| Project/Area Number |
14104011
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| Research Category |
Grant-in-Aid for Scientific Research (S)
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| Allocation Type | Single-year Grants |
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| Research Field |
Immunology
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| Research Institution | Tohoku University |
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Principal Investigator |
SUGAMURA Kazuo Tohoku Univ., Grad Sch.of Med, Professor, 大学院医学系研究科, 教授 (20117360)
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| Co-Investigator(Kenkyū-buntansha) |
ISHII Naoto Tohoku Univ., Grad Sch. of Med, Associate Professor, 大学院医学系研究科, 助教授 (60291267)
TANAKA Nobuyuki Miyagi Cancer Center, Dept.of Immunol., Director, 免疫学部, 部長 (60280872)
森田 英嗣 東北大学, 大学院・医学系研究科, 助手 (70344653)
浅尾 裕信 東北大学, 大学院・医学系研究科, 助教授 (80250744)
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| Project Period (FY) |
2002 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥110,630,000 (Direct Cost: ¥85,100,000、Indirect Cost: ¥25,530,000)
Fiscal Year 2006: ¥16,770,000 (Direct Cost: ¥12,900,000、Indirect Cost: ¥3,870,000)
Fiscal Year 2005: ¥22,360,000 (Direct Cost: ¥17,200,000、Indirect Cost: ¥5,160,000)
Fiscal Year 2004: ¥25,740,000 (Direct Cost: ¥19,800,000、Indirect Cost: ¥5,940,000)
Fiscal Year 2003: ¥27,950,000 (Direct Cost: ¥21,500,000、Indirect Cost: ¥6,450,000)
Fiscal Year 2002: ¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000)
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| Keywords | Cytokine / vesicle trafficking / T cell costimulatory signal / CD4 T cell / Inflammation / 抗原提示 / 抗原提示細胞 / γc鎖 / STAMs / Hrs / 小胞輸送 / 蛋白分解 / OX40 / OX40L / 自己免疫 / 制御性T細胞 / STAM / IL-2 / IL-7 / TCR / シグナル伝達 / OX40リガンド |
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| Research Abstract |
1.Immune regulation by intracellular vesicular trafficking
STAM1 and STAM2 are required for the ubitquitin-dependent sorting of protein cargos into multivesicular bodies. Using genetically manipulated mice, in which both STAM1 and STAM2 are lacking specifically in dendritic cells, we found that STAM1/2 play an important role in antigen presentation. In vitro analyses demonstrated that STAM1/2-double KO dendritic cells show aberrant intracellular localization of MHC II and overexpression of surface MHC II. Therefore, STAM1/2 is thought to critically regulate MHC II trafficking from intracellular vesicular compartments to the plasma membrane.
2.Autoimmune diseases mediated by T cell costimulatory signals
We previously reported that mice overexpressing OX40 ligand (OX4OL), which is a T-cell-costimulatory molecule expressed by antigen presenting cells, spontaneously develop IBD. A mechanism for IBD development in the OX40L-transgenic (Tg) mice may be mediated by excessive OX40 signals in CD4^+ T cells because deliberate OX40-0X4OL interaction makes effector CD4^+ T cells insensitive to regulatory-T-cell-mediated suppression, which is an important mechanism to maintain the homeostasis of mucosal immunity. Although this abnormal T cell response in OX40L-Tg mice was seen in all the mouse strains we used, IBD develops in a C57BL/6 strain-dependent manner. Thus, we have attempted to identify susceptibility genes for IBD seen in OX40L-Tg mice. A QTL analysis using the susceptible strain (C57BL/6) and a resistant strain (BALB/c) revealed three disease-associated loci on Ch. 4,Ch. 8,and Ch. 19. From these loci, we have identified a candidate susceptibility gene for IBD.
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