2005 Fiscal Year Final Research Report Summary
Pathogen recognition and signal transduction in Toll-like receptors
| Project/Area Number |
14021054
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | Osaka University |
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Principal Investigator |
SHIZUO Akira Osaka University, Research Institute for Microbial Diseases, Professor, 部生物病研究所, 教授 (50192919)
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| Project Period (FY) |
2002 – 2005
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| Keywords | Innate Immunity / TLR / signal transduction / TIR domain / type IIFN / pDC / RIG-I / IPS-1 |
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| Research Abstract |
The immune response is categorized into innate and adaptive immunity. Since the discovery of Toll-like receptors, innate immunity has been shown to specifically recognize the invasion of pathogens and to play an essential role for the activation of acquired immunity. In this project, we generated knockout mice of TLRs whose ligands were unknown and analyzed their function in pathogen recognition. We identified novel genes, which are involved in TLR signaling pathways. We generated knockout mice of these genes to elucidate their functions. Through all these analysis, we found the existence of TLR-independent immune responses. We identified some molecules in these pathways and generated knockout mice of them.
1) Identification of the ligands for some TLR family members (TLR1/TLR2 : triacyllipopeptide, TLR7 : imidazoquinoline derivatives and ssRNA, TLR9 : hemozoin)
2) Analysis of TIR-domain containing adapters (TIRAP-deficient mice, TRIF-deficient mice and TRAM-deficient mice)
3) Analysis of TBK1-deficient mice and IKKi-deficient mice : TBK1 and IKKi play an essential role for the activation of transcription factor IRF3 in both MyD88-independent pathway and viral infections.
4) Elucidation of the mechanism for TLR7-and TLR9-mediated IFN-a production in pDCs
5) Analysis of TLR-independent viral recognition : we generated and examined knockout mice of RIG-I, which recognize dsRNA in the cytoplasm and induce antiviral responses. We newly identified an adapter molecule, IPS-1, which works downstream of RIG-I and MDA5. We further showed that antiviral responses were induced by the transfection of dsDNA.
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