| Project/Area Number |
20500343
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Neurochemistry/Neuropharmacology
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| Research Institution | Tokai University |
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Principal Investigator |
MATSUDA Junko Tokai University, 糖鎖科学研究所, 准教授 (60363149)
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| Co-Investigator(Renkei-kenkyūsha) |
SUZUKI Akemi 東海大学, 糖鎖科学研究所, 教授 (70134533)
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| Project Period (FY) |
2008 – 2010
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| Project Status |
Completed (Fiscal Year 2010)
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| Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2010: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2009: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2008: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | スフィンゴ脂質 / 海馬 / 小腸上皮 / 尿細管上皮 / ノックアウトマウス / フィトスフィンゴ脂質 / スフィンゴ脂質-C4-水酸化酵素(DES2) / 脳海馬体 / スフィンゴ脂質-C4-水酸化酵素(Des2) |
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| Research Abstract |
Glycosphingolipids are ubiquitous eukaryotic membrane lipids with highly diverse structures with hundreds of head-groups attached to various ceramides. Structure of ceramide varies due to various alkyl chain length, hydroxylation, and desaturation in both the sphingoid base and the N-acyl chain. Dihydroceramide: sphinganine C-4 hydroxylase (DES2) introduces the hydroxyl group at C-4 of sphinganine to produce phytoceramide. In mammals, phytoglycosphingolipids (phytoGSLs) expressed in the small intestinal epithelial cells, renal tubular epithelial cells and skin keratinocytes. To investigate the physiological role of phytoGSLs, Des2 null mice (Des2^<-/->) were generated by gene targeting. By the thin-layer chromatography coupled to mass spectrometry, Des2^<-/-> lacked phytoGSLs in small intestine and kidney, proving that DES2 is responsible for their biosynthesis. Des2^<-/-> were born healthy, but about 50% of Des2^<-/-> began to show growth retardation at around 10 days of age and were subsequently died at around 2-3 weeks of age. However, the other half of the Des2^<-/-> survived up to 20 months. Des2^<-/-> showed the histopathological changes in the small intestinal epithelial cells and renal tubular epithelial cells. In the nervous system, some of the Des2^<-/-> displayed neuronal cell death in the dentate gyrus of the hippocampus. Gangliosides with the phytoceramide structures were detected as minor species in the cerebrum of wild type mice. These findings of Des2^<-/-> suggest us a critical role of phytoGSLs in the epithelial cells and neurons as membrane-specific lipid components.
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