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Involvement of endoplasmic reticulum stress in the pathophysiology of Fuchs endothelial corneal dystrophy

Research Project

Project/Area Number 16K11307
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Ophthalmology
Research InstitutionDoshisha University

Principal Investigator

Koizumi Noriko  同志社大学, 生命医科学部, 教授 (20373087)

Research Collaborator Okumura Naoki  
Sato Takahiko  
Friedrich Kruse  
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
KeywordsFuchs角膜内皮ジストロフィ / 小胞体ストレス / 角膜内皮障害 / 薬物治療 / TGF-βシグナル / 細胞・組織
Outline of Final Research Achievements

Fuchs endothelial corneal dystrophy (FECD) is a bilateral, progressive corneal endothelial disease. Corneal transplantation is the only current treatment option, though a pharmaceutical therapy has been anticipated. In this study, we showed that unfolded protein accumulates in the endoplasmic reticulum (ER) of corneal endothelial cells in FECD patients, and that unfolded protein progressively induces corneal endothelial cell (CEC) death via ER stress. We also showed the possibility of a pharmaceutical treatment of FECD by preventing the ER stress and apoptosis of CECs by using transforming growth factor beta (TGF-β) signaling inhibitors.

Academic Significance and Societal Importance of the Research Achievements

FECDの病態の詳細は不明であり薬物療法は存在せず、現在の治療法は角膜移植のみである。本研究によってFECDの病態が解明され、保存的治療法によって角膜内皮障害の進行を遅らせることができれば、多くの患者が生涯にわたって角膜移植を行わず良好な視力を維持することができる。また、角膜移植に代わる点眼治療薬の開発は、患者の身体的・経済的負担を軽減するのみならず、医療費削減、ドナー角膜の有効利用につながり、社会福祉に貢献する極めて重要性の高い研究である。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (34 results)

All 2019 2018 2017 2016 Other

All Int'l Joint Research (4 results) Journal Article (4 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 4 results,  Open Access: 4 results) Presentation (18 results) (of which Int'l Joint Research: 8 results,  Invited: 4 results) Remarks (2 results) Patent(Industrial Property Rights) (6 results) (of which Overseas: 3 results)

  • [Int'l Joint Research] エルランゲン大学(ドイツ)

    • Related Report
      2018 Annual Research Report
  • [Int'l Joint Research] カーディフ大学(英国)

    • Related Report
      2018 Annual Research Report
  • [Int'l Joint Research] エルランゲン大学(ドイツ)

    • Related Report
      2017 Research-status Report
  • [Int'l Joint Research] エルランゲン大学(ドイツ)

    • Related Report
      2016 Research-status Report
  • [Journal Article] Perspective of Future Potent Therapies for Fuchs Endothelial Corneal Dystrophy2018

    • Author(s)
      Okumura N, Hayashi R, Koizumi N
    • Journal Title

      Open Ophthalmol J

      Volume: 12 Issue: 1 Pages: 154-163

    • DOI

      10.2174/1874364101812010154

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Sustained activation of the unfolded protein response induces cell death in Fuchs endothelial corneal dystrophy2017

    • Author(s)
      Okumura N, Kitahara M, Okuda H, Hashimoto K, Ueda E, Nakahara N, Kinoshita S, Young RD, Quantock AJ, Tourtas T, Schlötzer-Schrehardt U, Kruse FE, Koizumi N
    • Journal Title

      Invest Ophthalmol

      Volume: 58(9) Issue: 9 Pages: 3697-3707

    • DOI

      10.1167/iovs.16-21023

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Activation of TGF-β signaling induces cell death via the unfolded protein response in Fuchs endothelial corneal dystrophy2017

    • Author(s)
      Okumura N, Hashimoto K, Kitahara M, Okuda H, Ueda E, Watanabe K, Nakahara M, Sato T, Kinoshita S, Tourtas T, Schlötzer-Schrehardt U, Kruse FE, Koizumi N
    • Journal Title

      Sci Rep

      Volume: 7(1) Issue: 1 Pages: 6801-6801

    • DOI

      10.1038/s41598-017-06924-3

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Effect of the Rho-Associated Kinase Inhibitor Eye Drop (Ripasudil) on Corneal Endothelial Wound Healing.2016

    • Author(s)
      Okumura N, Okazaki Y, Inoue R, Kakutani K, Nakano S, Kinoshita S, Koizumi N
    • Journal Title

      Invest Ophthalmol Vis Sci

      Volume: 57(3) Issue: 3 Pages: 1284-1292

    • DOI

      10.1167/iovs.15-18586

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] 角膜内皮細胞の小胞体ストレス応答におけるmitochondria-associated ER membranesの関与2019

    • Author(s)
      松本紗季, 奥村直毅, 奥田浩和, Robert D. Young, Quantock AJ, 小泉範子
    • Organizer
      角膜カンファランス2019第43回日本角膜学会総会・第35回日本角膜移植学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 薬剤スクリーニングによるフックス角膜内皮ジストロフィの治療薬の探索2019

    • Author(s)
      中川理咲子, 奥村直毅, 大西貴子, 大嶋剛史, 上田江美, 渡辺恭子, 小泉範子
    • Organizer
      角膜カンファランス2019第43回日本角膜学会総会・第35回日本角膜移植学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Establishment of a drug screening system for Fuchs endothelial corneal dystrophy.2018

    • Author(s)
      Oshima T, Okumura N, Onishi T, Ueda E, Watanabe K, Tourtas T, Schlötzer-Schrehardt U, Kruse FE, Koizumi N
    • Organizer
      The Association for Research in Vision and Ophthalmology 2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Involvement of mitochondria-associated endoplasmic reticulum membrane in the pathophysiology of Fuchs endothelial corneal dystrophy2018

    • Author(s)
      Matsumoto S, Okumura N, Okuda H, Schlötzer-Schrehardt U, Kruse FE, Young RD, Quantock AJ, Koizumi N
    • Organizer
      The 11th Joint Meeting of Japan-China-Korea Ophthalmologists
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 再生医療と創薬で角膜内皮治療の未来を切り拓く2018

    • Author(s)
      小泉範子
    • Organizer
      第14回滋賀県眼科治療フォーラム
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] 角膜内皮における小胞体ストレス応答による細胞死.2017

    • Author(s)
      奥田浩和, 奥村直毅, 北原美優, 橋本佳祐, 小泉範子
    • Organizer
      角膜カンファランス2017第41回日本角膜学会総会・第33回日本角膜移植学会
    • Place of Presentation
      アクロス福岡(福岡県・福岡市)
    • Year and Date
      2017-02-17
    • Related Report
      2016 Research-status Report
  • [Presentation] フックス角膜内皮ジストロフィにおける小胞体ストレスに対するTGF-βシグナルの影響.2017

    • Author(s)
      奥村直毅, 上田江美, Theofilos Tourtas, Friedrich E. Kruse, Ursula Schloetzer-Schrehardt, 小泉範子
    • Organizer
      角膜カンファランス2017第41回日本角膜学会総会・第33回日本角膜移植学会
    • Place of Presentation
      アクロス福岡(福岡県・福岡市)
    • Year and Date
      2017-02-17
    • Related Report
      2016 Research-status Report
  • [Presentation] Fuchs角膜内皮ジストロフィの小胞体ストレスにおけるp38 MAPK経路の関与.2017

    • Author(s)
      大西貴子, 奥村直毅, 橋本佳佑, 小泉範子
    • Organizer
      角膜カンファランス2017第41回日本角膜学会総会・第33回日本角膜移植学会
    • Place of Presentation
      アクロス福岡(福岡県・福岡市)
    • Year and Date
      2017-02-16
    • Related Report
      2016 Research-status Report
  • [Presentation] Activation of an intrinsic pathway by endoplasmic reticulum stress in corneal endothelial cells.2017

    • Author(s)
      Okuda H, Okumura N, Kitahara M, Hashimoto K, Koizumi N:
    • Organizer
      The Association for Research in Vision and Ophthalmology 2017
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Feasibility of caspase inhibitor to treat Fuchs endothelial corneal dystrophy.2017

    • Author(s)
      Endo M, Okumura N, Tourtas T, Schloetzer-Schrehardt U, Kruse FE, Koizumi N
    • Organizer
      The Association for Research in Vision and Ophthalmology 2017
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Feasibility of TGF-β inhibition for the treatment of Fuchs endothelial corneal dystrophy.2017

    • Author(s)
      Okumura N, Hashimoto K, Okuda H, Ueda E, Tourtas T, Schloetzer-Schrehardt U, Kruse FE, Koizumi N
    • Organizer
      The Association for Research in Vision and Ophthalmology 2017
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Involvement of p38 mitogen-activated protein kinase pathway in Fuchs endothelial corneal dystrophy.2017

    • Author(s)
      Onishi T, Okumura N, Hashimoto K, Koizumi N
    • Organizer
      The Association for Research in Vision and Ophthalmology 2017
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Fuchs角膜内皮ジストロフィにおけるmitochondria-associated membranesの病態への関与.2017

    • Author(s)
      奥田浩和, 奥村直毅, 松本紗季, Young Robert D, Quantock Andrew J, 小泉範子
    • Organizer
      角膜カンファランス2018第42回日本角膜学会総会・第34回日本角膜移植学会
    • Related Report
      2017 Research-status Report
  • [Presentation] Fuchs角膜内皮ジストロフィの治療薬開発を目指した薬剤スクリーニング法の確立.2017

    • Author(s)
      大西貴子, 奥村直毅, 上田江美, 渡辺恭子, Tourtas Theofilos, Schloetzer-Schrehardt Ursula, Kruse Friedrich E., 小泉範子
    • Organizer
      角膜カンファランス2018第42回日本角膜学会総会・第34回日本角膜移植学会
    • Related Report
      2017 Research-status Report
  • [Presentation] 基礎から臨床へ 角膜内皮トランスレーショナル研究2017

    • Author(s)
      小泉範子
    • Organizer
      第46回関西医科大学眼科同窓会春の勉強会
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] 角膜内皮治療の最前線2017

    • Author(s)
      小泉範子
    • Organizer
      北海道眼科医会北海道ブロック講習会
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] Translational research for corneal endothelial regeneration.2016

    • Author(s)
      Koizumi N
    • Organizer
      The 5th Biennial Scientific Meeting Asia Cornea Society
    • Place of Presentation
      ソウル(韓国)
    • Year and Date
      2016-12-10
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Unfolded protein accumulation induced endoplasmic reticulum stress of corneal endothelial cells in Fuchs endothelial corneal dystrophy.2016

    • Author(s)
      Okumura N, Hashimoto K, Kitahara M, Nakahara M, Kinoshita S, Tourtas T, Schloetzer-Schrehardt U, Kruse F, Koizumi N
    • Organizer
      The Association for Research in Vision and Ophthalmology
    • Place of Presentation
      シアトル(アメリカ合衆国)
    • Year and Date
      2016-05-03
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Remarks] 同志社大学ティッシュエンジニアリング研究室

    • URL

      http://www.tissue-engineering-doshisha.jp/

    • Related Report
      2018 Annual Research Report
  • [Remarks] 同志社大学生命医科学部医工学科ティッシュエンジニアリング研究室

    • URL

      http://tissue-engineering-doshisha.jp/

    • Related Report
      2017 Research-status Report 2016 Research-status Report
  • [Patent(Industrial Property Rights)] TGF-β阻害剤の新規スクリーニング法2018

    • Inventor(s)
      小泉範子, 奥村直毅
    • Industrial Property Rights Holder
      学校法人同志社
    • Industrial Property Rights Type
      特許
    • Filing Date
      2018
    • Related Report
      2018 Annual Research Report
    • Overseas
  • [Patent(Industrial Property Rights)] カスパーゼ阻害活性を有する化合物,これらの化合物を含む,角膜内皮の症状,障害または疾患を治療または予防するための医薬およびその応用2018

    • Inventor(s)
      小泉範子, 奥村直毅
    • Industrial Property Rights Holder
      学校法人同志社
    • Industrial Property Rights Type
      特許
    • Filing Date
      2018
    • Related Report
      2018 Annual Research Report
    • Overseas
  • [Patent(Industrial Property Rights)] mTORインヒビターを含む,眼の症状,障害または疾患を治療または予防するための医薬およびその応用2018

    • Inventor(s)
      小泉範子, 奥村直毅
    • Industrial Property Rights Holder
      学校法人同志社
    • Industrial Property Rights Type
      特許
    • Filing Date
      2018
    • Related Report
      2018 Annual Research Report
    • Overseas
  • [Patent(Industrial Property Rights)] TGF-β阻害剤の新規スクリーニング法2017

    • Inventor(s)
      小泉範子 奥村直毅
    • Industrial Property Rights Holder
      同志社大学
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2017-118615
    • Filing Date
      2017
    • Related Report
      2017 Research-status Report
  • [Patent(Industrial Property Rights)] カスパーゼ阻害活性を有する化合物、これらの化合物を含む、角膜内皮の症状、障害または疾患を治療または予防するための医薬およびその応用2017

    • Inventor(s)
      小泉範子 奥村直毅
    • Industrial Property Rights Holder
      同志社大学
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2018-053235
    • Filing Date
      2017
    • Related Report
      2017 Research-status Report
  • [Patent(Industrial Property Rights)] mTORインヒビターを含む、眼の症状、障害または疾患を治療または予防するための医薬およびその応用2017

    • Inventor(s)
      小泉範子 奥村直毅
    • Industrial Property Rights Holder
      同志社大学
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2017-118619
    • Filing Date
      2017
    • Related Report
      2017 Research-status Report

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Published: 2016-04-21   Modified: 2020-03-30  

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