A drug development study for a periodontal disease : Biological properties of synthetic lipid A of Porphyromonas gingivalis lipopolysaccharide
| Project/Area Number |
17592170
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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 |
Periodontal dentistry
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| Research Institution | Kanagawa Dental College |
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Principal Investigator |
KUMADA Hidefumi Kanagawa Dental College, School of Dentistry, Assistant Prof., 歯学部, 講師 (60120995)
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| Co-Investigator(Kenkyū-buntansha) |
WATANABE Kiyoko Kanagawa Dental College, School of Dentistry, Assistant Prof., 歯学部, 講師 (70148021)
HAISHIMA Yuji National Institute of Health Sciences, Medical Devices, Div.Chief, 療品部, 室長 (80228379)
HAMADA Nobushiro Kanagawa Dental College, School of Dentistry, Assistant Prof., 歯学部, 講師 (20247315)
TAKAHASHI Yusuke Kanagawa Dental College, School of Dentistry, Assistant Prof., 歯学部, 講師 (20267511)
AMANO Shigeru Meikai University, School of Dentistry, Associate Prof., 歯学部, 助教授 (90167958)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2006: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2005: ¥2,600,000 (Direct Cost: ¥2,600,000)
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| Keywords | periodontal disease / lipopolysaccharide / synthetic lipid A / biological properties / Porphyromanas gingivalis / 化学合成 |
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| Research Abstract |
A pentaacyl and diphosphoryl lipid A molecule (J Bacteriol 1995: 177: 2098) found in the lipid A isolated from P. gingivalis LPS was chemically synthesized, and its characteristics were evaluated to reconfirm its interesting bioactivities including low endotoxicity and activity against LPS-unresponsive C3H/HeJ mouse cells. The synthesized P. gingivalis lipid A (synthetic Pg-LA) exhibited strong activities almost equivalent to those of Escherichia coli-type synthetic lipid A (compound 506) in all assays on LPS-responsive mice, and cells. LPS and native lipid A of P. gingivalis displayed overall endotoxic activities, but its potency was reduced in comparison to the synthetic analogs. In the assays using C3H/HeJ mouse cells, the LPS and native lipid A significantly stimulated splenocytes to cause mitosis, and peritoneal macrophages to induce TNF-D and IL-6 production. However, synthetic Pg-LA and compound 506 showed no activity on the LPS-unresponsive cells. Inhibition assays using some i
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nhibitors including anti-human TLR 2 and TLR4/MD-2 complex monoclonal antibodies showed that the biological activity of synthetic Pg-LA was mediated only through the TLR4 signaling pathway that might act as a receptor for LPS, whereas TLR2, possibly together with CD14, was associated with the signaling cascade for LPS and native lipid A of P. gingivalis, in addition to the TLR4 pathway. These results suggested that the moderated and reduced biological activity of P. gingivalis LPS and native lipid A, including the activity on C3H/HeJ mouse cells by TLR2-mediated pathway, may be mediated by bioactive contaminants or low acylated molecules present in the native preparations having multiple lipid A moieties.
In conclusion, these findings suggested that the moderated and reduced biological activity of P. gingivalis LPS and native lipid A, including the activity on C3H/HeJ mouse cells by TLR2-mediated pathway, may be mediated by bioactive contaminants or low acylated molecules present in the native preparations having high heterogeneity in lipid A moiety. To elucidate these problems, we are now attempting to evaluate the biological characterizations of tetra-acylated monophosphorylated or diphosphorylated species with the predominant molecules found in P. gingivalis native lipid A, using each chemically synthesized analog. Less
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Report
(3 results)
Research Products
(2 results)
