| Project/Area Number |
14370750
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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 | 一般 |
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| Research Field |
Biological pharmacy
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| Research Institution | Nagoya City University |
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Principal Investigator |
ONOZAKI Kikuo Nagoya City University, Department of Molecular health Sciences, Graduate School of Pharmaceutical Sciences, Professor, 大学院・薬学研究科, 教授 (20101313)
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| Co-Investigator(Kenkyū-buntansha) |
HAYASHI Hidetoshi Nagoya City University, Department of Molecular health Sciences, Graduate School of Pharmaceutical Sciences, Associate Professor, 大学院・薬学研究科, 助教授 (80198853)
千葉 拓 名古屋市立大学, 大学院・薬学研究科, 講師 (10094385)
TAKII Takemasa Nagoya City University, Department of Molecular health Sciences, Graduate School of Pharmaceutical Silences, Assistant Professor, 大学院・薬学研究科, 助手 (80244573)
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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 |
¥12,900,000 (Direct Cost: ¥12,900,000)
Fiscal Year 2004: ¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2003: ¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 2002: ¥6,800,000 (Direct Cost: ¥6,800,000)
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| Keywords | IL-1 / IL-1 receptor / cytokine / TLR / sialic acid / TRB3 / TGFβ / メラノーマ / 細胞増殖 / TLR / インターロイキンレセプター / アンチザイム |
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| Research Abstract |
IL-1 plays an important role in host reactions, including immunologic, inflammatory and hematologic reactions, and in regulation of cell proliferation and differentiation. Therefore, it is important to elucidate the mechanism of EL-1 action, production and its regulation. In this study we studied the many aspects of IL-1 action and its regulatory mechanisms.
1) IL-1 signaling. We analyzed the mechanism of IL-1 action leading to the inhibition of cell proliferation of A375 human melanoma cells. We discovered a novel protein TRB3 in the downstream of CHOP, which is regulated by p38 MAPK By the analysis of the promoter region of TRB3 gene, CHOP-ATP region appeared to be important for the gene activation. Furthermore, TRB3 inhibited the transcriptional activity of CHOP.
2) IL-1 receptor family. Toll like receptors, the IL-1 family, are known to be signaling molecule for bacteria and synthetic oligonudeotide. We found that IL-1 augments the expression and gene activation of TLR2 in mouse hepa
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tocytes. TGFR down regulated the IL-1-induced TLR2 expression by down-regulation the IL-1 induced up-regulation of IL-1 receptor type I(IL--1RI). TGFβ also inhibited the IL-1 induced IL-1RI expression in human fibroblasts.
3) Gene expression mechanism of IL-1α: A375R8 cells constitutively produce IL-1α. We found that GC-rich region of the IL-1α gene promoter is important for the constitutive gene activation. Furthermore, the binding of Sp1 to the GC rich region and an association of Sp1 and HDAC1 are important for the IL-1α gene activation. Estrogen induced the activation of IL-1α promoter activity via estrogen receptor a in human rheumatoid arthritis patient-derived fibroblast like synovial cells.
4) Carbohydrate conjugated IL-1: Sialic acid or sialylgalactose with C9 arm was conjugated to human IL-1α. In vitro activity of the carbohydrate-conjugated IL-1α generally exhibited the reduction in its biological activities in vitro. However, the carbohydrate-conjugated IL-1α exhibited selective activities in viva Sialic acid with C9 arm was also could be conjugated to TNFα. The carbohydrate conjugated TNFα exhibited reduced toxicity to mouse but enhanced anti-tumor activity to tumor in mice. Less
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