| Project/Area Number |
14570424
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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 | Hyogo College of Medicine |
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Principal Investigator |
SANO Hajime Hyogo College of Medicine, Faculty of Medicine, Professor, 医学部, 教授 (00196304)
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| Co-Investigator(Kenkyū-buntansha) |
KAWAHITO Yutaka Kyoto Prefectual University of Medicine, Faculty of Medicine, Assistant Professor, 医学部, 講師 (50336731)
OGATA Atsushi Hyogo College of Medicine, Faculty of Medicine, Research Associate, 医学部, 助手 (90309451)
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| Project Period (FY) |
2002 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2004: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2003: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2002: ¥1,600,000 (Direct Cost: ¥1,600,000)
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| Keywords | rheumatoid arthritis / cyclooxygenase-2 / synovial cells / PPAR-γ / 15d-PGJ_2 / apoptosis / sphingoshine-1-phosohate / Cyclooxygenase-2 Inhibitors / PGJ_2 / COX-2阻害薬 / 核内受容体 |
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| Research Abstract |
Rheumatoid arthriris(RA) is a chronic inflammatory disease which induces generaralized joint destruction. Prostaglandin(PG) E2 is an important factor in the pathogenesis of RA. PGE2 induces the synovial proliferation, angiogenesis and activation of osteoclast. Cyclooxygenase(COX)-2 is up-regulated in synoviocytes by the stimulation of IL-1 and TNF-α, and COX-2 inhibitors such as COX-2 antisense, nonsteroidal anti-inflammatory durg(NSAID), disease modifying anti-rheumatic drug (DMARD), and biologics supresss adjuvant-induced arthritis in rats as well as human arthritis. COX-2 is strongly associated with pathogensesis of RA. In this study we have demonstrated the mechanism of COX-2 expression in RA, the therapy of RA through COX-2 inhibition, COX-2 inhibition by PPAR-γ and sphingolipid, and the induction of apoptosis by COX-2 inhibition in RA synoviocytes.
<Results & Conclusion>
COX-2 is up-regulated in colon cancer, breast cancer, renal cell carcinoma and urological cancer as well as RA synovia. PPAR-γ is expressed in synovial cells (synovial cell layer, inflammatory mononuclear cells, fibroblast like cells, endothelial cells) in RA and the ligands of PPAR-γ (15 deoxy-Δ^<12,14> -PGJ2, Troglitazone) induce apoptosis in RA synoviocytes by inhibition of cPLA2 as wall as COX-2. PPAR-γ is also expressed in several cancer tissues such as prostate, testis and bladder. Mucins produced by colon cancer cells induce COX-2 expression in infiltrative cells as well as colon cancer cells. Sphingosin-1-phosphate (S1P) induces COX-2 expression in IL-1- or TNF-α- treated synoviocytes through the receptor(S1P1). S1P induces the synovial proliferation and PGE2 production as well as angiogenesis. S1P inhibitors may be a factor of therapy of RA.
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