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The cellular interplay between RPE cells and macrophages through extracellular vesicles

Research Project

Project/Area Number 20K09807
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 56060:Ophthalmology-related
Research InstitutionKyoto Prefectural University of Medicine

Principal Investigator

Hamuro Junji  京都府立医科大学, 医学(系)研究科(研究院), 客員教授 (80536095)

Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥390,000 (Direct Cost: ¥300,000、Indirect Cost: ¥90,000)
Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2020: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Keywords網膜色素上皮細胞 / マイクロ / ミトコンドリア機能 / miR-494-3p / 細胞外小胞 / 加齢黄斑変性 / マイクロRNA / 細胞外小胞体 / 核酸医薬 / マクロファージ / 加齢黄斑変性症 / エキソソーム / エキソゾーム
Outline of Research at the Start

核心をなす問は下記3点に集約される。①Mps/RPE間の細胞干渉を介在する細胞外微粒子包含分子種は何か。②AMD治療薬として限界がありながらも用いられている抗VEGF抗体治療を代替できるような血管新生/Subretinal線維化の阻害作用にどう係るのか、③我々の見出したMps/RPE間の細胞間干渉をAMD病態に関与するとされる酸化ストレスがどの様に攪乱するか。期待する成果は、網膜下組織炎症における脈絡膜浸潤MpsとRPE 間の相互細胞干渉による機能変性を分子動態レベルで解明し、新規創薬標的の創出につなげるPOCを確立することである。

Outline of Final Research Achievements

The production of MCP1, IL6 and VEGF was synergistically elevated when Mps and RPE cells were co-cultured. The protein expressions of these cytokines were increased even in Transwell inserts vertically connected with 0.40 μm membrane filters. Semi-purified CD63+ extracellular vesicle (EV) released from RPE cells, enhanced the secretion of these cytokines. Culture chamber separation horizontally connected with 0.03μm membrane filters reduced this increased cytokine secretion. The increased EV production was associated with elevated production of these cytokines from induced pluripotent stem cell-derived (iPS)-hRPE cells. The microarray analysis revealed a
the selectively increased release of miR-494-3p in EVs during the interplay with Mps. The transfection of the miR mimics modulated the functional homeostasis of mitochondria in hRPE cells through the inhibition of PTEN/PI3K signal pathway. MiR-494-3p may be a candidate molecular target for the diagnosis and therapy of AMD.

Academic Significance and Societal Importance of the Research Achievements

本研究は、RPEとMps間の細胞間ネットワークの破綻によるRPE細胞のミトコンドリア機能変性をAMDの早期病態の実態とする新概念である。病態増悪経路に細胞外小胞(EV)が関与することを明らかにし、miR494-3pを機能分子として同定したことは世界初である。本研究で確立した擬似モデル系を創薬探索系として活用することで、早期診断技術と併せてコンパニオン診断薬への道も拓かれる可能性も秘める。RPE細胞のミトコンドリア機能不全を修復する新規作用機序を持つAMD治療に繋げられる可能性がある。安価安全な医療・早期診断技術開発の基盤を構築するものである。

Report

(4 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (8 results)

All 2023 2022 2021 2020

All Journal Article (3 results) (of which Peer Reviewed: 3 results,  Open Access: 1 results) Presentation (4 results) (of which Int'l Joint Research: 2 results,  Invited: 1 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] Spatiotemporal Coordination of RPE Cell Quality by Extracellular Vesicle miR-494-3p Via Competitive Interplays With SIRT3 or PTEN2023

    • Author(s)
      Junji Hamuro,Tomoko Yamashita,Yohei Otsuki, Nao Hiramoto, Mayuka Adachi, Takafumi Miyatani, Hiroshi Tanaka, Morio Ueno, Shigeru Kinoshita, and Chie Sotozono
    • Journal Title

      Invest Ophthalmol Vis Sci

      Volume: - Pages: 36955-36955

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] CD63+ extracellular vesicles from retinal pigment epithelial cells2021

    • Author(s)
      Otsuki Y, Ito E, Mukai A, Ueno M, Yamawaki T, Sotozono C, Kinoshita S, Hamuro
    • Journal Title

      Exp. Eye Res.

      Volume: 206 Pages: 1-14

    • DOI

      10.1016/j.exer.2021.108496

    • Related Report
      2021 Research-status Report 2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Mitochondrial miRNA494-3p in extracellular vesicles participates in cellular interplay of iPS-Derived human retinal pigment epithelium with macrophages.2021

    • Author(s)
      Mukai A, Otsuki Y, Ito E, Fujita T, Ueno M, Maeda T, Kinoshita S, Sotozono C, Hamuro J.
    • Journal Title

      Exp Eye Res.

      Volume: 208 Pages: 108621-108621

    • DOI

      10.1016/j.exer.2021.108621

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Presentation] Spatiotemporal Coordination of RPE Cell Quality by miR-494-3p in Extracellular Vesicle, EV, through Competitive Interplays with SIRT3 and PTEN.2023

    • Author(s)
      Tomoko Yamashita, Yohei Otsuki, Nao Hiramoto, Mayuka Adachi, Takafumi Miyatani, Hiroshi Tanaka, Morio Ueno, Shigeru Kinoshita,Chie Sotozono and Junji Hamuro
    • Organizer
      ISER 2023
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] MiRNA-494-3p in extracellular vesicles is a potent new molecular target for diagnosis and treatment of age-related macular degeneration2023

    • Author(s)
      Yohei Otsuki,Tomoko Yamashita, Nao Hiramoto, Mayuka Adachi, Takafumi Miyatani, Hiroshi Tanaka, Morio Ueno, Shigeru Kinoshita, Chie Sotozono and Junji Hamuro
    • Organizer
      ISER 2023
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] ヒト網膜色素上皮細胞のミトコンドリア機能不全病態へのmiRNAの関与2022

    • Author(s)
      大槻陽平, 向敦史, 山下智子, 足立麻由香, 藤田智子, 上野盛夫, 木下茂, 羽室淳爾.
    • Organizer
      第126回日本眼科学会総会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Involvement of miRNAs in the pathogenesis of mitochondrial dysfunction in human retinal pigment epithelial cells2022

    • Author(s)
      大槻陽平
    • Organizer
      日本眼科学会
    • Related Report
      2021 Research-status Report
  • [Patent(Industrial Property Rights)] 炎症性網膜疾患の判定方法、炎症性網膜疾患治療剤、及び炎症性網膜疾患治療剤のスクリーニング方法2020

    • Inventor(s)
      羽室淳爾、外園千恵、木下茂
    • Industrial Property Rights Holder
      京都府立医科大学
    • Industrial Property Rights Type
      特許
    • Filing Date
      2020
    • Related Report
      2020 Research-status Report

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Published: 2020-04-28   Modified: 2024-12-25  

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