Control of sphingosine-1-phosphate distribution.

信号转导脂鞘氨醇-1-磷酸(S1P)在哺乳动物生物学中起着重要作用。S1P在血液中的浓度很高，血浆S1P稳定血管内皮细胞之间的连接。与血液和淋巴相比，淋巴组织中S1P的浓度较低，需要S1P区隔来维持适当的淋巴细胞循环。虽然淋巴器官中S1P的稳态较低，但炎症时S1P的浓度可能会增加，组织中S1P的增加被报道为促进血管生成和增强先天免疫细胞和获得性免疫细胞的促炎反应。针对S1P信号和S1P代谢的药物目前正在作为免疫抑制剂进行临床试验。这些药物通过阻止淋巴细胞从淋巴器官出口，防止激活的T细胞到达移植器官或受到自身免疫攻击的器官。这些药物也可能具有直接的抗炎作用。尽管S1P具有重要功能，但人们对其分布是如何控制的知之甚少。为了维持较低的组织S1P，必须包含两个来源。首先，组织不断地沐浴在血浆中，以带来营养并清除废物。必须防止血浆S1P进入器官或从器官中移除。第二，所有细胞都被认为在膜鞘磷脂代谢过程中在细胞内制造S1P。这种细胞内的S1P在分泌到间质之前必须被破坏。这项拨款调查淋巴器官中S1P浓度是如何调节的。

The signaling lipid sphingosine-1-phosphate (S1P) plays critical roles in mammalian biology. The concentration of S1P is high in blood, and plasma S1P stabilizes junctions between vascular endothelial cells. The concentration of S1P is low in lymphoid tissues compared to blood and lymph, and S1P compartmentalization is required to maintain proper lymphocyte circulation. Although S1P in lymphoid organs is low in homeostasis, the concentration of S1P may increase upon inflammation, and increases in tissue S1P have been reported to promote angiogenesis and to enhance pro-inflammatory responses of innate and adaptive immune cells. Drugs targeting S1P signaling and S1P metabolism are currently in clinical trials as immune suppressants. By blocking lymphocyte exit from lymphoid organs, these drugs prevent activated T cells from reaching transplanted organs or organs that are subject to autoimmune attack. These drugs may also have direct anti-inflammatory effects. Despite S1P's vital functions, little is understood about how its distribution is controlled. To maintain low tissue S1P, two sources must be contained. First, tissues are constantly bathed with plasma to bring nourishment and remove waste. Plasma S1P must be prevented from entering, or removed from, the organs. Second, all cells are thought to make S1P intracellularly during the course of membrane sphingolipid metabolism. This intracellular S1P must be destroyed before it is secreted into the interstitial space. This grant investigates how S1P concentrations in the lymphoid organs are regulated.