| Project/Area Number |
18K08412
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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 | Nara Medical University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
伊藤 利洋 奈良県立医科大学, 医学部, 教授 (00595712)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | インターフェロン / ヒストン修飾酵素 / 自己抗体 / B細胞 / SETDB2 / ヒストン修飾 |
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| Outline of Final Research Achievements |
In this study, we found that SET domain, bifurcated 2 (SETDB2) was induced in B1a cells by the stimulation of lipopolysaccharide (LPS), which induces the proliferation, antibody production and type-I IFN production. We also showed that SETDB2 expression was lower in B1a cells from autoimmune prone mice. Thus, we have developed the SETDB2 deficient mice by improved-Genome editing via Oviductal Nucleic Acids Delivery (iGONAD) method, which bases on in situ electroporation of CRISPR/Cas9 complex to embryos. SETDB2 deficient B1a cells highly expressed the type-I IFN by LPS or IFN stimulation. In addition, expression of xbp1 and prdm1, which relate to plasma cell differentiation, was highly induced in SETDB2 deficient B cells. These results suggest that SETDB2 suppressed the positive feedback of type-I IFN signaling and plasma cell differentiation, and its abnormality might cause the autoantibody production thorough the excessive IFN signaling.
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| Academic Significance and Societal Importance of the Research Achievements |
全身性エリテマトーデスなどの全身性自己免疫疾患では、自己反応性B細胞が排除されずに活性化・増殖し、高親和性のIgG型自己抗体を産生して組織障害を引き起こす。この過程では、I型インターフェロンの産生亢進による免疫系細胞の活性化が関与していることが明らかとなっているが、その分子機構は未解明な点が多い。本研究成果は、I型IFNシグナルの異常亢進と自己抗体産生にSETDB2の発現低下が関与することを示すもので、自己免疫疾患発症の分子機構の解明に繋がる。また、SETDB2やその制御因子に対する分子標的薬の開発により、自己免疫疾患に対する新規の治療法や診断法の開発へと発展が期待できる。
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