| Project/Area Number |
09672245
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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 |
Biological pharmacy
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| Research Institution | HEALTH SCIENCES UNIVERSITY OF HOKKAIDO |
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Principal Investigator |
TAMOTO Koichi HEALTH SCIENCES UNIVERSITY OF HOKKAIDO,FACULTY OF PHARMACEUTICAL SCIENCES,ASSOCIATE PROFESSOR, 薬学部, 助教授 (50088861)
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| Co-Investigator(Kenkyū-buntansha) |
NOCHI Hiromi HEALTH SCIENCES UNIVERSITY OF HOKKAIDO,FACULTY OF PHARMACEUTICAL SCIENCES,LECTUR, 薬学部, 助手 (30183552)
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| Project Period (FY) |
1997 – 1998
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| Project Status |
Completed (Fiscal Year 1998)
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| Budget Amount *help |
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 1998: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 1997: ¥2,500,000 (Direct Cost: ¥2,500,000)
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| Keywords | hyaluronan / rheumatoid arthritis / synovial cells / fibroblast / hyaluronan receptor / cyclooxygenase 2 / prostaglandine E2 / monoclonal antibody / ヒアルロン酸レセプター / プロスタグランジンE2 |
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| Research Abstract |
The spontaneous and IL-lalpha-induced prostaglandin E2 (PGE2) generation in human synovial cells from a patient of rheumatoid arthritis (RASCs) were inhibited by high-molecular-weighthyaluronates (HAs) in a molecular-weight-and concentration-dependent maimer. On the otherhand, HAs with lower molecular sizes than 4x1O^4 Da, especially HA oligomers, rather augmented PGE2 generation. The inhibitory and stimulatory effects of HAs on PGE2 generation were due to the signaling events via HA receptor that control negatively or positively the transcription of COX2 gene. In noninflammatory cells, human dermal fibroblast (HDF), HA oligomers failed to induce the expression of COX2 protein, suggessting that certain inflammatory signals may be required for the action of HA oligomers. When HA-binding proteins were isolatedfrom RASC and HDF, a various types of membrane proteins that did not required Ca^<2+> and Mg^<2+> for their HA-binding ability were identified. Newly prepared monoclonal antibodies directed to these HA-binding proteins never inhibited the expression of COX2 protein but some of the antibodies rather induced the expression of COX2 protein in RASC and HDF.These results suggest that the extent of cross-linkage of HA receptors that mediated by a single HA molecule may determine the property of intracellular signals that regulate the transcription of COX2 gene. The binding of HA oligomer to a single HA receptor molecule may not be enough to generate signals that may induce the expression of COX2 protein. We could not have a evidence that the elevation of concentration in intracellular free calcium ion and the activation of MAP kinase are involved in the signaling pathway through HA receptors which regulates the transcription of COX2 gene.
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