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Novel therapeutic targets regarding autoimmune neurodegeneration in diabetic retinopathy

Research Project

Project/Area Number 20K09788
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 University

Principal Investigator

Murakami Tomoaki  京都大学, 医学研究科, 講師 (50549095)

Co-Investigator(Kenkyū-buntansha) 大音 壮太郎  京都大学, 医学研究科, 講師 (10511850)
池田 華子  京都大学, 医学研究科, 特定准教授 (20372162)
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: ¥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: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords糖尿病網膜症 / 糖尿病黄斑虚血 / 網膜変性 / 細胞外小胞 / 細胞外ミトコンドリア / XRCC5, XRCC6 / 網膜色素上皮 / 糖尿病黄斑浮腫 / 自己免疫 / 橋渡し研究 / 微小小胞 / 神経変性 / 自己抗体 / OCT angiography / 抗fumarase抗体 / 抗hexokinase 1抗体 / 視細胞障害 / 光干渉断層計アンギオグラフィー / 補体
Outline of Research at the Start

(A) 抗網膜抗体のバイオマーカーとしての有用性   糖尿病網膜症における抗網膜抗体を包括的に同定し、獲得免疫が惹起されるメカニズムを絞り込む。また、これらの自己抗体のバイオマーカーとしての有用性を検討する。
(B) 自然免疫に関する臨床的プロファイリング   ヒトの自己免疫疾患における自然免疫で重要な役割を果たすDAMPs、PRR、インフラマソームを中心に、臨床サンプルにおける定量的評価を行う。
(C) 動物実験を用いた橋渡し研究   臨床サンプル中の自己抗体やDAMPを精製し、モデル動物に投与し、機能評価を行う。重要な分子メカニズムに関しては、治療標的となる可能性を検討する。

Outline of Final Research Achievements

We demonstrated that automatically quantified intercapillary spaces have clinical relevance in diabetic macular ischemia and hyperreflective walls in foveal cystoid spaces are a sign of diabetic macular edema refractory to anti-VEGF treatment. They might be designated as the candidates for the markers of neurovascular unit disturbance.
We investigated extracellular mitochondria as the stimulants of innate immunity and found that they induce cellular damage mediated via DNA. We further identified XRCC5 and XRCC6 as novel DNA receptors and demonstrated that the inhibition of the signal transduction from these molecules reversed cellular damage. It suggests that these molecules may be a novel therapeutic target.

Academic Significance and Societal Importance of the Research Achievements

本研究では、糖尿病網膜症における血管と神経の変性に関する臨床的特徴の一部を明らかにした。また、細胞外ミトコンドリアによる神経変性のメカニズムの一端を解明した。これらの結果は、現在治療方法が存在しない糖尿病による網膜変性の診断基準の確立と治療方法の探索に大きく寄与するものであった。また、網膜には免疫寛容があると従来考えられていたが、実際は、自然免疫と獲得免疫が生じうることを新たに見出し、寛容は相対的なものであることを明らかにしたことは、学術的意義が高い。

Report

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

    (33 results)

All 2023 2022 2021 2020

All Journal Article (22 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 22 results,  Open Access: 9 results) Presentation (11 results) (of which Invited: 2 results)

  • [Journal Article] Clinically Significant Nonperfusion Areas on Widefield OCT Angiography in Diabetic Retinopathy2023

    • Author(s)
      Kawai Kentaro、Murakami Tomoaki、Mori Yuki、Ishihara Kenji、Dodo Yoko、Terada Noriko、Nishikawa Keiichi、Morino Kazuya、Tsujikawa Akitaka
    • Journal Title

      Ophthalmology Science

      Volume: 3 Issue: 1 Pages: 100241-100241

    • DOI

      10.1016/j.xops.2022.100241

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Clinical Relevance of Parafoveal Intercapillary Spaces and Foveal Avascular Zone in Diabetic Retinopathy Without Macular Edema2022

    • Author(s)
      Terada Noriko、Murakami Tomoaki、Ishihara Kenji、Dodo Yoko、Nishikawa Keiichi、Kawai Kentaro、Tsujikawa Akitaka
    • Journal Title

      Investigative Opthalmology & Visual Science

      Volume: 63 Issue: 12 Pages: 4-4

    • DOI

      10.1167/iovs.63.12.4

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] MACULAR BLOOD FLOW CHANGES IN BRANCH RETINAL VEIN OCCLUSION EXAMINED BY OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY VARIABLE INTERSCAN TIME ANALYSIS2022

    • Author(s)
      Nishigori Naomi、Muraoka Yuki、Ishikura Masaharu、Kadomoto Shin、Mori Yuki、Numa Shogo、Murakami Tomoaki、Ooto Sotaro、Tsujikawa Akitaka
    • Journal Title

      Retina

      Volume: 42 Issue: 11 Pages: 2210-2217

    • DOI

      10.1097/iae.0000000000003596

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] DETECTION AND CHARACTERISTICS OF UNRUPTURED RETINAL ARTERIAL MACROANEURYSMS2022

    • Author(s)
      Sakaguchi Saori、Muraoka Yuki、Nishigori Naomi、Ishikura Masaharu、Kadomoto Shin、Miyata Manabu、Murakami Tomoaki、Ooto Sotaro、Tsujikawa Akitaka
    • Journal Title

      Retina

      Volume: 42 Issue: 10 Pages: 1909-1914

    • DOI

      10.1097/iae.0000000000003548

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Pigmentary lesions in eyes with rhegmatogenous retinal detachment with flap tears: a retrospective observational study2022

    • Author(s)
      Ideyama Midori、Muraoka Yuki、Kawai Kentaro、Ishikura Masaharu、Kadomoto Shin、Nishigori Naomi、Kameda Takanori、Ishihara Kenji、Miyata Manabu、Miyake Masahiro、Murakami Tomoaki、Ooto Sotaro、Tsujikawa Akitaka
    • Journal Title

      Scientific Reports

      Volume: 12 Issue: 1 Pages: 12470-12470

    • DOI

      10.1038/s41598-022-16508-5

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Factors predicting the treatment frequency of ranibizumab injections during the second year in diabetic macular edema2022

    • Author(s)
      Nishikawa Keiichi、Murakami Tomoaki、Ishihara Kenji、Dodo Yoko、Terada Noriko、Morino Kazuya、Tsujikawa Akitaka
    • Journal Title

      Japanese Journal of Ophthalmology

      Volume: 66 Issue: 3 Pages: 296-304

    • DOI

      10.1007/s10384-022-00905-4

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Foveal Thickness Fluctuation in Anti-VEGF Treatment for Branch Retinal Vein Occlusion: A Long-term Study2022

    • Author(s)
      Nagasato Daisuke、Muraoka Yuki、Tanabe Mao、Nishigori Naomi、Osaka Rie、Mitamura Yoshinori、Tabuchi Hitoshi、Kadomoto Shin、Murakami Tomoaki、Ooto Sotaro、Suzuma Kiyoshi、Tsujikawa Akitaka
    • Journal Title

      Ophthalmology Retina

      Volume: - Issue: 7 Pages: 567-574

    • DOI

      10.1016/j.oret.2022.02.008

    • Related Report
      2022 Annual Research Report 2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] The intercapillary space spectrum as a marker of diabetic retinopathy severity on optical coherence tomography angiography2022

    • Author(s)
      Terada Noriko、Murakami Tomoaki、Uji Akihito、Ishihara Kenji、Dodo Yoko、Nishikawa Keiichi、Morino Kazuya、Tsujikawa Akitaka
    • Journal Title

      Scientific Reports

      Volume: 12 Issue: 1 Pages: 3089-3089

    • DOI

      10.1038/s41598-022-07128-0

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Retinal arterial macroaneurysm rupture caused by dissection-like change in the vessel wall2022

    • Author(s)
      Ishikura Masaharu、Muraoka Yuki、Kadomoto Shin、Nishigori Naomi、Murakami Tomoaki、Ooto Sotaro、Tsujikawa Akitaka
    • Journal Title

      American Journal of Ophthalmology Case Reports

      Volume: 25 Pages: 101346-101346

    • DOI

      10.1016/j.ajoc.2022.101346

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Three-dimensional locations of ruptured retinal arterial macroaneurysms and their associations with the visual prognosis2022

    • Author(s)
      Sakaguchi Saori、Muraoka Yuki、Kadomoto Shin、Ooto Sotaro、Murakami Tomoaki、Nishigori Naomi、Ishikura Masaharu、Miyake Masahiro、Miyata Manabu、Uji Akihito、Tsujikawa Akitaka
    • Journal Title

      Scientific Reports

      Volume: 12 Issue: 1 Pages: 503-503

    • DOI

      10.1038/s41598-021-04500-4

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Peripheral Chorioretinal Imaging Through a Front Prism on Optical Coherence Tomography Angiography2021

    • Author(s)
      Kawai Kentaro、Murakami Tomoaki、Sakaguchi Saori、Yamada Tatsuya、Kadomoto Shin、Uji Akihito、Tsujikawa Akitaka
    • Journal Title

      Translational Vision Science & Technology

      Volume: 10 Issue: 14 Pages: 36-36

    • DOI

      10.1167/tvst.10.14.36

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Hemodynamic and structural changes in retinal arterial macroaneurysm after intravitreal anti-vascular endothelial growth factor injection2021

    • Author(s)
      Kadomoto Shin、Muraoka Yuki、Uji Akihito、Ooto Sotaro、Murakami Tomoaki、Tsujikawa Akitaka
    • Journal Title

      American Journal of Ophthalmology Case Reports

      Volume: 23 Pages: 101182-101182

    • DOI

      10.1016/j.ajoc.2021.101182

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] IMAGE EVALUATION OF ARTIFICIAL INTELLIGENCE SUPPORTED OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY IMAGING USING OCT-HS100 DEVICE IN DIABETIC RETINOPATHY2020

    • Author(s)
      Kawai K, Uji A, Murakami T, Kadomoto S, Oritani Y, Dodo Y, Muraoka Y, Akagi T, Miyata M, Tsujikawa A
    • Journal Title

      Retina

      Volume: 00 Issue: 8 Pages: 00-00

    • DOI

      10.1097/iae.0000000000003101

    • Related Report
      2021 Research-status Report 2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Factors associated with extremely poor visual outcomes in patients with central retinal vein occlusion2020

    • Author(s)
      Nagasato Daisuke、Muraoka Yuki、Osaka Rie、Iida-Miwa Yuko、Mitamura Yoshinori、Tabuchi Hitoshi、Kadomoto Shin、Murakami Tomoaki、Ooto Sotaro、Suzuma Kiyoshi、Tsujikawa Akitaka
    • Journal Title

      Scientific Reports

      Volume: 10 Issue: 1 Pages: 19667-19667

    • DOI

      10.1038/s41598-020-76840-6

    • NAID

      120007193759

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Intensive treat-to-target statin therapy and severity of diabetic retinopathy complicated by hypercholesterolaemia2020

    • Author(s)
      Murakami Tomoaki、for the ophthalmology substudy of EMPATHY Investigators、Kato Satoshi、Shigeeda Takashi、Itoh Hiroshi、Komuro Issei、Takeuchi Masahiro、Yoshimura Nagahisa
    • Journal Title

      Eye

      Volume: online ahead of print Issue: 8 Pages: 0-0

    • DOI

      10.1038/s41433-020-01202-5

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Review of clinical studies and recommendation for a therapeutic flow chart for diabetic macular edema2020

    • Author(s)
      Yoshida Shigeo、Murakami Tomoaki、Nozaki Miho、Suzuma Kiyoshi、Baba Takayuki、Hirano Takao、Sawada Osamu、Sugimoto Masahiko、Takamura Yoshihiro、Tsuiki Eiko
    • Journal Title

      Graefe's Archive for Clinical and Experimental Ophthalmology

      Volume: 259 Issue: 4 Pages: 815-836

    • DOI

      10.1007/s00417-020-04936-w

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Hyperreflective Walls in Foveal Cystoid Spaces as a Biomarker of Diabetic Macular Edema Refractory to Anti-VEGF Treatment2020

    • Author(s)
      Terada Noriko、Murakami Tomoaki、Uji Akihito、Dodo Yoko、Mori Yuki、Tsujikawa Akitaka
    • Journal Title

      Scientific Reports

      Volume: 10 Issue: 1 Pages: 7299-7299

    • DOI

      10.1038/s41598-020-64332-6

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Disproportion of lamellar capillary non-perfusion in proliferative diabetic retinopathy on optical coherence tomography angiography2020

    • Author(s)
      Uchitomi Daiki、Murakami Tomoaki、Dodo Yoko、Yasukura Shota、Morino Kazuya、Uji Akihito、Yoshitake Tatsuya、Fujimoto Masahiro、Tsujikawa Akitaka
    • Journal Title

      British Journal of Ophthalmology

      Volume: 104 Issue: 6 Pages: 857-862

    • DOI

      10.1136/bjophthalmol-2019-314743

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] ANGIOGRAPHIC RISK FACTORS FOR RECURRENCE OF MACULAR EDEMA ASSOCIATED WITH BRANCH RETINAL VEIN OCCLUSION2020

    • Author(s)
      Kogo Takahiro、Muraoka Yuki、Uji Akihito、Ooto Sotaro、Murakami Tomoaki、Kadomoto Shin、Iida-Miwa Yuko、Miyake Masahiro、Miyata Manabu、Tsujikawa Akitaka
    • Journal Title

      Retina

      Volume: Publish Ahead of Print Issue: 6 Pages: 0-0

    • DOI

      10.1097/iae.0000000000003026

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Ultrastructure and hemodynamics of microaneurysms in retinal vein occlusion examined by an offset pinhole adaptive optics scanning light ophthalmoscope2020

    • Author(s)
      Kadomoto S, Muraoka Y, Uji A, Tamiya R, Ooto S, Murakami T, Oritani Y, Kawai K, Tsujikawa A
    • Journal Title

      Biomed Opt Express

      Volume: 11 Issue: 11 Pages: 6078-6092

    • DOI

      10.1364/boe.402331

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] NONPERFUSION AREA QUANTIFICATION IN BRANCH RETINAL VEIN OCCLUSION2020

    • Author(s)
      KADOMOTO SHIN、MURAOKA YUKI、UJI AKIHITO、TAMIYA RYOSUKE、ORITANI YASUYUKI、KAWAI KENTARO、OOTO SOTARO、MURAKAMI TOMOAKI、IIDA-MIWA YUKO、TSUJIKAWA AKITAKA
    • Journal Title

      Retina

      Volume: Publish Ahead of Print Issue: 6 Pages: 0-0

    • DOI

      10.1097/iae.0000000000002999

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Effect of image averaging on optical coherence tomography angiography data in eyes with branch retinal vein occlusion2020

    • Author(s)
      Uji A, Sadda SR, Muraoka Y, Kadomoto S, Ooto S, Murakami T, Akagi T, Miyata M, Tsujikawa A
    • Journal Title

      Graefes Arch Clin Exp Ophthalmol

      Volume: 258 Issue: 8 Pages: 1639-1648

    • DOI

      10.1007/s00417-020-04713-9

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Presentation] 糖尿病黄斑浮腫におけるmicrovesicleによる網膜色素上皮障害2022

    • Author(s)
      西川 慶一, 村上 智昭, 石原 健司, 百々 蓉子, 寺田 紀子, 森野 数哉, 辻川 明孝
    • Organizer
      第126回日本眼科学会総会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 糖尿病網膜症におけるOCT angiographyでのintercapillary spaceと視力の関連2022

    • Author(s)
      村上 智昭, 寺田 紀子, 石原 健司, 百々 蓉子, 西川 慶一, 森野 数哉, 辻川 明孝
    • Organizer
      第126回日本眼科学会総会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 広角OCTAを用いた糖尿病網膜症における臨床的に重要な無灌流領域2022

    • Author(s)
      河合健太郎、村上智昭、森雄貴、石原健司、百々蓉子、寺田紀子、西川慶一、森野数哉、辻川明孝
    • Organizer
      第76回日本臨床眼科学会
    • Related Report
      2022 Annual Research Report
  • [Presentation] OCT angiographyを用いた糖尿病黄斑虚血の定量的診断の可能性2022

    • Author(s)
      村上智昭, 寺田紀子, 石原健司, 百々蓉子, 西川慶一, 河合健太郎, 和田沙織, 谷垣裕子, 辻川明孝
    • Organizer
      第76回日本臨床眼科学会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 糖尿病黄斑浮腫における細胞外ミトコンドリアによるDNA依存性の網膜障害2022

    • Author(s)
      西川 慶一, 村上 智昭, 石原 健司, 百々 蓉子, 寺田 紀子, 森野 数哉, 辻川 明孝
    • Organizer
      第28回日本糖尿病眼学会総会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 糖尿病網膜症における硝子体中の細胞外ミトコンドリアのDNA量と臨床所見2022

    • Author(s)
      西川 慶一, 村上 智昭, 石原 健司, 百々 蓉子, 寺田 紀子, 辻川 明孝
    • Organizer
      第61回日本網膜硝子体学会総会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 糖尿病黄斑浮腫におけるOCT angiography画像上のflow signalの自動検出2022

    • Author(s)
      寺田紀子, 村上智昭, 石原健司, 西川慶一, 和田沙織, 谷垣裕子, 辻川明孝
    • Organizer
      第61回日本網膜硝子体学会総会
    • Related Report
      2022 Annual Research Report
  • [Presentation] ラニビズマブ硝子体投与後の糖尿病黄斑浮腫寛解の予測因子2020

    • Author(s)
      村上 智昭, 宇治 彰人, 百々 蓉子, 寺田 紀子, 森 雄貴, 辻川 明孝
    • Organizer
      第124回日本眼科学会総会
    • Related Report
      2020 Research-status Report
  • [Presentation] 糖尿病黄斑浮腫に対する抗VEGF療法2020

    • Author(s)
      村上智昭
    • Organizer
      第124回日本眼科学会総会
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] 眼底イメージングからはじめる糖尿病網膜症研究2020

    • Author(s)
      村上智昭
    • Organizer
      第124回日本眼科学会総会
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] プリズムレンズを用いたOCT angiography撮影による周辺部網膜の微小循環の評価2020

    • Author(s)
      河合健太郎 村上智昭 山田達矢 阪口沙織 宇治彰人 村岡勇貴 加登本伸 宮澤隆史 辻川明孝
    • Organizer
      第59回日本網膜硝子体学会総会
    • Related Report
      2020 Research-status Report

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

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