2023 Fiscal Year Final Research Report
Analysis of molecular mechanisms underlying vasculitis in ADA2 deficiency
Project/Area Number |
22K15939
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Research Category |
Grant-in-Aid for Early-Career Scientists
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Allocation Type | Multi-year Fund |
Review Section |
Basic Section 52050:Embryonic medicine and pediatrics-related
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Research Institution | Kyoto University |
Principal Investigator |
Nihira Hiroshi 京都大学, 医学研究科, 特定助教 (00881301)
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Project Period (FY) |
2022-04-01 – 2024-03-31
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Keywords | 自己炎症性疾患 / ADA2欠損症 / 血管炎 / ADA2 |
Outline of Final Research Achievements |
ADA2 deficiency is a hereditary autoinflammatory disease characterized by systemic small- to medium-sized arteritis. Its mechanism of vasculitis remains unknown. In this study, we performed ADA2 knockout in a human cell line using CRISPR/Cas9 and constructed an assay system to reproduce the pathological condition of vasculitis by co-culturing with fibroblasts. We also performed drug screening using the same assay system, and confirmed the efficacy of JAK inhibitors. In addition, we used immunoprecipitation and proximal-dependent biotinylation labeling to reveal molecules that directly bind to or interact with ADA2, which had not been shown before. These results indicate a new possibility that could lead to elucidation of the molecular mechanism of ADA2 deficiency.
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Free Research Field |
自己炎症性疾患
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Academic Significance and Societal Importance of the Research Achievements |
ADA2欠損症は結節性多発動脈炎類似の臨床型を呈し、本結果で得られた知見は、非単一遺伝子性のその他の血管炎症候群の病態理解に寄与する。また患者細胞を使用しない形での病態再現系を構築した事により、継続的な病態解析や新規薬剤評価が可能となった。加えて、既存のデアミナーゼ活性解析以外のADA2機能評価を行う事で、従来とは異なる変異疾患原性評価を可能とした。
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