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Biological functions of Sphingolipids and their relevance to pathological phenomena

鞘脂的生物学功能及其与病理现象的相关性

基本信息

批准号：
18370050
负责人：
YASUYUKI Igarashi
金额：
$ 11.28万
依托单位：
Hokkaido University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

项目摘要

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.

1-磷酸鞘氨醇(S1P)通过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，S1P及其受体成为阻力研究的新靶点。在这项研究中，我们发现了鞘氨醇激酶1和2对基因转录的不同调控，并对S1P-分泌的机制有了新的见解。尽管血液中的S1P被认为来自于血小板，但我们发现红细胞可能是S1P的新供给者。在对S1P-受体的研究中，我们发现S1P-受体的C端手足运动调节了S1P-受体的激动剂刺激内化，从而导致其细胞功能的发挥。合成的S1P受体激动剂FTY-720是一种新的免疫抑制药，可以调节淋巴细胞的迁移。然而，FTY-720的具体作用机制尚未完全阐明。我们发现了FTY-720的新的代谢途径，其中包括LPP家族的磷酸酶。我们还研究了另一种具有生物活性的鞘磷脂，神经酰胺(Cer)。我们鉴定了一个新的Cer合酶，LAS3(CerS3)。LAS3可以比LAS5转移更长的脂肪酸，而LAS5以前被认为是Cer-sythase。由于鞘磷脂的特点之一是其结构上具有长链，因此LAS3可能在长链鞘脂的生物合成中起重要作用。另一方面，我们还对新近发现的Cer代谢酶神经酰胺酶(Cerk)进行了研究，证明Cerk在小脑Purkinje细胞中高表达，并可能参与情绪行为。如上所述，我们通过本研究揭示了S1P、S1P受体、Cer和Cer代谢物中新的机制和功能。