| Project/Area Number |
20K08815
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 54020:Connective tissue disease and allergy-related
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| Research Institution | University of Occupational and Environmental Health, Japan |
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Principal Investigator |
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2022: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
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| Keywords | 全身性エリテマトーデス / 濾胞性ヘルパーT細胞 / 濾胞制御性ヘルパーT細胞 / 末梢性ヘルパーT細胞 / エピジェネティクス / サイトカイン / ジェネティクス / ヘルパーT細胞 / ゲノム |
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| Outline of Research at the Start |
本研究では、(1) Tfh細胞の可塑性に関わるゲノム異常とエピゲノム修飾との関連、(2) Tfh細胞に特異的なスーパーエンハンサー・エピゲノム修飾とその誘導因子の同定、(3) Tfh細胞のエピゲノム制御による濾胞性制御性T細胞への形質転換の検証によって、Tfh細胞の人為的なエピゲノム制御によるT細胞の機能修復の可能性を探索する。
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| Outline of Final Research Achievements |
In SLE patients, decreased IL-2 resulted in increased Tfh cells and decreased Tfr cells. IL-2 reduction in SLE patients was associated with genetic regulation of IL-2 by the disease susceptibility gene IL21-AS1. IL-2 induced the conversion of memory Tfh cells to functional Tfr cells by epigenetic regulation via activation of STAT3/STAT5. On the other hand, Tph cells increased in SLE, and their differentiation was induced by TGF-β3 produced from tissue macrophages, unlike Tfh cells, and promoted B cell differentiation and antibody production. These results suggest that IL-2 and TGF-β3, which are involved in the differentiation of pathological T cells in SLE, are novel therapeutic targets mediated by epigenome repair.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究の結果は、SLEの病態においてT細胞の分化や機能の異常がゲノム異常により規定されるSLE特異的なエピゲノム記憶に基づく可能性を示唆する。これらを標的とした創薬はSLEの治療抵抗性難治性病態への新たな治療戦略に有望である。本研究は、免疫難病であるSLEへの疾患特異的治療の開発に重要な示唆を与え、医療および社会の発展に資するものである。
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