Development of a new therapy for periodontitis by regulation of proteinase cascades
| Project/Area Number |
12557193
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
Periodontal dentistry
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| Research Institution | Kagoshima University |
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Principal Investigator |
TORII Mitsuo (2002) Kagoshima University, Dental School, Professor, 歯学部, 教授 (30116066)
松下 健二 (2000-2001) 鹿児島大学, 歯学部, 助手 (90253898)
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| Co-Investigator(Kenkyū-buntansha) |
TOMIKAWA Munehiro Daiichi pharmaceutical Co., Ltd., Manager, 開発企画部, 調査役
IMAMURA Takahisa Kumamoto University, Faculty of Medicine, Associate Professor, 医学部, 助教授 (20176499)
MARUYAMA Ikuro Kagoshima University, Faculty of Medicine, Professor, 歯学部, 教授 (20082282)
鳥居 光男 鹿児島大学, 歯学部, 教授 (30116066)
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| Project Period (FY) |
2000 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| Budget Amount *help |
¥12,700,000 (Direct Cost: ¥12,700,000)
Fiscal Year 2002: ¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2001: ¥4,100,000 (Direct Cost: ¥4,100,000)
Fiscal Year 2000: ¥5,400,000 (Direct Cost: ¥5,400,000)
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| Keywords | Periodontitis / Porphyromonas gingivalis / gingipain / DX-9065a / IL-6 / MMP-1 / Drug for periodontitis / DX9065a / プロテアーゼ阻害剤 / DNAマイクロアレイ / 活性化血液凝固第X因子 / cDNAマイクロアレイ / KIAA 0263 / 炎症性サイトカイン / P.gingivalis / MMP |
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| Research Abstract |
Proteolytic enzymes released from the periodontopathic bacteria and the host cells are considered to be important virulent factors of periodontal diseases. However, there is no therapeutic reagent of inhibit those enzyme activities and the enzyme-associated proinflammatory events. In this study, we investigated proinflammatory activities of arginine-specific cysteine protease (Rgp) from Porphyromonas gingivalis, a causative bacterium of adult periodontitis, and activated coagulation factor X (Fxa), a product by Rgps, and the effect of DX-9065a, a new selective inhibitor of Fxa, on the proinflammatory events induced by these proteinases. Rgps and Fxa increased of interleukin-6 (IL-6) and MMP-1 by human gingival fibroblasts (HGF) at 1 nM and above, which were completely inhibited by DX-9065a in a dose-dependent manner from a concentration of 0.18μM. DX-9065a also strongly inhibited Fxa-induced IL-6 mRNA expression and NF-kB activation. DX-9065a inhibited vascular permeability enhancing activity production from human plasma both by Rgps and whole cells of P. gingivalis almost completely at 100μM. DX-9065a selectively inhibited the growth of 3 strains of P. gingivalis and prevotella intermedia in a dose-dependent manner, and the effect on p. gingivalis was bactericidal. Trypsin-like proteinase activity was detected in P. gingivalis, and the activity was strongly by DX-9065a. DX-9065a even inhibited amidolytic activity of purified trypsin-like proteinase gingipain (RgpA and RgpB) from P. gingivalis. Furthermore, trypsin-like proteinase activity in gingival crevicular fluids was strongly inhibited by DX-9065a. These results suggest that Rgps and Fxa are potential inflammatory mediators at the periodontitis site and DX-9065a is a useful therapeutic drug for the periodontal disease.
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Report
(4 results)
Research Products
(4 results)
