| Project/Area Number |
14380385
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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 |
Laboratory animal science
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| Research Institution | JUNTENDO UNIVERSITY |
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Principal Investigator |
HIROSE Sachiko Juntendo Univ. Sch. Med., Dept. Pathol., Associate Prof., 医学部, 助教授 (00127127)
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| Co-Investigator(Kenkyū-buntansha) |
多田 昇弘 順天堂大学, 医学部, 講師 (50338315)
上野 博夫 国立がんセンター, 研究所・ウイルス部, 室長 (60332368)
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| Project Period (FY) |
2002 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥9,900,000 (Direct Cost: ¥9,900,000)
Fiscal Year 2003: ¥4,800,000 (Direct Cost: ¥4,800,000)
Fiscal Year 2002: ¥5,100,000 (Direct Cost: ¥5,100,000)
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| Keywords | Ltk / Systemic lupus erythematosus / Gain-of-function polymorphism / B1 cell / SNP / Linkage study / PI3 kinase / Susceptible gene |
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| Research Abstract |
Systemic lupus erythematosus (SLE), a complex multigenic disease, is a typical antibody-mediated autoimmune disease characterized by production of autoantibodies against a variety of autoantigens and immune complex-type tissue inflammation, most prominently in the kidney. Evidence suggests that genetic factors predisposing to aberrant proliferation/maturation of self-reactive B cells initiate and propagate the disease. In SLE-prone New Zealand Black (NZB) mice and their F1 cross with New Zealand White (NZW) mice, B cell abnormalities can be ascribed mainly to self-reactive CD5^+ B1 cells. Our genome-wide scans to search for susceptibility genes for aberrant activation of B1 cells in these mice showed evidence that the gene, Ltk, encoding leukocyte tyrosine kinase (LTK), is a possible candidate. LTK is a receptor-type protein tyrosine kinase, belonging to the insulin receptor superfamily, and is mainly expressed in B lymphocyte precursors and neuronal tissues. Sequence and functional analyses of the gene revealed that NZB has a gain-of-function polymorphism in the LTK kinase domain near YXXM, a binding motif of the p85 subunit of phosphatidylinositol 3-kinase (P13K). SLE patients also had this type of Ltk polymorphism with a significantly higher frequency compared to the healthy controls. Our findings suggest that these polymorphic LTKs cause up-regulation of the PI3K pathway and possibly form one genetic aspect for susceptibility to abnormal proliferation of self-reactive B cells in SLE.
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