| Project/Area Number |
11694329
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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 |
Functional biochemistry
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| Research Institution | Kurume University |
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Principal Investigator |
YOSHIMURA Akihkio Kurume University Institute of Life Science Professor, 分子生命科学研究所, 教授 (90182815)
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| Co-Investigator(Kenkyū-buntansha) |
KAI Hisashi Kurume University School of Medicine Assistant Professor, 医学部, 助手 (60281531)
MINOGUCHI Shigeru Kurume University Institute of Life Science Assistant Professor, 分子生命科学研究所, 助手 (60322757)
WAKIOKA Toru Kurume University Institute of Life Science Assistant Professor, 分子生命科学研究所, 助手 (40330873)
JAMES Ihle St, Jude Children's Hospital, 部長
MATSUMOTO Akira Kurume University Institute of Life Science Post-doctoral fellow, 分子生命科学研究所, 日本学術振興会特別研究員(PD)
IHLE James St.Jude Children's Hospital Director of Biochemistry
安川 秀雄 久留米大学, 分子生命科学研究所, 助手 (60289361)
大坪 素秋 久留米大学, 分子生命科学研究所, 助手 (10211799)
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| Project Period (FY) |
1999 – 2000
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| Project Status |
Completed (Fiscal Year 2000)
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| Budget Amount *help |
¥8,000,000 (Direct Cost: ¥8,000,000)
Fiscal Year 2000: ¥3,800,000 (Direct Cost: ¥3,800,000)
Fiscal Year 1999: ¥4,200,000 (Direct Cost: ¥4,200,000)
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| Keywords | tyrosine kinase / JAK / STAT / CIS / cytokine / knockout mice / tyrosine phosphorylation / kinase inhibitor |
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| Research Abstract |
Immune and inflammatory systems are controlled by multiple cytokines, including interleukins (ILs) and interferons. These cytokines exert their biological functions through Janus tyrosine kinases and STAT transcription factors. We recently identified two intrinsic JAK inhibitors, JAB (also referred to as SOCS1/SSI1) and CIS3 (or SOCS3/SSI3), which play an essential role in the negative regulation of cytokine signaling. We have shown that JAB is strongly induced by interferon-γ. JAB deficient mice die perinatally with altered lymphoid development including the generation of activated T cells in vivo. The lethality is eliminated on a Rag2 or interferon-γdeficient background. Based on the results, we propose that JAB plays an essential role in negative feedback regulation of interferon-γ.
During embryonic development CIS3 is highly expressed in some but not all erythroid lineage cells of the fetal liver. Deletion of CIS3 gene results in an embryonic lethality at 12-16 days that is associat
… More
ed with a marked erythrocytosis. Moreover, the individual in vitro proliferative capacity of fetal liver progenitors is greatly increased. The results suggest a specific negative regulatory effect of CIS3 on EPO signaling. We have investigated the role of STATs and these JAK inhibitors in intestinal inflammation. Among STAT family members, we found that STAT3 showed the strongest tyrosine phosphorylation in human ulcerative colitis and Crohn's disease patients as well as in dextran sulfate sodium (DSS)-induced colitis in mice. Development of DSS-induced colitis as well as STAT3 activation was significantly reduced in IL6-deficient mice, suggesting that STAT3 plays an important role in the perpetuation of colitis. CIS3, but not JAB, was highly expressed in the colon of DSS-treated mice. To define the physiological role of CIS3 induction in colitis, we developed a JAB mutant (F59D-JAB) that overcame the inhibitory effect of both JAB and CIS3 and created transgenic mice. DSS induced stronger STAT3 activation and more severe colitis in F59D-JAB-transgenic mice than in their wild-type littermates. These data suggest that hyperactivation of STAT3 results in severe colitis and that CIS3 plays a negative regulatory role in acute intestinal inflammation by down-regulating STAT3 activity. Less
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