| Project/Area Number |
14370300
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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 |
Hematology
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| Research Institution | The University of Tokyo |
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Principal Investigator |
CHIBA Shigeru The University of Tokyo, Faculty of Medicine, Associate Professor, 医学部附属病院, 講師 (60212049)
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| Co-Investigator(Kenkyū-buntansha) |
MOTOKURA Toru The University of Tokyo, Faculty of Medicine, Lecturer, 医学部附属病院, 講師 (00192823)
OGAWA Seishi The University of Tokyo, Faculty of Medicine, visiting Associate Professor, 医学部附属病院, 寄付講座教員 (60292900)
KANDA Yoshinobu The University of Tokyo, Faculty of Medicine, Research Associate, 医学部附属病院, 助手 (30334379)
SUZUKI Takahiro The University of Tokyo, Faculty of Medicine, visiting Associate Professor, 医学部附属病院, 寄付講座教員 (40345210)
KUMANO Keiki The University of Tokyo, Faculty of Medicine, Project Researcher, 医学部附属病院, 研究拠点形成特任研究員
高橋 強志 東京大学, 医学部附属病院, 助手 (70332608)
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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 |
¥11,300,000 (Direct Cost: ¥11,300,000)
Fiscal Year 2004: ¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 2003: ¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2002: ¥4,700,000 (Direct Cost: ¥4,700,000)
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| Keywords | Notch / allogeneic hematopoietic stem cell transplantation / graft-versus-host disease / transgenic mouse / MHC class II promoter / Jagged1 / conditional knockout mouse / innate immunity / シランスジェニックマウス / Notchシグナル / 造血幹細胞 / 免疫調節 / GVHD / T細胞 / コンディショナルノックアウトマウス |
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| Research Abstract |
Signaling through Notch receptors regulates various aspects of immune system, such as development of T cells in the thymus, formation of marginal zone B cells in the spleen, Th1/Th2 differentiation and regulation of T cell activation. Therefore, it is expected that we will be able to establish a new technology to regulate immune reconstitution after allogeneic hematopoietic stem cell transplantation if we can modulate Notch signaling using its agonists or antagonists. In this study, we aimed at obtaining basic data supporting establishment of a method to prevent graft-versus-host disease (GVHD) by Notch signaling modulation.
We have generated transgenic mice expressing wild-type and dominant-negative form of Notch ligands under the MHC class I and MHC class II promoters, and characterized the phenotype and function of lymphocytes. We found that the T cell activation by the mixed lymphocyte culture was markedly reduced in the transgenic mice expressing wild-type Jagged1, one of the five known Notch ligands, under the MHC class II promoter. Using these mice as donors and recipients in the acute GVHD, rejection and chronic GVHD models, ongoing are allogeneic transplantation experiments. Based on the results deriving from these experiments, we plan to study, using Notch agonists and antagonists, how the modulation of individual Notch system affects development of GVHD.
Furthermore, we found that Notch2 signaling regulates the expression of surface molecules which are considered to be important for the innate immunity, using Notch2 conditional knockout mice. Based on this finding, we are currently studying how the signaling through Notch2 receptor plays a role in the T cell-independent antibody production by the marginal zone B cells.
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