| Project/Area Number |
16017323
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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 | HOKKAIDO UNIVERSITY |
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Principal Investigator |
SEYA Thukasa Hokkaido Univ., Grad. School of Med., Professor, 大学院医学研究科, 教授 (10301805)
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| Co-Investigator(Kenkyū-buntansha) |
MATSUMOTO Misako Hokkaido Univ., Grad. School of Med., Asso., Professor, 大学院医学研究科, 助教授 (30332456)
HAZEKI Kaoru Hiroshima Univ., Grad. School of Biomed. Sci., Assistant Professor, 医歯薬学総合研究科, 助手 (50146007)
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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 |
¥18,000,000 (Direct Cost: ¥18,000,000)
Fiscal Year 2005: ¥9,000,000 (Direct Cost: ¥9,000,000)
Fiscal Year 2004: ¥9,000,000 (Direct Cost: ¥9,000,000)
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| Keywords | Virus / Antitumor immunity / antigen presenting cells / NK cell / cytotoxicity T lymphocytes / IFN-β / cross-priming / 抗原掲示細胞 / Toll様受容体 / IRF-3 / Poly I:C(dsRNA) / 骨髄性樹状細胞 / NK活性化 / CTL誘導 / MyD88 / TICAM-1(TRIF) |
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| Research Abstract |
We have investigated a) the functional difference between TLR adaptors MyD88 and TICAM-1 in the mode of maturation of dendritic cells, b) the TLR response to viral infection and c) how NK and CTL are induced secondary to activation of TLR in dendritic cells. Our finding are that the TICAM-1 pathway in dendritic cells has a crucial role in induction of NK activation and the MyD88 pathway plays a role in CTL induction. Accordingly, TLR3 agonists such as polyl : C allowed NK activation and TLR2/4 agonists including BCG-CWS activates CTL during dendritic cell maturation.
We have focused on the molecular cascade of the TICAM-1 pathway. It has been reported that TICAM-1 directly binds TLR3 and transmits signal to activate virus-activated kinase (VAK). VAK involves IKKe and TBK1 and participates in production of IFN-beta. We found that TICAM-1 is recruited to endosomal TLR3 in response to polyI : C stimulation and within 60 min moved from the endosome to a cytosolic signalosome, named 'speckle'. By immunoprecipitation, TICAM-1 bound TRAF2, TRAF6 and TRAF3. These TRAF complex coupled with NAP1, a regulatory subunit of VAK. On the other hand, the speckle contained RIP 1, NAP1 and FADD. Thus, we speculated that the early TICAM-1 complex forms around TLR3 in the endosome while the late TICAM-1 complex forms in the speckle, which is a center of IRF-3 activation and following IFN signaling. The relationship between this speckle signaling complex and NK/CTL activation needs to be clarified.
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