New treatment of rheumatoid arthritis
| Project/Area Number |
17390289
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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 | Tokyo Medical and Dental University |
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Principal Investigator |
KOHSAKA Hitoshi Tokyo Medical and Dental University, Graduate School, Associate Professor, 大学院医歯学総合研究科, 准教授 (00251554)
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| Co-Investigator(Kenkyū-buntansha) |
MIYASAKA Nobuyuki Tokyo Medical and Dental University, Graduate School, Professor, 大学院医歯学総合研究科, 教授 (30157622)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥15,400,000 (Direct Cost: ¥15,400,000)
Fiscal Year 2006: ¥6,700,000 (Direct Cost: ¥6,700,000)
Fiscal Year 2005: ¥8,700,000 (Direct Cost: ¥8,700,000)
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| Keywords | rheumatoid arthritis / cell cycle / treatment / サイクリン依存性性キナーゼ / コラーゲン誘導性関節炎 |
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| Research Abstract |
Intra-articular gene transfer of cyclin-dependent kinase inhibitors (CDKI) to suppress synovial cell cycling has shown efficacy in treating animal models of rheumatoid arthritis (RA). CDKIs also modulate immune function via a CDKindependent pathway. Accordingly, systemic administration of small molecules that inhibit CDK might ameliorate arthritis. In order to address this issue, alvocidib (flavopiridol), known to be tolerated clinically for treating cancers, and also a newly synthesized CDK4/6-selective inhibitor were tested for anti-arthritic effects. In vitro, they inhibited proliferation of synovial fibroblasts without inducing apoptosis. In vivo, treatment of collagen-induced arthritis (CIA) with alvocidib suppressed synovial hyperplasia and joint destruction while serum concentrations of anti- type II collagen (CII) antibodies were maintained. Treated mice developed arthritis after termination of treatment. Thus, immune responses to CII were unimpaired. The same treatment ameliorated arthritis induced by K/BxN serum transfer to lymphocyte-deficient mice. Similarly, the CDK4/6-selective inhibitor suppressed CIA, even when administered after onset of clinical disease. Both small molecule (sm) CDK inhibitors were effective in treating animal models of RA by suppressing synovial cell growth but not immune function. We believe that smCDK inhibitors hold promise as a new class of anti-rheumatic drugs that inhibit a distinct phase of rheumatoid pathogenesis.
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Report
(3 results)
Research Products
(14 results)
