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Unmet Needs in the Beyond VEGF Era: Macrophage Educational Therapy for Retinal Fibrosis and Ischemia

Research Project

Project/Area Number 17K11456
Research Category

Grant-in-Aid for Scientific Research (C)

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

Principal Investigator

Nakao Shintaro  九州大学, 医学研究院, 講師 (50583027)

Co-Investigator(Kenkyū-buntansha) 園田 康平  九州大学, 医学研究院, 教授 (10294943)
吉田 茂生  久留米大学, 医学部, 教授 (50363370)
Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywords糖尿病網膜症 / 加齢黄斑変性 / マクロファージ / 抗VEGF療法 / 炎症 / 網膜虚血 / 網膜下線維化 / シングルセル / 上皮間葉移行 / 細胞・組織 / 糖尿病 / トランスレーショナルリサーチ
Outline of Final Research Achievements

In a retinal ischemia mouse model, we observed infiltration of M1and M2 macrophages and increased expression of M1and M2 marker at mRNA level. We also observed that M1 macrophages were significantly present in the ischemic area. Gadolinium chloride, which mainly deletes M1 macrophages, was found to improve ischemia, suggesting that M1 macrophages could be a therapeutic target for retinal ischemia.
Fate mapping analysis in a subretinal fibrosis mouse model revealed that myofibroblast, which is a major component of fibrosis, is derived from RPE. The process involves epithelial-mesenchymal transition via ROCK suggesting that ROCK is a candidate drug for molecular target of subretinal fibrosis.

Academic Significance and Societal Importance of the Research Achievements

糖尿病網膜症や加齢黄斑変性などの網膜疾患は近年抗VEGF療法の汎用により失明を免れる症例も増えてきた。しかし、抗VEGF療法においても治癒しない網膜虚血、網膜下線維化は現在のUnmet needsと言える。本研究はこれらの細胞レベルでのメカニズムを一部明らかにした。また今後の治療開発への一助となると考える。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (21 results)

All 2020 2019 2018 2017

All Journal Article (12 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 10 results,  Open Access: 5 results) Presentation (9 results) (of which Int'l Joint Research: 8 results,  Invited: 1 results)

  • [Journal Article] Claudin-5 Redistribution Induced by Inflammation Leads to Anti-VEGF-Resistant Diabetic Macular Edema.2020

    • Author(s)
      Arima M, Nakao S, Yamaguchi M, Feng H, Fujii Y, Shibata K, Wada I, Kaizu Y, Ahmadieh H, Ishibashi T, Stitt AW, Sonoda KH.
    • Journal Title

      Diabetes

      Volume: 69 Issue: 5 Pages: 981-999

    • DOI

      10.2337/db19-1121

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Branch retinal artery occlusion in the untreated contralateral eye following aflibercept injections during heparin treatment: Possible contribution of a heparin-induced thrombocytopenia-like condition.2020

    • Author(s)
      Nakao S, Yoshimitsu M, Kaizu Y, Wada I, Yamaguchi M, Sonoda KH.
    • Journal Title

      Am J Ophthalmol Case Rep.

      Volume: 16 Pages: 100549-100549

    • DOI

      10.1016/j.ajoc.2019.100549

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Innate immune response in retinal homeostasis and inflammatory disorders.2020

    • Author(s)
      Murakami Y, Ishikawa K, Nakao S, Sonoda KH.
    • Journal Title

      Prog Retin Eye Res.

      Volume: 74 Pages: 100778-100778

    • Related Report
      2019 Annual Research Report
  • [Journal Article] Microaneurysm Imaging using Multiple En Face Optical Coherence Tomography Angiography Image Averaging: Morphology and Visualization2019

    • Author(s)
      Kaizu Y, Nakao S, Wada I, Arima M, Yamaguchi M, Ishikawa K, Akiyama M, Kishimoto J, Hisatomi T, Sonoda KH
    • Journal Title

      Ophthalmology Retina

      Volume: 4 Issue: 2 Pages: 175-186

    • DOI

      10.1016/j.oret.2019.09.010

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Flow Density in Optical Coherence Tomography Angiography is Useful for Retinopathy Diagnosis in Diabetic Patients.2019

    • Author(s)
      Kaizu Y, Nakao S, Arima M, Hayami T, Wada I, Yamaguchi M, Sekiryu H, Ishikawa K, Ikeda Y, Sonoda KH.
    • Journal Title

      Sci Rep.

      Volume: 9 Issue: 1 Pages: 8668-8668

    • DOI

      10.1038/s41598-019-45194-z

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] apillary Dropout is Dominant in Deep Capillary Plexus in Early Diabetic Retinopathy in Optical Coherence Tomography Angiography2018

    • Author(s)
      Kaizu Y, Nakao S*, Arima M, Wada I, Yamaguchi M, Sekiryu H, Hayami T, Ishikawa K, Ikeda Y, Sonoda KH.
    • Journal Title

      Acta Ophthalmol.

      Volume: 印刷中 Issue: 5

    • DOI

      10.1111/aos.14041

    • Related Report
      2019 Annual Research Report 2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Retinal flow density by optical coherence tomography angiography is useful for detection of nonperfused areas in diabetic retinopathy.2018

    • Author(s)
      Kaizu Y, Nakao S*,, Sekiryu H, Wada I, Yamaguchi M, Hisatomi T, Ikeda Y, Kishimoto J, Sonoda KH.
    • Journal Title

      Graefes Arch Clin Exp Ophthalmol.

      Volume: 256 Issue: 12 Pages: 2275-2282

    • DOI

      10.1007/s00417-018-4122-6

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Microaneurysm Detection in Diabetic Retinopathy using OCT Angiography May Depend on Intra-microaneurysm Turbulence.2018

    • Author(s)
      Nakao S*, Yoshida S, Kaizu Y, Yamaguchi M, Wada I, Ishibashi T, Sonoda KH.
    • Journal Title

      Ophthalmology Retina

      Volume: 2 Pages: 1171-1173

    • Related Report
      2018 Research-status Report
  • [Journal Article] Cathepsin B-mediated CD18 shedding regulates leukocyte recruitment from angiogenic vessels2018

    • Author(s)
      Nakao Shintaro、Zandi Souska、Sun Dawei、Hafezi-Moghadam Ali
    • Journal Title

      The FASEB Journal

      Volume: 32 Issue: 1 Pages: 143-154

    • DOI

      10.1096/fj.201601229r

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Imaging of Retinal Vascular Layers: Adaptive Optics Scanning Laser Ophthalmoscopy Versus Optical Coherence Tomography Angiography2017

    • Author(s)
      Kaizu Yoshihiro、Nakao Shintaro、Wada Iori、Yamaguchi Muneo、Fujiwara Kohta、Yoshida Shigeo、Hisatomi Toshio、Ikeda Yasuhiro、Hayami Takehito、Ishibashi Tatsuro、Sonoda Koh-hei
    • Journal Title

      Translational Vision Science & Technology

      Volume: 6 Issue: 5 Pages: 2-2

    • DOI

      10.1167/tvst.6.5.2

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Optical Coherence Tomography Angiography Reveals Spatial Bias of Macular Capillary Dropout in Diabetic Retinopathy2017

    • Author(s)
      Kaizu Yoshihiro、Nakao Shintaro、Yoshida Shigeo、Hayami Takehito、Arima Mitsuru、Yamaguchi Muneo、Wada Iori、Hisatomi Toshio、Ikeda Yasuhiro、Ishibashi Tatsuro、Sonoda Koh-Hei
    • Journal Title

      Investigative Opthalmology & Visual Science

      Volume: 58 Issue: 11 Pages: 4889-4889

    • DOI

      10.1167/iovs.17-22306

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Rho-Kinase/ROCK as a Potential Drug Target for Vitreoretinal Diseases2017

    • Author(s)
      Yamaguchi Muneo、Nakao Shintaro、Arima Mitsuru、Wada Iori、Kaizu Yoshihiro、Hao Feng、Yoshida Shigeo、Sonoda Koh-hei
    • Journal Title

      Journal of Ophthalmology

      Volume: 2017 Pages: 1-8

    • DOI

      10.1155/2017/8543592

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Local Proliferation of CD206+ CX3CR1+ Macrophages at the Vitreoretinal Interface in Diabetic Retinopathy2019

    • Author(s)
      Nakao S, Yamaguchi M, Wada I, Kaizu Y, Arima M, Ishikawa K, Nakama T, Shiraishi W, Yamasaki R, Kira J, Ishibashi T, Sonoda KH
    • Organizer
      ARVO
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Local Proliferation of Macrophages at the Vitreal Interface in Diabetic Retinopathy2019

    • Author(s)
      Nakao S
    • Organizer
      Aegean Retina XVI
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Hyperreflective membrane at Vitreoretinal Interface Contributes to Retinal Thickness in DME but not Response to IVR Therapy : A Ultra High-Resolution Optical Coherence Tomography Study2019

    • Author(s)
      Nakao S
    • Organizer
      The 12th Joint Meeting of Chinese-Japanese-Korean Ophthalmologists
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Microaneurysm Imaging using Multiple En Face OCTA Image Averaging: Morphology and Visualization2019

    • Author(s)
      Nakao S, Kaizu Y, Wada I, Arima M, Yamaguchi M, Ishikawa K, Akiyama M, Sonoda KH
    • Organizer
      52th Retina Society Meeting
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 糖尿病網膜症におけるCD206+CX3CR1+ 硝子体界面マクロファージ局所増殖2019

    • Author(s)
      山口宗男, 中尾新太郎, 和田伊織, 海津嘉弘, 有馬充, 石川桂二郎, 中間崇仁, 白石渉, 山崎亮, 吉良潤一, 石橋達朗, 園田康平
    • Organizer
      日本眼科学会総会
    • Related Report
      2018 Research-status Report
  • [Presentation] Microaneurysm Detection in Diabetic Retinopathy using OCT Angiography May Depend on Intra-microaneurysm Turbulence2018

    • Author(s)
      Nakao S, Yoshida S, Kaizu Y, Yamaguchi M, Wada I, Ishibashi T, Sonoda KH
    • Organizer
      Retina Society
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] OCT angiography detects re-dilation of choroidal neovasculatures before exudative recurrence in multifocal choroiditis with panuveitis: a case report2018

    • Author(s)
      Nakamura S, Nakao S, Shiose S, Kohno RI, Hasegawa E, Kano K, Kaizu Y, Seki E, Sonoda KH
    • Organizer
      The 11th Joint Meeting of Japan-China-Korea Ophthalmologists
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Microaneurysms Imaging in Diabetic Retinopathy using Multiple en face Optical Coherence Tomography Angiography Image Averaging2018

    • Author(s)
      Kaizu Y, Nakao S, Arima M, Wada I, Yoshitomi K, Sugino M, Hashiguchi N, Hirashima Kota, Sonoda KH
    • Organizer
      The 11th Joint Meeting of Japan-China-Korea Ophthalmologists
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] The evaluation of disease activity in exudative age-related macular degeneration using en face hyperreflective foci2018

    • Author(s)
      Wada I, Nakao S, Shiose S, Kaizu Y, Yamaguchi M, Arima M, Ishikawa K, Kano K, Oshima Yuji, Ishibashi T, Sonoda KH
    • Organizer
      The 11th Joint Meeting of Japan-China-Korea Ophthalmologists
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research

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Published: 2017-04-28   Modified: 2021-02-19  

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