| Project/Area Number |
18590292
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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 |
Pathological medical chemistry
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| Research Institution | Kyoto University (2007)
Osaka University (2006) |
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Principal Investigator |
KAWANE Kohki Kyoto University, Department of Medical Chemistry, Graduate School of Medicine, Assistant Professor (60362589)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥4,010,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥510,000)
Fiscal Year 2007: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2006: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Keywords | DNase II / rheumatoid arthritis / autoimmune disease / TNF-α / macrophage / DNA degradation / 自然免疫 / IFN-β / IRF / 造血 / 赤血球分化 / 脱核 / 関節炎 |
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| Research Abstract |
During erythropoiesis, erythroid cells undergo enucleation. We have shown that the expelled nuclei were engulfed by macrophages and that subsequently DNaseII in macrophages degraded DNA of the nuclei. In DNaseII-/- mice, a large number of macrophages carry undigested DNA and are constitutively activated. DNaseII-/- mice die in embryonal stage due to severe anemia caused by IFN-β produced by the macrophages. In this research we generated DNaseII deficient adult mice by introducing the mutation for IFN-β receptor gene to DNaseII-/- mice or by conditional gene targeting method. Both of DNaseII deficient adult mice developed chronic polyarthritis resembling rheumatoid arthritis with age. A set of cytokine genes was strongly activated in the affected joints of these mice. Early in the pathogenesis, expression of the gene encoding TNF-α was upregulated in the bone marrow, and administration of anti-TNF-α antibody prevented the development of arthritis. These results indicate that if macrophages cannot degrade mammalian DNA from erythroid precursors cells, they produce TNF-α, which activates synovial cells to produce various cytokines, leading to the development of chronic polyarthritis. This finding is expected to give a clue for revealing pathogenesis of rheumatoid arthritis. DNaseII deficient mice generated in the research can be a good model animal for rheumatoid arthritis.
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