Investigation of novel therapeutic targets in dendritic cells for systemic lupus erythematosus
Project/Area Number |
17K09971
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Research Field |
Collagenous pathology/Allergology
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Research Institution | The University of Tokyo |
Principal Investigator |
SHODA HIROFUMI 東京大学, 医学部附属病院, 講師 (20529036)
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Project Period (FY) |
2017-04-01 – 2020-03-31
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Project Status |
Completed (Fiscal Year 2019)
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Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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Keywords | 全身性エリテマトーデス / iPS細胞 / 遺伝子変異 / インターフェロン / PADI4 / 好中球 / rare variant / 創薬 / 樹状細胞 / 膠原病 |
Outline of Final Research Achievements |
Disease-specific iPS cell lines were established from the patients with systemic lupus erythematosus (SLE). SLE-iPS cells were differentiated into dendritic cells with over secretion of type I interferon (IFN), which were thought to be a SLE pathological model in vitro. Whole exome analysis aidentified a novel rare variant associated with SLE. Functional analysis was performed using SLE-iPS cells, indicating that this variant was involved in excessive inflammatory cytokine production in SLE. In addition, we identified a new mechanism of exacerbation of mice model of lupus nephritis by the PADI4-JLP-p38 MAPK pathway in neutrophils, which was involved in renal migration. These results suggested that these mechanisms are expected as new therapeutic targets for SLE.
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Academic Significance and Societal Importance of the Research Achievements |
全身性エリテマトーデス(SLE)は難病であり、治療薬もステロイドが中心でその副作用による臓器障害が大きな問題となっている。従って副作用の少ない疾患特異的な創薬標的の探索と創薬が必須である。一方で、SLE患者からの検体を用いた病態研究は技術的・倫理的な限界があり、従来の方法では推進が困難であった。本研究はSLE患者から疾患特異的iPS細胞を作成することで、SLEの病態モデルを作成し、研究を推進した。研究成果として家族歴のあるSLE-iPS細胞株での遺伝子変異が炎症性サイトカインの過剰産生に関与していることを明らかとなり、新規創薬標的として期待できる。
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Report
(4 results)
Research Products
(24 results)
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[Journal Article] HLA-DRB1 Shared Epitope Alleles and Disease Activity Are Correlated with Reduced T Cell Receptor Repertoire Diversity in CD4+ T Cells in Rheumatoid Arthritis.2018
Author(s)
Sakurai K, Ishigaki K, Shoda H, Nagafuchi Y, Tsuchida Y, Sumitomo S, Kanda H, Suzuki A, Kochi Y, Yamamoto K, Fujio K.
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Journal Title
Journal of Rheumatology
Volume: 45
Issue: 7
Pages: 905-914
DOI
Related Report
Peer Reviewed
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[Journal Article] .Polygenic burdens on cell-specific pathways underlie the risk of rheumatoid arthritis.2017
Author(s)
Ishigaki K, Kochi Y, Suzuki A, Tsuchida Y, Tsuchiya H, Sumitomo S, Yamaguchi K, Nagafuchi Y, Nakachi S, Kato R, Sakurai K, Shoda H, Ikari K, Taniguchi A, Yamanaka H, Miya F, Tsunoda T, Okada Y, Momozawa Y, Kamatani Y, Yamada R, Kubo M, Fujio K, Yamamoto K.
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Journal Title
Nat Genet.
Volume: 49
Pages: 1120-1125
Related Report
Peer Reviewed / Int'l Joint Research
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