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Controlling hypoxia-induced cell death for the treatment of retinal Degeneration

Research Project

Project/Area Number 20K18393
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 56060:Ophthalmology-related
Research InstitutionKeio University

Principal Investigator

Miwa Yukihiro  慶應義塾大学, 医学部(信濃町), 特任助教 (30870430)

Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywords低酸素誘導因子 / Hypoxia-inducible Factor / HIF / 網膜変性 / 網膜病的血管新生 / HIF-1α / 低酸素応答 / 網膜 / 視細胞 / 視細胞死 / 神経変性 / Hypoxia-inducible factor / 難治性網膜疾患 / 細胞死
Outline of Research at the Start

我が国の中途失明原因疾患の上位を占める難治性網膜疾患の主な病態機序は神経細胞死である。本研究では、低酸素誘導因子(Hypoxia-inducible Factor; HIF)という転写因子に着目し、HIFを制御することで、網膜視細胞死が抑制され、網膜変性疾患の進行抑制効果が得られるという仮説を立てた。そして、マウス網膜変性モデルを用いてHIF阻害剤による視細胞死抑制の分子メカニズムを検証し、HIF阻害剤の治療的効果を確認することで、上記仮説を検証することを目的とする。

Outline of Final Research Achievements

Our research focused on investigating the efficacy of novel treatment approaches for refractory retinal diseases. Specifically, we explored the involvement of hypoxia-inducible factor (HIF) in the pathogenesis of various mouse models of retinal degeneration. Through our investigations, we discovered that targeting HIF could yield therapeutic benefits in these disease models. Additionally, we shed light on the potential molecular mechanism involving the HIF-1α/BNIP3 axis. Furthermore, our study involved a screening of a natural product library to identify potential HIF inhibitors. Remarkably, we found that various food-derived extracts exhibited significant HIF inhibitory activity. We subsequently evaluated the effects of several novel HIF inhibitors obtained from this screening process in mouse models of refractory retinal diseases. Encouragingly, our findings demonstrated the inhibitory effects of these compounds on retinal neurodegeneration and pathological angiogenesis.

Academic Significance and Societal Importance of the Research Achievements

網膜色素変性や萎縮型加齢黄斑変性などの網膜変性疾患は、網膜視細胞死を特徴とする難治性網膜疾患である。現在までに、確立された治療法や予防法は存在せず、我が国における中途失明原因の20%超を占める。その社会的コストは20兆円とされており、早急な治療法の確立が求められている。
本研究で得られた新規HIF阻害剤は、その多くが食品物に由来することからその安全性が担保されている。また、日常の食事に取り入れることが可能であると考えられることから、本研究で得られた新規HIF阻害剤は、より初期の網膜変性疾患に対し、より長期に渡って介入できる可能性を有している。

Report

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

    (16 results)

All 2022 2021 2020

All Journal Article (10 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 10 results,  Open Access: 10 results) Presentation (5 results) (of which Int'l Joint Research: 1 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] Nicotinamide Mononucleotide Protects against Retinal Dysfunction in a Murine Model of Carotid Artery Occlusion.2022

    • Author(s)
      Lee D, Tomita Y, Miwa Y, Jeong H, Shinojima A, Ban N, Yamaguchi S, Nishioka K, Negishi K, Yoshino J, Kurihara T.
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 23 Issue: 23 Pages: 14711-14711

    • DOI

      10.3390/ijms232314711

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Nicotinamide mononucleotide prevents retinal dysfunction in a mouse model of retinal ischemia/reperfusion injury.2022

    • Author(s)
      Lee D, Tomita Y, Miwa Y, Shinojima A, Ban N, Yamaguchi S, Nishioka K, Negishi K, Yoshino J, Kurihara T
    • Journal Title

      International Journal of Molecular Sciences.

      Volume: 23 Issue: 19 Pages: 11228-11228

    • DOI

      10.3390/ijms231911228

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] HIF Inhibition Therapy in Ocular Diseases2022

    • Author(s)
      Lee Deokho、Miwa Yukihiro、Kunimi Hiromitsu、Ibuki Mari、Shoda Chiho、Nakai Ayaka、Kurihara Toshihide
    • Journal Title

      The Keio Journal of Medicine

      Volume: 71 Issue: 1 Pages: 1-12

    • DOI

      10.2302/kjm.2021-0004-IR

    • NAID

      130008023602

    • ISSN
      0022-9717, 1880-1293
    • Related Report
      2022 Annual Research Report 2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Retinal Degeneration in a Murine Model of Retinal Ischemia by Unilateral Common Carotid Artery Occlusion2021

    • Author(s)
      Lee Deokho、Nakai Ayaka、Miwa Yukihiro、Tomita Yohei、Serizawa Naho、Katada Yusaku、Hatanaka Yusuke、Tsubota Kazuo、Negishi Kazuno、Kurihara Toshihide
    • Journal Title

      BioMed Research International

      Volume: 2021 Issue: 1 Pages: 1-17

    • DOI

      10.1155/2021/7727648

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Bilateral cataract surgery in a Japanese macaque (Macaca fuscata): A case report2021

    • Author(s)
      Miwa Yukihiro、Komatsu Hiroyuki、Shinojima Ari、Oda Ayako、Inagaki Mao、Usami Kensuke、Akasaka Minori、Kobayashi Yoshitaka
    • Journal Title

      Clinical Case Reports

      Volume: 9 Issue: 11

    • DOI

      10.1002/ccr3.5112

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Pemafibrate Prevents Retinal Dysfunction in a Mouse Model of Unilateral Common Carotid Artery Occlusion2021

    • Author(s)
      Lee Deokho、Tomita Yohei、Jeong Heonuk、Miwa Yukihiro、Tsubota Kazuo、Negishi Kazuno、Kurihara Toshihide
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 22 Issue: 17 Pages: 9408-9408

    • DOI

      10.3390/ijms22179408

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Retinal dysfunction induced in a mouse model of unilateral common carotid artery occlusion2021

    • Author(s)
      Lee Deokho、Jeong Heonuk、Miwa Yukihiro、Shinojima Ari、Katada Yusaku、Tsubota Kazuo、Kurihara Toshihide
    • Journal Title

      PeerJ

      Volume: 9 Pages: e11665-e11665

    • DOI

      10.7717/peerj.11665

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] A Murine Model of Ischemic Retinal Injury Induced by Transient Bilateral Common Carotid Artery Occlusion2020

    • Author(s)
      Lee Deokho、Miwa Yukihiro、Jeong Heonuk、Ikeda Shin-ichi、Katada Yusaku、Tsubota Kazuo、Kurihara Toshihide
    • Journal Title

      Journal of Visualized Experiments

      Volume: Nov 12 Issue: 165 Pages: 1-19

    • DOI

      10.3791/61865

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] A Fairy Chemical Suppresses Retinal Angiogenesis as a HIF Inhibitor2020

    • Author(s)
      Lee Deokho、Miwa Yukihiro、Wu Jing、Shoda Chiho、Jeong Heonuk、Kawagishi Hirokazu、Tsubota Kazuo、Kurihara Toshihide
    • Journal Title

      Biomolecules

      Volume: 10 Issue: 10 Pages: 1405-1405

    • DOI

      10.3390/biom10101405

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Hypoxia-Inducible Factor Inhibitors Derived from Marine Products Suppress a Murine Model of Neovascular Retinopathy2020

    • Author(s)
      Shoda Chiho、Miwa Yukihiro、Nimura Kazumi、Okamoto Kazutoshi、Yamagami Satoru、Tsubota Kazuo、Kurihara Toshihide
    • Journal Title

      Nutrients

      Volume: 12 Issue: 4 Pages: 1055-1055

    • DOI

      10.3390/nu12041055

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Protective effects of a HIF Inhibitor halofuginone on light-induced retinal damage via suppression of HIF/BNIP3 axis2022

    • Author(s)
      三輪 幸裕
    • Organizer
      The Association for Research in Vision and Ophthalmology Annual Meeting
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 魚類由来HIF阻害物質による網膜病的血管新生・神経変性に対する治療的効果2022

    • Author(s)
      三輪 幸裕
    • Organizer
      第41回 比較眼科学会年次大会
    • Related Report
      2022 Annual Research Report
  • [Presentation] HIF阻害剤ハロフジノンによるマウス網膜光障害モデルに対する治療的効果2022

    • Author(s)
      三輪 幸裕
    • Organizer
      第126回 日本眼科学会総会
    • Related Report
      2022 Annual Research Report
  • [Presentation] HIF阻害剤ハロフジノンのマウス網膜変性モデルに対する治療的効果とその分子機序に関する検討2022

    • Author(s)
      三輪 幸裕
    • Organizer
      第30回中部小動物臨床研究会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 緑内障チューブシャント術時の抗線維化処置に関する検討2021

    • Author(s)
      三輪 幸裕
    • Organizer
      第40回 比較眼科学会年次大会
    • Related Report
      2021 Research-status Report
  • [Patent(Industrial Property Rights)] 低酸素誘導因子阻害剤2020

    • Inventor(s)
      河岸洋和、呉静、栗原俊英、三輪幸裕、正田千穂、イドクホ、坪田一男
    • Industrial Property Rights Holder
      河岸洋和、呉静、栗原俊英、三輪幸裕、正田千穂、イドクホ、坪田一男
    • Industrial Property Rights Type
      特許
    • Filing Date
      2020
    • Acquisition Date
      2021
    • Related Report
      2021 Research-status Report

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Published: 2020-04-28   Modified: 2024-01-30  

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