| Project/Area Number |
16390287
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
膠原病・アレルギー・感染症内科学
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| Research Institution | Kyoto University |
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Principal Investigator |
MIMORI Tsuneyo Kyoto University, Grad.School of Med., Professor, 医学研究科, 教授 (10157589)
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| Co-Investigator(Kenkyū-buntansha) |
FUJII Takao Kyoto University, Grad.School of Med., Instructor, 医学研究科, 講師 (70255462)
TANAKA Masao Kyoto University, Grad.School of Med., Assistant professor, 医学研究科, 助手 (10332719)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥14,400,000 (Direct Cost: ¥14,400,000)
Fiscal Year 2005: ¥5,500,000 (Direct Cost: ¥5,500,000)
Fiscal Year 2004: ¥8,900,000 (Direct Cost: ¥8,900,000)
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| Keywords | calpastatin / calpain / calpain inhibitor / rheumatoid arthritis / IL-6 / autoantibody / Th1 / Th2 balance / synoviocyte / T細胞 / IL-1 / マウス関節炎モデル |
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| Research Abstract |
We have previously reported that one of target autoantigens recognized by autoantibodies in rheumatoid arthritis (RA) patients is calpastatin, an endogenous inhibitor of calcium-dependent cysteine proteinase (calpain), and that IgG fraction of RA patient sera inhibits the function of calpastatin and increases the proteolytic activity of calpain. Calpain is thought to be a neutral proteinase that regulates activation of various inflammation factors and may be involved in cartilage degradation. Our study aims to investigate the pathogenesis and new therapeutic strategy of RA by calpain-calpastatin system.
1.Amelioration of mouse model arthritis by calpain inhibitor
Monoclonal anti-type II collagen antibodies-induced arthritis in Balb/c mice was significantly inhibited by intraperitoneal injection of calpain inhibitor E-64-d. Quantitative RT-PCR demonstrated that mRNA levels of IL-1 and IL-6 were significantly suppressed in the joint tissues of E-64-d-treated mice. Production of IL-6 and IL-1 was also suppressed in dose-dependent manner in cultured synoviocytes from RA patients when E-64-d was added.
2.Effect of over expression of calpastatin in activation of fibroblasts and T cells
Natural expression of calpastatin was significantly decreased in Th1 cells, especially in activated Th1 cells, than in Th2 cells. When splenic CD4+T cells from Balb/c mice and 3T3 fibroblasts were transfected by human calpastatin cDNA-recombinant retrovirus vector, production of IL-6 and interferon-γ was significantly suppressed.
Thus, in RA patients, increased calpain activity may be involved in exacerbation of arthritis by differentiating CD4+T cells from Th2 to Th1, as well as over production of IL-6 in synovial cells.
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