| Co-Investigator(Kenkyū-buntansha) |
KIHARA Akio Hokkaido University, Faculty of Pharmaceutical Sciences, Associate Professor (50333620)
MITSUTAKE Susumu Hokkaido University, Faculty of Pharmaceutical Sciences, Assistant (10344475)
MIZUTANI Yukiko Hokkaido University, Faculty of Advanced Life Science, Assistant (30396296)
IWAKI Soichiro Nagoya City University, Pharmaceutical Sciences, Assistant (60399962)
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| Research Abstract |
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.
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