| Project/Area Number |
14082207
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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 | Hokkaido University (2006)
Kobe Pharmaceutical University (2002-2005) |
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Principal Investigator |
SUGAHARA Kazuyuki Hokkaido University, Faculty of Advanced LifeScience, Professor (60154449)
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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 |
¥31,500,000 (Direct Cost: ¥31,500,000)
Fiscal Year 2006: ¥5,800,000 (Direct Cost: ¥5,800,000)
Fiscal Year 2005: ¥5,800,000 (Direct Cost: ¥5,800,000)
Fiscal Year 2004: ¥6,800,000 (Direct Cost: ¥6,800,000)
Fiscal Year 2003: ¥6,800,000 (Direct Cost: ¥6,800,000)
Fiscal Year 2002: ¥6,300,000 (Direct Cost: ¥6,300,000)
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| Keywords | chondroitin sulfate / heparan sulfate / chondroitin synthase / proteoglycan / chondroitin polymerizing factor / glycosyltransferase / EXT tumor suppressor gene / glycosaminoglycan / rib-1 / へパラン硫酸 / 硫酸基転移酵素 / herpes simplex virus / 線虫 / EXT / chondroitin synthase / 細胞分裂 / chondroitin Polymerizing factor / 棟転移酵素 / ガン抑制遺伝子 / chondroitin polymerizing factor / 糖転位酵素 / GalNAc転位酵素 / ショウジョウバエ |
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| Research Abstract |
Sulfated glycosaminoglycans, which are side polysaccharide chains of proteoglycans, can be largely classified into a heparan sulfate type and a chondroitin sulfate type, and regulate functions of a wide variety of signaling protein molecules. However, the biosynthetic mechanism of these glycans had not been well understood before this project was launched. Therefore, the aim of this project was to clarify the scenario of the biosynthesis of sulfated glycosaminoglycans. During the project period, we clarified various aspects of the biosynthetic mechanism including the chain initiation, elongation, polymerization and the regulation of the chain length using the in vivo and in vitro systems of human, fly and nematode, and accomplished the aim of the project. The results included identification of glycosyltransferases, sulfotransferases and regulatory factors as well as molecular interactions of these ensymes and factors. Furthermore, it was demonstrated that chondroitin is essential in the cell division of C. elegans by the RNAi approach using the RNAs of the chondroitin synthase and the chondroitin polymerizing factor of the namatode. A human genetic disease caused by a deficiency of a chondroitin 6-O-sulfotransferase was discovered. On the other hand we clarified the molecular mechanism whereby the neurite outgrowth of mouse hippocampal neurons is promoted by pleiotrophin and hepatocyte growth factor through specific interactions with chondoitin sulfate chains in the extracellular matrices. It was also proved that chondroitin sulfate plays a role as a receptor for virus infection. The sugar sequences required for the interactions with a growth factor pleiotrohin and a few cytokines were also revealed. These results have started influencing considerably not only the glycobiology field but also other related fields. The on-going analysis of the GlcAT-I-KO and EXTL2-KO-mice will also confirm the importance of the functions of these sulfated glycosaminoglycan chains.
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