| Project/Area Number |
16590246
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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 | Osaka University |
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Principal Investigator |
KAWANE Kohki Osaka University, Graduate School of Frontier Biosciences, Assistant, 生命機能研究科, 助手 (60362589)
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| Co-Investigator(Kenkyū-buntansha) |
NAGATA Shigekazu Osaka University, Graduate School of Frontier Biosciences, Professor, 生命機能研究科, 教授 (70114428)
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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 |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2005: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2004: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Keywords | DNase II / erythropoiesis / enucleation / macrophages / IFNβ / DNA / TLR / IFN-β |
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| Research Abstract |
Erythrocytes produced by definitive erythropoiesis lack nuclei because the nuclei are expelled from erythroid precursor cells during their differentiation. Previously we have demonstrated that the nuclei expelled from eryhtroid precursor cells were engulfed by macrophages and DNaseII in the macrophages degraded the DNA. The livers of DNaseII-deficient mouse embryos contain many macrophages carrying undigested DNA. The embryos die in utero suffering from severe anemia. However it remains unclear why the accumulation of undigested DNA results in the impairment of erythropoiesis. Our purpose in this project was to reveal the mechanism.
In fetal liver of DNaseII-deficient embryos, interferon β(IFNβ) gene was strongly activated in macrophages. Double mutant mice which lack both DNaseII and typeI interferon receptor genes were born alive with restored erythropoiesis. These results indicate that the inability to degrade DNA derived from erythroid precursor cells results in IFNβ production which then causes the embryonic lethality in DNaseII-deficient mice. Furthermore, we examined whether Toll-like receptor (TLR) system which recognizes components of microbes was involved in the production of IFNβ in DNaseII-deficient mice. Our results indicate that TLR system does not play a role in the IFNβ gene activation in DNaseII-deficient macrophages.
These findings in this project lead us to propose a new concept that when DNA degradation is impaired, accumulated self DNA causes harmful effects on organisms. Also these findings suggest a novel TLR-independent pathway which recognizes DNA to activate innate immunity.
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