| Project/Area Number |
14021012
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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 | The University of Tokyo |
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Principal Investigator |
MIYAKE Kensuke The University of Tokyo, The Institute of Medical Science, Professor, 医科学研究所, 教授 (60229812)
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| Co-Investigator(Kenkyū-buntansha) |
赤司 祥子 東京大学, 医科学研究所, 助手 (00325599)
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| Project Period (FY) |
2002 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥56,000,000 (Direct Cost: ¥56,000,000)
Fiscal Year 2005: ¥15,000,000 (Direct Cost: ¥15,000,000)
Fiscal Year 2004: ¥15,000,000 (Direct Cost: ¥15,000,000)
Fiscal Year 2003: ¥16,000,000 (Direct Cost: ¥16,000,000)
Fiscal Year 2002: ¥10,000,000 (Direct Cost: ¥10,000,000)
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| Keywords | endotoxin / Toll-like receptor / innate immunity / Toll-like receptor / Lipopolysaccharide / MD-2 / Toll like receptor / Lipopolyaccharide / 病原体 |
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| Research Abstract |
Little is known about mechanisms underlying microbial recognition in the innate immune system. Toll-like receptors (TLR) sense the presence of pathogens and trigger defense responses by transducing activating signals. This project focuses on endotoxin (LPS, lipopolysaccharide) recognition and aim to reveal molecular mechanism for LPS recognition. We previously discovered MD-2 that is associated with TLR4 and indispensable for LPS responses by TLR4. Further, we showed direct interaction between LPS and the receptor complex consisting of TLR4 and MD-2 (TLR4/MD-2). We next focused on the event following ligand interaction with TLR4/MD-2, oligomerization of TLR4/MD-2. Further, antagonistic lipid A analogue lipid IVa was found to bind to TLR4/MD-2 but not to induce oligomerization. These results suggest that LPS responses are triggered not by ligand binding but by the following receptor oligomerization. MD-2 has a critical role in triggering TLR4/MD-2 oligomerization. LPS, a ligand to TLR4/MD-2 is not homogenous but differ in its structure with Gram-negative bacteria. TLR4/MD-2 is able to discriminate such a difference in structure between bacteria and MD-2 has a critical role in the discrimination.
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