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Drug screening for Retnitis pigmentosa by using reporter knock-in human iPSCs

Research Project

Project/Area Number 19K09977
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 56060:Ophthalmology-related
Research InstitutionKeio University

Principal Investigator

HOMMA Kohei  慶應義塾大学, 医学部(信濃町), 特任助教 (80462729)

Co-Investigator(Kenkyū-buntansha) 小澤 洋子  慶應義塾大学, 医学部(信濃町), 特任准教授 (90265885)
Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
KeywordsヒトiPS細胞 / 網膜色素変性 / 網膜視細胞 / 活性酸素種 / ドラッグスクリーニング / ゲノム編集 / 網膜色素変性症
Outline of Research at the Start

先行研究で、申請者らは網膜視細胞の変性をきたす網膜色素変性症患者由来iPS細胞を作製した。また、近年開発されたゲノム編集技術により、網膜視細胞を特異的に標識できるノックインiPS細胞のラインを樹立した。そこで本研究では、これらの蛍光タンパク質標識された分化視細胞を用いて、網膜色素変性患者由来視細胞と正常視細胞を比較することにより、各原因遺伝子が引き起こす(1)細胞死関連シグナル遺伝子発現や、(2)代謝物の産生に与える影響を調べ、(3)蛍光タンパク質標識を指標とした薬剤スクリーニングを行う。

Outline of Final Research Achievements

In this study, we examined (1) signal gene expression associated with retinal photoreceptor cell death caused by each causative gene. (2) By using disease iPSCs from the mitochondrial disease MELAS patient, we examined the effects of metabolites involved in the disease and found that oxidative stress is involved, and that taurine alleviates these signals. (3) We conducted drug screening using the vulnerability of MELAS diseased iPSCs to 2-deoxyglucose and established a system that can screen candidate compounds.

Academic Significance and Societal Importance of the Research Achievements

網膜色素変性症は、緑内障、糖尿病網膜症に次いで日本国内第3位の主要な失明原因となっている(厚生労働省資料)。様々な遺伝子の変異により、網膜で光を感受する視細胞が細胞死を引き起こす。近年の遺伝子解析技術の発達により、これまでに200以上の原因遺伝子が特定されているが、未だその遺伝子変異による遺伝子発現や、それに伴うエネルギー代謝変化による視細胞死のメカニズムについて、詳細は明らかではなく、これらを防ぐ治療法は現在存在しない。本研究では、ノックインiPS細胞を利用して、網膜変性の疾患メカニズムを詳細に解析し、それぞれの疾患に対応したいくつかの新規治療方法を提案することができた。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (13 results)

All 2021 2020 2019

All Journal Article (3 results) (of which Peer Reviewed: 3 results,  Open Access: 3 results) Presentation (10 results) (of which Int'l Joint Research: 2 results)

  • [Journal Article] Taurine rescues mitochondria-related metabolic impairments in the patient-derived induced pluripotent stem cells and epithelial-mesenchymal transition in the retinal pigment epithelium2021

    • Author(s)
      Homma Kohei、Toda Eriko、Osada Hideto、Nagai Norihiro、Era Takumi、Tsubota Kazuo、Okano Hideyuki、Ozawa Yoko
    • Journal Title

      Redox Biology

      Volume: 41 Pages: 101921-101921

    • DOI

      10.1016/j.redox.2021.101921

    • Related Report
      2021 Annual Research Report 2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Neuroprotective Effect of 4-Phenylbutyric Acid against Photo-Stress in the Retina2021

    • Author(s)
      Guzman Mendoza Naymel Alejandra、Homma Kohei、Osada Hideto、Toda Eriko、Ban Norimitsu、Nagai Norihiro、Negishi Kazuno、Tsubota Kazuo、Ozawa Yoko
    • Journal Title

      Antioxidants

      Volume: 10 Issue: 7 Pages: 1147-1147

    • DOI

      10.3390/antiox10071147

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] ADIPOR1 deficiency-induced suppression of retinal ELOVL2 and docosahexaenoic acid levels during photoreceptor degeneration and visual loss2021

    • Author(s)
      Osada Hideto、Toda Eriko、Homma Kohei、Guzman Naymel A.、Nagai Norihiro、Ogawa Mamoru、Negishi Kazuno、Arita Makoto、Tsubota Kazuo、Ozawa Yoko
    • Journal Title

      Cell Death & Disease

      Volume: 12 Issue: 5 Pages: 458-458

    • DOI

      10.1038/s41419-021-03741-5

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] Antioxidant effects of Taurine in the MELAS patient-derived induced pluripotent stem cells and the suppression of EMT signals in retinal pigment epithelium.2021

    • Author(s)
      Homma K, Tsubota K, Okano H, Ozawa Y.
    • Organizer
      The International Society for Stem Cell Research (ISSCR) 2021.
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] タウリンはミトコンドリア病MELAS疾患iPS細胞の代謝不全と網膜色素上皮細胞の上皮間葉転換を抑制する.2021

    • Author(s)
      本間耕平, 坪田一男, 岡野栄之, 小沢洋子.
    • Organizer
      第44回日本神経科学大会
    • Related Report
      2021 Annual Research Report
  • [Presentation] ミトコンドリア病疾患iPS細胞を用いたドラッグスクリーニングシステム構築.2021

    • Author(s)
      本間耕平, 坪田一男, 岡野栄之, 小沢洋子.
    • Organizer
      第44回日本分子生物学会年会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Analysis of retinal disease mechanism by using MELAS patient-derived induced pluripotent stem cell lines2020

    • Author(s)
      Kohei Homma; Toshio Narimatsu; Kazuo Tsubota; Hideyuki Okano; Yoko Ozawa.
    • Organizer
      ARVO Annual Meeting 2020
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] ミトコンドリア脳筋症疾患iPS細胞由来網膜色素上皮細胞の遺伝子発現解析2020

    • Author(s)
      本間 耕平、坪田一男、岡野栄之、小澤 洋子
    • Organizer
      第41回日本炎症・再生医学会
    • Related Report
      2020 Research-status Report
  • [Presentation] Analysis of degeneration mechanism in retinal pigment epithelium-derived from human induced pluripotent stem cells with mitochondria DNA mutation.2020

    • Author(s)
      Kohei Homma, Toshio Narimatsu, Kazuo Tsubota, Hideyuki Okano, Yoko Ozawa.
    • Organizer
      第43回日本神経科学大会
    • Related Report
      2020 Research-status Report
  • [Presentation] ミトコンドリア病疾患iPS細胞由来網膜色素上皮細胞の変性メカニズム解析2020

    • Author(s)
      本間 耕平、坪田一男、岡野栄之、小澤 洋子
    • Organizer
      第23回 視覚科学フォーラム
    • Related Report
      2020 Research-status Report
  • [Presentation] ミトコンドリア病疾患iPS細胞由来網膜色素上皮細胞を用いた網膜変性メカニズム解析2019

    • Author(s)
      本間 耕平
    • Organizer
      日本分子生物学会
    • Related Report
      2019 Research-status Report
  • [Presentation] Analysis of energy metabolism in retinal pigment epithelium of age-related macular degeneration models.2019

    • Author(s)
      本間 耕平
    • Organizer
      反分野的生物医療学会
    • Related Report
      2019 Research-status Report
  • [Presentation] ミトコンドリア機能不全モデルにおける網膜色素上皮細胞の機能解析2019

    • Author(s)
      本間 耕平
    • Organizer
      ミトコンドリアシンポジウム
    • Related Report
      2019 Research-status Report

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Published: 2019-04-18   Modified: 2023-01-30  

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