2019 Fiscal Year Final Research Report
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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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 |
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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Free Research Field |
膠原病学、免疫学、内科学
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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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