| Project/Area Number |
15590337
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Experimental pathology
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| Research Institution | KYOTO UNIVERSITY |
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Principal Investigator |
HATTORI Masakazu KYOTO UNIVERSITY, Graduate School of Biostudies, Associate Professor, 生命科学研究科, 助教授 (40211479)
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| Co-Investigator(Kenkyū-buntansha) |
TANAKA Yoshimasa KYOTO UNIVERSITY, Graduate School of Biostudies, Assistant Researcher, 生命科学研究科, 助手 (90280700)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2004: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2003: ¥2,300,000 (Direct Cost: ¥2,300,000)
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| Keywords | Ran1 / SPA-1 / chronic myelogenous leukemia / Autoimmune disease / B1 cell / B-CLL / OcaB / SCIDマウス / T細胞免疫不全 / Ras-ERKシグナル経路 / 免疫監視 / 癌抑制遺伝子 / アナジー |
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| Research Abstract |
Rap1 is a member of the Ras family of GTPases and, depending on the cellular context, has an important role in the regulation of proliferation or cell adhesion. In lympho-hematopoietic tissues, SPA-1 is a principal Rap1 GTPase-activating protein. Mice that were deficient for the SPA-1 gene developed age-dependent progression of T-cell immunodeficiency followed by a spectrum of late onset myeloproliferative disorders, mimicking human chronic myeloid leukemia. Deregulated Rap1 activation in SPA-1-deficient mice caused enhanced expansion of the bone marrow hematopoietic progenitors, but induced progressive unresponsiveness or anergy in T cells. Rap1 and its regulator, SPA-1, could, therefore, provide unique molecular targets for the control of human hematologic malignancy.
SPA-1-deficiency also caused the age-dependent expansion of B1a cell producing anti-dsDNA and anti-nuclear antibodies in the peritoneal cavity resulting in lupus-like autoimmunity. Sustained Rap1 activation in the bone marrow B cell precursors in SPA-1-deficient mice induced markedly biased Vκ gene repertoire and extensive "partial" receptor editing by activating OcaB gene controlling Vκ gene recombination, thereby leading to the generation of pathogenic self-reactive B1 cells. Furthermore, SPA-1-deficient mice frequently developed leukemia preferentially of B1 cell origin along with hemolytic autoantibody production. The results suggest that antigen-receptor repertoire formation in developing B cells can be significantly modified by the stimuli from bone marrow microenvironment, in which Rap1-signal plays an important role.
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