| Project/Area Number |
10670436
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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 |
内科学一般
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| Research Institution | Institute of Medical Science, St.Marianna University |
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Principal Investigator |
KAWAI Shinichi Institute of Medical Science, St.Marianna University School of Medicine, 難病治療研究センター, 教授 (70129401)
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| Co-Investigator(Kenkyū-buntansha) |
MAEKAWA Kohtaroh Hisamitsu Pharmaceutical Co., 筑波研究所, 研究員
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| Project Period (FY) |
1998 – 1999
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| Project Status |
Completed (Fiscal Year 1999)
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| Budget Amount *help |
¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 1999: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 1998: ¥1,700,000 (Direct Cost: ¥1,700,000)
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| Keywords | antisense DNA / new carrier / IL-1β / TNF-α / synovial cells / rheumatoid arthritis / Ki-ras gene / Tripterygium wilfordii Hook F |
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| Research Abstract |
To investigate novel anti-inflammatory therapies, we studied a novel carrier for antisense DNA, targeted to pro-inflammatory cytokines. We developed poly-L-lysine/L-serine-polyethylene glycol (PLSP) as a carrier for antisense DNA. Our previous study (Antisense Nucl Acid Drug Dev 6:55-61, 1996) showed that antisense phosphorothioate oligonucleotide targeted to the initiation codon of human interliukin-1β(Il-1β) suppressed production of IL-1β of U937 cells. Then, we used the antisense DNA of IL-1β to examine the effects of several kinds of PLSP. 10kDa and 15kDa molecules of the PSLP were the most potent among them. However, a considerable toxicity and instability were observed when the PSLP was used. We further examined the effects of antisense phosphorothioate oligonucleotide targeted to some sequences of human tumor necrosis factor (TNF)-α gene. In this case, no positive effect was observed. We then studied the anti-inflammatory effects of Tripterygium wilfordii Hook F extract (GTW). GTW inhibited prostaglandin EィイD22ィエD2 production in the human synovial cells due to suppression of cyclooxgenase-2 protein and mRNA, which is similar to those of glucocorticoid. However, the mechanism of action of the GTW was different from that of glucocorticoid. It inhibited nuclear factor-ィイD2KィエD2B activity without acting on glucocorticoid receptor. We also examined effects of changes in signal transduction by introduction of Ki-ras gene into human synovial cells from patients with rheumatoid arthritis. Stimulation by cytokines including TNF-α reduced proliferation rate of ras-introduced synovial cells, whereas they enhanced proliferation on nontreated synovial cells. The mechanism remains to be studied.
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