The basic research for the therapy of Gram-negative bacterial sepsis by LPS-receptors fusion protein
| Project/Area Number |
16591807
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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 |
Emergency medicine
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| Research Institution | The University of Tokyo |
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Principal Investigator |
KARIMA Risuke The University of Tokyo, Environmental Science center, Associate Professor (50281308)
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| Co-Investigator(Kenkyū-buntansha) |
MATSUSHIMA Kouji The University of Tokyo, Graduated School of Medicine, Professor (50222427)
NISHIDA Masamichi Teikyo University, School of Medicine, Lecturer (80292944)
OHBAYASHI Toshihiko The University of Tokyo, The Hospital of School of Medicine, Assistant Professor (30250442)
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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 | lipopolysaccharide (LPS) / Sepsis / Gram-negative bacteria / Receptor / CD14 / Toll-like receptor 4 (TLR4) / Recombinant fusion protein / Interleukin 8 (IL-8) / toll-like受容体4(TLR4) / Fc融合タンパク / LPS阻害剤 / MD2 / BIAcore |
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| Research Abstract |
LPS plays a pivotal
and initiative role in the development of pathophysiological response of sepsis in gram-negative bacterial infection. It has been revealed that two distinct receptors, CD14 and toll-like receptor 4 (TLR4), are involved in the recognition of LPS stimulation by cells. For the purpose of developing a novel therapy in the early phase of gram-negative bacterial sepsis, the inhibitory effect of recombinant CD14-TLR4-Fc fusion protein against cell stimulation by LPS, comparing the effect of recombinant CD14-Fc fusion protein on the LPS-induced interleukin-8 (IL-8) production by U373 cell line and human peripheral blood mononuclear cells (PBMC). As a result, while CD14-Fc only partially suppressed LPS-induced IL-8 production by cells, CD14-TLR4-Fc significantly inhibited IL-8 production by cells in response to 10ng/ml-1000ng/ml LPS. Especially, the administration of 5 μg/ml of CD14-TLR4-Fc almost completely blocked LPS-induced IL-8 production both in U373 and in human PBMC. The reason why CD14-TLR4-Fc strongly inhibited LPS stimulation may be that LPS cannot associated with TLR4 in the cell surface because of the incorporation with the TLR4 region of the CD14-TLR4-Fc after trapping by this fusion protein. In contrast, LPS trapped by CD14-Fc may still remain the activity of stimulating TLR4 in the cell surface, resulting in the only partial suppression of LPS-induced IL-8 production by cells. The results of this study demonstrate the strong blocking effect of recombinant CD14-TLR4-Fc fusion protein against LPS-induced inflammatory response, indicating the potential possibility for the development of the novel drug for the suppression of excessive inflammatory response in sepsis by gram-negative bacterial infection.
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Report
(3 results)
Research Products
(3 results)
