| Project/Area Number |
23K09036
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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 56060:Ophthalmology-related
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| Research Institution | National Defense Medical College |
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Principal Investigator |
竹内 大 防衛医科大学校(医学教育部医学科進学課程及び専門課程、動物実験施設、共同利用研究施設、病院並びに防衛, 眼科学, 教授 (40260939)
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| Co-Investigator(Kenkyū-buntansha) |
佐藤 智人 防衛医科大学校(医学教育部医学科進学課程及び専門課程、動物実験施設、共同利用研究施設、病院並びに防衛, 眼科学, 講師 (00724246)
伊藤 正孝 防衛医科大学校(医学教育部医学科進学課程及び専門課程、動物実験施設、共同利用研究施設、病院並びに防衛, 再生発生学, 准教授 (30534896)
播本 幸三 防衛医科大学校(医学教育部医学科進学課程及び専門課程、動物実験施設、共同利用研究施設、病院並びに防衛, 眼科学, 助教 (80626804)
西尾 佳明 防衛医科大学校(医学教育部医学科進学課程及び専門課程、動物実験施設、共同利用研究施設、病院並びに防衛, 眼科学, 助教 (80727347)
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| Project Period (FY) |
2023-04-01 – 2026-03-31
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| Project Status |
Granted (Fiscal Year 2023)
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| Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2025: ¥390,000 (Direct Cost: ¥300,000、Indirect Cost: ¥90,000)
Fiscal Year 2024: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2023: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000)
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| Keywords | diabetes mellitus / 実験的自己免疫性ぶどう膜網膜炎 / Th17 cells / reguratory T cells / T-cell mediated immunity / AP-1 signaling pathway / 糖尿病網膜症 / IL-17A / オステオポンチン / Th17細胞 / 老化T細胞 |
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| Outline of Research at the Start |
我々は、増殖糖尿病網膜症（PDR）患者の眼内液中では、IL-17Aおよびオステオポンチン(OPN)濃度が他の網膜疾患よりも有意に高いこと、糖尿病（DM）を自然発症するAkitaマウスとTh17細胞優位のIFN-g欠損マウスとを掛け合わせたAkita-GKOマウスではAkitaマウスよりも早期に糖尿病網膜症（DR）所見を呈し、IL-17A
およびOPN産生T細胞が増加していることを認めた．本研究では、DMマウスモデルを用いて加齢、DRの進行に伴うT細胞のレパートア変化をシングルセルRNAシーケンシングにて解析し、DRの進行に最も相関するT細胞、およびそのマーカー遺伝子の同定を目的としている．
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| Outline of Annual Research Achievements |
PURPOSE. Inflammation is involved in the pathogenesis of diabetes, however the impact of diabetes on organ-specific autoimmune diseases remains unexplored. Experimental autoimmune uveoretinitis (EAU) is a widely accepted animal model of human endogenous uveitis. In this study, we investigated the effects of diabetic conditions on the development of EAU using a mouse diabetes model. METHODS. EAU was induced in wild-type C57BL/6 (WT) mice and Ins2Akita (Akita) mice with spontaneous diabetes by immunization with IRBP peptide. Clinical and histopathological examinations, and analysis of T cell activation state were conducted. In addition, alternations in the composition of immune cell types and gene expression profiles of relevant immune functions were identified using single-cell RNA sequencing. RESULTS. The development of EAU was significantly attenuated in immunized Akita (Akita-EAU) mice compared with immunized WT (WT-EAU) mice, although T cells were fully activated in Akita-EAU mice, and the differentiation into Th17 cells and regulatory T (Treg) cells was promoted. However, Th1 cell differentiation was inhibited in Akita-EAU mice, and single-cell analysis indicated that gene expression associated AP-1 signaling pathway (JUN, FOS, and FOSB) was downregulated not only in Th1 cells but also in Th17, and Treg cells in Akita-EAU mice at the onset of EAU. CONCLUSIONS. In diabetic mice, EAU was significantly attenuated. This was related to selective inhibition of Th1 cell differentiation and downregulated AP-1 signaling pathway in both Th1 and Th17 cells.
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| Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
上記内容の論文を投稿し、major revisionを受け、現在再投稿中である．Akita-EAUマウスで上昇がみられたA100A8/A9が糖尿病慢性炎症に関与すると考え、今年度はそのKnock out miceで検討を行う予定である．
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| Strategy for Future Research Activity |
．Akita-EAUマウスで上昇がみられたA100A8/A9が糖尿病慢性炎症に関与すると考え、今年度はそのKnock out miceで検討を行う予定である．
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