Biological functions of Sphingolipids and their relevance to pathological phenomena

1-磷酸鞘氨醇（S1 P）通过一个G蛋白偶联受体家族在血管和免疫系统中发挥重要作用。近十年来，S1 P及其受体成为药物发现的新靶点。本研究发现了鞘氨醇激酶1和2在基因转录调控上的差异，为S1 P的产生机制提供了新的认识。虽然血液中的S1 P一直被认为来自血小板，但我们发现红细胞可能是S1 P的新供应者。在对S1 P受体的研究中，我们发现S1 P受体的C端棕榈酰化可以调节激动剂刺激的S1 P受体内化，从而发挥其细胞功能。合成的S1 P受体激动剂FTY-720是一种新的免疫抑制剂候选物，调节淋巴细胞迁移。然而，FTY-720的详细工作机制尚未完全阐明。我们发现了FTY-720新的代谢途径，其中包括LPP-家族磷酸酶，并研究了另一种具有生物活性的鞘脂神经酰胺（Cer）。我们发现了一个新的铈合酶，LAS 3（CerS 3）。LAS 3比LAS 5能转运更长的脂肪酸，LAS 5被鉴定为Cer-合酶。由于鞘脂的结构特征之一是具有长链，因此LAS 3可能对长链鞘脂的生物合成具有重要意义。另一方面，我们还对新发现的铈代谢酶--神经酰胺激酶（ceramide kinase，CERK）进行了研究，并利用CERK基因敲除小鼠证明CERK在小脑浦肯野细胞中高表达，可能参与情绪行为，从而揭示了S1 P、S1 P受体、铈及其代谢产物的新机制和功能。

Sphingosine 1-phosphate (S1P) have important roles in vascular and immune system, acting through a family of G-protein coupled receptor. In this decade, S1P and its receptor are emerged as a new target of drag discovery. In this research, we found different regulation of gene transcription between sphingosine kinase 1 and 2, and added new insights in the mechanism of S1P-pridution. Although S1P in the blood has been considered from platelet, we showed that the red blood cells could be new supplier of S1P. In the research of S1P-receptor, we revealed that C-terminal palmitation of S1P-receptor regulated agonist-stimulating internalization of S1P-receptor, leading to its cellular functions. The synthetic agonist of S1P-receptor, FTY-720, is a candidate of new immune suppressor, regulating lymphocyte migration. However, the detail working mechanisms of FTY-720 is not fully elucidated. We showed new metabolic pathway of FTY-720 which include the LPP-familly phosphatase.We also researched another bioactive sphingolipid, ceramide (Cer). We identified a new Cer-synthase, LAS3 (CerS3). The LAS3 could transfer longer fatty acid than LAS5 which was previously identified as Cer-sythase. Since one of the feature of sphingolipid is having long chain in its structure, LAS3 might be important for biosynthesis of long-chain sphingolipid. One the other hand, we also researched ceramide kinase (CERK), newly discovered Cer-metabolizing enzyme, and demonstrated that CERK was highly expressed at Purkinje cell in cerebellum, and might be involved in emotional behavior using CERK-knock out mice.As described above, we revealed new mechanisms and functions in S1P, S1P-receptor, Cer, and Cer-metabolite through this research.