞中，因此在血浆中以三位数纳摩尔水平循环，在全血中以个位数微摩尔水平循环。循环S1 P与淋巴细胞运输的紧张性控制、内皮完整性的维持和心率的控制有关。血液S1 P在分钟的时间尺度上降解。然而，我们既不知道S1 P从循环中清除的机制，也不知道它是如何从细胞转运到血浆的。对开发阻断S1 P合成或作用的治疗方法的兴趣增加了了解循环S1 P水平如何调节以及降低循环S1 P张力的急性和慢性后果的紧迫性。在过去的支持期间，我们发现了新的小分子S1 P受体激动剂、拮抗剂和合成抑制剂，并开发了针对S1 P信号传导和代谢进行遗传改变的小鼠。此外，我们还增加了复杂的分析化学功能，可以在小样本中定量鞘脂种类。现在，我们建议通过使用我们的化学和分子生物学工具来更深入地了解S1 P生物学。具体而言，我们将：（目的1）确定循环S1 P水平的范围，检验脂质磷酸酶LPP 1负责血浆S1 P降解和Spns 2转运S1 P的假设，以及（目的2）使用S1 P合成抑制剂急性和慢性降低循环S1 P，并确定对淋巴细胞运输、毛细血管通透性和心率的影响。我们在S1 P化学生物学方面的丰富经验，如我们成功发现具有药物样特性的S1 P受体激动剂和拮抗剂所证明的那样，使我们能够解决有关循环S1 P的重要问题。这些答案将提供更多关于S1 P生物学的基础知识和实用信息，以指导S1 P靶向治疗的进一步发展。

DESCRIPTION (provided by applicant): Sphingosine 1-phosphate (S1P) is a bioactive lipid that circulates at triple digit nanomolar levels in plasma and at single digit micromolar levels in whole blood due to S1P's storage in erythrocytes. Circulating S1P is implicated in tonic control of lymphocyte trafficking, maintenance of endothelial integrity and control of heart rate. Blood S1P is degraded on a time scale of minutes. However, we know neither the mechanism(s) whereby S1P is cleared from circulation nor how it is transported from cells to plasma. The interest in developing therapeutics that block S1P synthesis or action add urgency to developing an understanding of how circulating S1P levels are regulated and the acute and chronic consequences of lowering circulating S1P tone. During the past period of support, we discovered new small molecule S1P receptor agonists, antagonists and synthesis inhibitors and we developed mice genetically altered for S1P signaling and metabolism. Further, we added sophisticated analytical chemistry capabilities that enable quantification of sphingolipid species in small samples. Now we propose to build on this success by using our chemical and molecular biology tools to understand S1P biology more deeply. Specifically, we will: (Aim 1) determine the range of circulating S1P levels, test the hypotheses that the lipid phosphatase LPP1 is responsible for plasma S1P degradation and that Spns2 transports S1P and (Aim 2) use S1P synthesis inhibitors to lower circulating S1P acutely and chronically and determine the effects on lymphocyte trafficking, capillary permeability and heart rate. Our extensive experience in S1P chemical biology, as evidenced by our success in discovering S1P receptor agonist and antagonists with drug-like properties, enables us to address important questions about circulating S1P. The answers will provide both increased fundamental knowledge about S1P biology and practical information to guide the further development of S1P-targeted therapeutics.