Control of sphingosine-1-phosphate distribution.

信号脂质鞘氨醇-1-磷酸（S1 P）在哺乳动物生物学中起着关键作用。血液中S1 P的浓度很高，血浆S1 P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S1 P的浓度较低，需要S1 P区室化以维持适当的淋巴细胞循环。尽管淋巴器官中的S1 P在体内平衡中较低，但S1 P的浓度可在炎症时增加，并且已报道组织S1 P的增加促进血管生成并增强先天性和适应性免疫细胞的促炎反应。靶向S1 P信号传导和S1 P代谢的药物目前正作为免疫抑制剂进行临床试验。通过阻断淋巴细胞从淋巴器官中排出，这些药物阻止活化的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S1 P的重要功能，很少有人知道它的分布是如何控制的。为了保持低的组织S1 P，必须包含两个来源。首先，组织不断地被血浆浸泡，以带来营养并清除废物。必须防止血浆S1 P进入器官或从器官中取出。第二，所有的细胞都被认为在膜鞘脂代谢过程中产生胞内S1 P。这种细胞内S1 P必须在分泌到间隙空间之前被破坏。该基金研究淋巴器官中S1 P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.