2002 Fiscal Year Final Research Report Summary
New Therapy for Rheumatoid Arthritis with Cell Cycle Regulators
| Project/Area Number |
12557048
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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 | 展開研究 |
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| Research Field |
内科学一般
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| Research Institution | Tokyo Medical & Dental University |
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Principal Investigator |
KOHSAKA Hitoshi Tokyo Medical and Dental University, Graduate School, Department of Bioregulatory Medicine and Rheumatology, Associate professor, 大学院・医歯学総合研究科, 助教授 (00251554)
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| Co-Investigator(Kenkyū-buntansha) |
SASAO Minoru Head R&D, Santen Pharmaceuticals, 開発本部, グループ長
MIYASAKA Nobuyuki Tokyo Medical and Dental University, Graduate School, Department of Bioregulatory Medicine and Rheumatology, Professor, 大学院・医歯学総合研究科, 教授 (30157622)
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| Project Period (FY) |
2000 – 2002
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| Keywords | rheumatoid arthritis / cell cycle / gene therapy |
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| Research Abstract |
Forced expression of a cyclin-dependent kinase inhibitor (CDKI) gene, pl6INKa and p21Cipl in the synovial tissues was effective in treating animal models of rheumatoid arthritis (RA). Synovial hyperplasia in the treated joints was suppressed, reflecting the inhibitory effect of p16INKa and p21Cipl on cell cycle progression. Additionally, lymphocyte infiltration, expression of inflammatory cytokines, and destruction of the bone and cartilage were inhibited. To discern how the cell cycle regulator gene exerted such complementary effects, we investigated gene expression by rheumatoid synovial fibroblasts with or without the p21 gene transferred. DNA array and subsequent conventional analyzes have demonstrated downregulation of various inflammatory mediators and tissue-degrading proteinases that are critically involved in the pathology of RA. These molecules included IL-6, -8, type I IL-1 receptor (IL-1R1), monocyte chemoattractant protein-1, macrophage inflammatory protein-3α, cathepsins B and K, MMP-1 and -3. Downregulation of IL-1R1 by p21Cipl actually resulted in attenuated responsiveness to IL-1. Inhibition of the inflammatory gene expression by p21 was seen even when IL-1 is absent. This IL-1R1-independent suppression accompanied inactivation of NF-kB and activator protein-1 transcription factors. These multiple effects could assist inhibition of cell cycling in ameliorating the arthritis, and suggest a heretofore unexplored relationship between CDKIs and immunological effector molecules.
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Research Products
(10 results)
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[Publications] Nasu, K, Kohsaka, H, Nonomura, Y, Terada, Y, Ito, H, Hirokawa, K, Miyasaka, N.: "Adenoviral Transfer of Cyclin-Dependent Kinase Inhibitor Genes Suppresses Collagen-Induced Arthritis in Mice"J Immunol. 165(12). 7246-7252 (2000)
Description
「研究成果報告書概要(和文)」より
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