| Project/Area Number |
14082203
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | Ritsumeikan University (2005-2006)
Kyoto University (2002-2004) |
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Principal Investigator |
KAWASAKI Toshisuke Ritsumeikan University, Organization for the promotion of the COE Program, Professor (50025706)
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| Co-Investigator(Kenkyū-buntansha) |
NAGANO Seido Ritsumeikan University, College of INformation Science and Engineering, Professor (40367991)
OKA Shogo Kyoto University, Faculty of Medicine, Professor (60233300)
MA Bruce Yong Ritsumeikan University, Organization for the prornotion of the COE Program, Associate Professor (00378788)
KAWASAKI Nobuko Ritsumeikan University, Research Organization of Science and Engineering, Professor (70077676)
上村 和秀 京都大学, 薬学研究科, 助手 (20303844)
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| Project Period (FY) |
2002 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥160,900,000 (Direct Cost: ¥160,900,000)
Fiscal Year 2006: ¥35,000,000 (Direct Cost: ¥35,000,000)
Fiscal Year 2005: ¥35,000,000 (Direct Cost: ¥35,000,000)
Fiscal Year 2004: ¥36,000,000 (Direct Cost: ¥36,000,000)
Fiscal Year 2003: ¥36,000,000 (Direct Cost: ¥36,000,000)
Fiscal Year 2002: ¥18,900,000 (Direct Cost: ¥18,900,000)
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| Keywords | HNK-1 carbohydrate antigen / Glucuronyltransferase / HNK-1 deficient mouse / Morris water maze test / Animal lectin / Mannan-binding protein / Host defence / Tumor associated carbohydrate antigen / 糖鎖 / パターン認識 / 補体活性化 / 免疫学 / がん / 発生・分化 / 分子認識 / 脳・神経 / NHK-1 / 酵素 / MBP / HNK-1糖鎖 / 硫酸基転移酵素 / 腎臓上皮細胞 / PCR / ホスホマンナン / マンノース6-リン酸 / マクロファージ / C型レクチン / LPS / TLR4 / NF-κB |
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| Research Abstract |
Studies on the roles of glycans in the nervous and host defence Systems.
1. The role of HNK-1 antigen (SO_3-G1cA-LacNAc) in nervous system: Two glucuronyltransferase (G1cAT-P and G1cAT-S) genes associated with the biosynthesis of the HNK-lepitope were cloned and their gene-deficient mice were successfully generated. The G1cAT-P gene deficient mice lost the HNK-1 antigen in the brain almost completely. These mice exhibited reduced Long-term potentiation at the Schaffer collateral-CA1 synapses and a defect in spatial memory formation in the Morris water maize test. This is the first evidence that the loss of a single non-reducing terminal carbohydrate residue attenuates brain higher functions. We found that catalytic domains of G1cAT-P and G1cAT-S formed functional complexes with a sulfotransferase (HNK-1 ST) in the Golgi apparatus and facilitated the sequential biosynthesis of the complete HNK-1 antigen. Furthermore, we determined the x-ray crystal structures of human G1cAT-P and G1cAT-S
… More
and explain the reasons why these enzymes express their enzymic activity only in their homodimeric forms.
2. Identification of endogenous ligands to mannan-binding protein, MBP: We previously noticed that the human MBP gene was shown to exhibit potent growth inhibitory activity toward human colorectal carcinoma, SW 1116 cells in nude mice via MBP-dependent cell-mediated cytotoxicity (MDCC). We successfully isolated the endogenous ligand glycans from SW1116 cells and their structures were characterized out in collaboration with Dr. Kay-Hooi Khoo in Academia Sinica. They were shown to be as large, multiantennary N-glycans carrying a highly fucosylated polylactosamine type structure and interestingly, at the nonreducing termini, Le^b/Le^a or tandem repeats of the Le^a structure prevail. These structures are unique and distinct from those of the previously reported tumor specific carbohydrate antigens. We also demonstrate that MBP binds specifically metalloproteases meprin α and β, which are highly expressed in kidney and small intestinal epithelial cells, leukocytes and certain cancer cells. Interestingly, MBP was found to inhibited the protease activity and matrix-degrading activity of meprins, suggesting the possibility that MBP may contribute as a potential therapeutic target to tumor progression. Less
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