| Project/Area Number |
14370165
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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 |
内科学一般
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| Research Institution | RIKEN (2004)
Tokyo University of Science (2002-2003) |
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Principal Investigator |
KUBO Masato RIKEN Yokohama Institute, Laboratory for Signal Network, Laboratory head, シグナル・ネットワーク研究チーム, チームリーダー (40277281)
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| Co-Investigator(Kenkyū-buntansha) |
KOUYAMA Masako Tokyo University of Science, Research associate, 生命科学研究所, 助手 (80318229)
HAYASHI Katsuhiko Research Institutes, Osaka Medical Center for Maternal and Child Health, Department of Molecular Embryology, Research scientist, 病因病態部門, 常勤研究員 (20287486)
SEKI Yoh-ichi Japan Society for the Promotion of Science, Post-doctoral Fellows, 生命科学研究所・分子生物学研究部門, 学術振興会特別研究員
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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 |
¥13,600,000 (Direct Cost: ¥13,600,000)
Fiscal Year 2004: ¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 2003: ¥4,700,000 (Direct Cost: ¥4,700,000)
Fiscal Year 2002: ¥4,900,000 (Direct Cost: ¥4,900,000)
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| Keywords | Cytokine signal / Effector T cell differentiation / Th1 / Th2 / IL-4 / chromatin / epileptics / 記憶型T細胞 / NKT細胞 / 肥満細胞 / 好塩基球 / STAT6 / 転写制御 |
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| Research Abstract |
After the advanced economic growth, allergic disease, such as pollinosis, asthma and Atopic dermatitis, seriously become social problem in urban area of Japan. Although a steroid and immunosuppressant agent are so far commonly used for the therapeutic treatment of allergic patients, these treatment carried on the harmful side effect in some case, thus the development of novel therapeutic strategy to function more than the side effect would be necessary in the future. We focus on Th2 developmental process as therapeutic target for allergic disease.
An initial activation signal via the T cell antigen receptor(TCR) in a restricted cytokine environment is critical for the onset of helper T(Th) cell development. Cytokines regulate the expression of key transcriptional factors, T-bet and GATA-3,which instruct the direction of Th1 and Th2 differentiation, through changes in chromatin conformation. In this study, we investigated the kinetics of IL-4-mediated signaling in a transgenic mouse, exp
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ressing human IL-4 receptor (hIL-4R Tg) on a mouse IL-4 receptor deficient background. These experiments demonstrated that an IL-4 signal was required at the early stage of TCR mediated T cell activation for lineage commitment to Th2, along with structural change in chromatin, in conserved non-coding sequences (CNS)-1 and -2 within the IL-4 locus.
Epigenetic changes in the chromatin structure of the Th2 locus tightly associate with cytokine expression profile during the differentiation process from naive CD4 T cells to effecter Th2 cells. Using a transgenic approach, we studied cis-acting activity of considerable conservation of noncording sequences on II4 locus. CNS-2 corresponding to Th2 specific-remodeling site located at downstream of II4 gene, regulated the primary IL-4 production in CD62L^<lo> CD44^<hi> memory like CD4^+ T cells. The depletion of the CNS-2-regulated T cells resulted complete loss of Th2 differentiation. This CNS-2 contains putative binding site for RBP-J, which is a critical modulator for Notch signaling. CD4 T cell specific RBP-J deficient mice showed abrogation of primary IL-4 production from the memory like T cells and Th2 development. Therefore, Notch/RBP-J signaling mediated CNS-2 regulation is a crucial for primary IL-4 production in Th2 differentiation. Less
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