Kurihara, Toshihide



School of Medicine, Department of Ophthalmology (Shinanomachi)


Associate Professor

Profile 【 Display / hide

  • Toshihide Kurihara is an Associate Professor of Ophthalmology at Keio University, Tokyo, Japan. He has also been appointed as an Adjunct Assistant Professor at the Scripps Research Institute (TSRI) in La Jolla, CA, USA. He received his M.D. degree from the Faculty of Medicine, University of Tsukuba, Ibaraki, Japan, in 2001. He completed his ophthalmology residency at Keio University Hospital in 2005, and obtained his Ph.D. degree under the supervision of Professor Kazuo Tsubota from Keio University Graduate School of Medicine in 2009. Dr. Kurihara did his postdoctoral training under the mentorship of Professor Martin Friedlander at TSRI. His research interest is hypoxia responses in development, physiology, and pathophysiology of the retina. Editorial Board Member: BioMed Research International, Journal of Ophthalmology, and Case Reports in Ophthalmological Medicine

Career 【 Display / hide

  • 2001.04

    Keio University Hospital, Department of Ophthalmology, Resident

  • 2002.07

    National Kasumigaura Hospital, Department of Ophthalmology, Resident

  • 2003.04

    Keio University Hospital, Department of Ophthalmology, Clinical Fellow

  • 2004.01

    Tokyo Saiseikai Central Hospital, Ophthalmology, Clinical Fellow

  • 2005.04

    Keio University Graduate School of Medicine, Doctoral Course

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Academic Background 【 Display / hide

  • 1995.04

    University of Tsukuba, School of Medicine

    University, Graduated

  • 2005.04

    Keio University, Graduate School of Medicine

    Graduate School, Completed

Academic Degrees 【 Display / hide

  • PhD in Medicine, Keio University, Coursework, 2009.03

    Angiotensin 2 type 1 receptor signaling contributes to synaptophysin degradation and neuronal dysfunction in the diabetic retina


Research Areas 【 Display / hide

  • Life Science / Ophthalmology (Ophthalmology)


Papers 【 Display / hide

  • Scleral remodeling during myopia development in mice eyes: a potential role of thrombospondin-1

    Chen J*, Ikeda SI*, Yang Y, Zhang Y, Ma Z, Liang Y, Negishi K, Tsubota K†, Kurihara T†

    Mol Med. (Molecular Medicine)  30 ( 1 ) 25 2024.02

    Last author, Corresponding author, Accepted,  ISSN  10761551

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    Background: Scleral extracellular matrix (ECM) remodeling plays a crucial role in the development of myopia, particularly in ocular axial elongation. Thrombospondin-1 (THBS1), also known as TSP-1, is a significant cellular protein involved in matrix remodeling in various tissues. However, the specific role of THBS1 in myopia development remains unclear. Method: We employed the HumanNet database to predict genes related to myopic sclera remodeling, followed by screening and visualization of the predicted genes using bioinformatics tools. To investigate the potential target gene Thbs1, we utilized lens-induced myopia models in male C57BL/6J mice and performed Western blot analysis to detect the expression level of scleral THBS1 during myopia development. Additionally, we evaluated the effects of scleral THBS1 knockdown on myopia development through AAV sub-Tenon’s injection. The refractive status and axial length were measured using a refractometer and SD-OCT system. Results: During lens-induced myopia, THBS1 protein expression in the sclera was downregulated, particularly in the early stages of myopia induction. Moreover, the mice in the THBS1 knockdown group exhibited alterations in myopia development in both refraction and axial length changed compared to the control group. Western blotting analysis confirmed the effectiveness of AAV-mediated knockdown, demonstrating a decrease in COLA1 expression and an increase in MMP9 levels in the sclera. Conclusion: Our findings indicate that sclera THBS1 levels decreased during myopia development and subsequent THBS1 knockdown showed a decrease in scleral COLA1 expression. Taken together, these results suggest that THBS1 plays a role in maintaining the homeostasis of scleral extracellular matrix, and the reduction of THBS1 may promote the remodeling process and then affect ocular axial elongation during myopia progression.

  • Slowing of Greater Axial Length Elongation Stemming from the COVID-19 Pandemic with Increasing Time Outdoors: The Tokyo Myopia Study

    Yotsukura E, Torii H†, Mori K, Ogawa M, Hanyuda A, Negishi K, Kurihara T†, Tsubota K†

    Ophthalmol Sci. (Elsevier BV)     100491 - 100491 2024.02

    Corresponding author, Accepted,  ISSN  2666-9145

  • Deep Learning Segmentation of Non-perfusion Area from Color Fundus Images and AI-generated Fluorescein Angiography

    Masayoshi K*, Katada Y*, Ozawa N, Ibuki M, Negishi K, Kurihara T†

    Res Sq. (Research Square Platform LLC)     https://doi.org/10.21203/rs.3.rs-3871406/v1 2024.01

    Last author, Corresponding author

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    The non-perfusion area (NPA) of the retina is an important indicator in the visual prognosis of patients with retinal vein occlusion (RVO). However, the current evaluation method of NPA, fluorescein angiography (FA), is invasive and burdensome. In this study, we examined the use of deep learning models for detecting NPA in color fundus images, bypassing the need for FA, and we also investigated the utility of synthetic FA generated from color fundus images. The models were evaluated using the Dice score and Monte Carlo dropout uncertainty. We retrospectively collected 403 sets of color fundus and FA images from 319 RVO patients. We trained three deep learning models on FA, color fundus images, and synthetic FA. As a result, though the FA model achieved the highest score, the other two models also performed comparably. We found no statistical significance in median Dice scores between the models. However, the color fundus model showed significantly higher uncertainty than the other models (p < 0.05). In conclusion, deep learning models can detect NPAs from color fundus images with reasonable accuracy, though with somewhat less prediction stability. Synthetic FA stabilizes the prediction and reduces misleading uncertainty estimates by enhancing image quality.

  • Modulation of Hypoxia-Inducible Factors and Vascular Endothelial Growth Factor Expressions by Superfood Camu-Camu (Myrciaria dubia) Treatment in ARPE-19 and Fetal Human RPE Cells

    Nakai A, Lee D, Shoda C, Negishi K, Nakashizuka H, Yamagami S, Kurihara T†

    J Ophthalmol. (Hindawi Limited)  2023   6617981 2023.12

    Last author, Corresponding author, Accepted,  ISSN  2090-004X

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    Background. Anti-vascular endothelial growth factor (anti-VEGF) therapy via intravitreal injection is an effective treatment for patients with abnormal ocular neovascularization, such as age-related macular degeneration (AMD) and diabetic macular edema (DME). However, prolonged and frequent anti-VEGF treatment is associated with a risk of local and systemic adverse events, including geographic atrophy, cerebrovascular disease, and death. Furthermore, some patients do not adequately respond to anti-VEGF therapy. Hypoxia-inducible factor (HIF) is a transcription factor that controls the expression of hypoxia-responsive genes involved in angiogenesis, inflammation, and metabolism. The HIF/VEGF pathway plays an important role in neovascularization, and the inhibition of HIF activation could be an effective biomolecular target for neovascular diseases. The demand for disease prevention or treatment using functional foods such as superfoods has increased in recent years. Few reports to date have focused on the antineovascular effects of superfoods in the retinal pigment epithelium (RPE). In light of the growing demand for functional foods, we aimed to find novel HIF inhibitors from superfoods worked in RPE cells, which could be an adjuvant for anti-VEGF therapy. Methods. Seven superfoods were examined to identify novel HIF inhibitor candidates using luciferase assay screening. We used the human RPE cell line ARPE-19 and fetal human RPE (fhRPE) to investigate the biomolecular actions of novel HIF inhibitors using quantitative PCR and western blotting. Results. Under CoCl2-induced pseudohypoxic condition and 1% oxygen hypoxic incubation, camu-camu (Myrciaria dubia) showed HIF inhibitory effects determined by luciferase assays. Camu-camu downregulated HIF-1α and VEGFA mRNA expressions in a concentration-dependent manner. Camu-camu also inhibited HIF-1α protein expressions, and its inhibitory effect was greater than that of vitamin C, which is present at high levels in camu-camu. Conclusion. The camu-camu extract suppressed the activation of HIF and VEGF in RPE cells. This could assist anti-VEGF therapy in patients with abnormal ocular neovascularization.

  • Inhibition of hypoxia-inducible factors suppresses subretinal fibrosis

    Shoda C*, Lee D*, Miwa Y, Yamagami S, Nakashizuka H, Nimura K, Okamoto K, Kawagishi H, Negishi K, Kurihara T†

    bioRxiv. (Cold Spring Harbor Laboratory)     571193 2023.12

    Last author, Corresponding author

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    Age-related macular degeneration (AMD) is a common cause of vision loss. The aggressive form of AMD is associated with ocular neovascularization and subretinal fibrosis, representing a responsive outcome against neovascularization mediated by epithelial-mesenchymal transition of retinal pigment epithelium cells. A failure of the current treatment (anti-vascular endothelial growth factor therapy) has also been attributed to the progression of subretinal fibrosis. Hypoxia-inducible factors (HIFs) increase gene expressions to promote fibrosis and neovascularization. HIFs act as a central pathway in the pathogenesis of AMD. HIF inhibitors may suppress ocular neovascularization. Nonetheless, further investigation is required to unravel the aspects of subretinal fibrosis. In this study, we used RPE-specific HIFs or von Hippel-Lindau (VHL, a regulator of HIFs) conditional knockout (cKO) mice, along with pharmacological HIF inhibitors, to demonstrate the suppression of subretinal fibrosis. Fibrosis was suppressed by treatments of HIF inhibitors, and similar suppressive effects were detected in RPE-specific Hif1a/Hif2a- and Hif1a-cKO mice. Promotive effects were observed in RPE-specific Vhl-cKO mice, where fibrosis-mediated pathologic processes were evident. Marine products extracts and their component taurine suppressed fibrosis as HIF inhibitors. Our study shows critical roles of HIFs in the progression of fibrosis, linking them to the potential development of therapeutics for AMD.

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Papers, etc., Registered in KOARA 【 Display / hide

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Reviews, Commentaries, etc. 【 Display / hide

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Presentations 【 Display / hide

  • 網膜内長鎖脂肪酸アシルCoA合成酵素ACSL6欠損によるDHA代謝系の破綻と視細胞変性

    黒羽小羊子, 堅田侑作, 磯部洋輔, 内野春希, 宍倉匡祐, 根岸一乃, 栗原俊英, 有田誠



  • 光生物学を基盤とした 網膜疾患・近視進行抑制治療への取り組み




  • 分子・細胞レベルで理解する近視進行メカニズム




  • 光受容の進化の理解と眼疾患への応用


    第21回 群馬大学大学院医学系研究科・大学院生によるワークショップ「生体制御のこれまでと未来」, 


  • キメラロドプシンを用いた視覚再生技術の確立




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Research Projects of Competitive Funds, etc. 【 Display / hide

  • 非視覚型光受容体による光マルチセンシング機構の解明と光新規治療法開発


    国立研究開発法人日本医療研究開発機構(AMED), 令和4年度 「革新的先端研究開発支援事業(AMED-CREST)」, No Setting

  • 低酸素応答制御機能を持つ静岡県産魚類由来成分の探索と疾患制御に関する研究


    静岡県, マリンバイオテクノロジーを核としたシーズ創出研究業務委託 ¥286,800,000-, No Setting

  • 低酸素応答を標的とした予防から治療までを網羅する網膜疾患制御技術開発


    MEXT,JSPS, Grant-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (C), Principal investigator

  • Approach for retinal diseases based on regulation of hypoxia response


    MEXT,JSPS, Grant-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (C), Principal investigator

Awards 【 Display / hide

  • 第62回日本網膜硝子体学会総会優秀演題

    Ayaka Naka, Deokho Lee, Yan Zhang, Chiho Shoda, Satoshi Imanishi, Hiroyuki Nakashizuka, Satoru Yamagami, Kazuno Negishi, Akiharu Kubo, Toshihide Kurihara, 2023.11, 日本網膜硝子体学会, Claudin-1 deficiency in RPE leads to age-related retinal degeneration in mic

  • The Keio Medical Science Rising Star Award

    Toshihide Kurihara, 2023.01, Keio University, Exploring the pathophysiology of the retina and myopia based on photobiology and the clinical adaptation

  • 第72回日本臨床眼科学会学術展示優秀賞

    栗原俊英, 2019.04, 日本眼科学会, 白内障手術患者を対象とした血漿-房水グルコース濃度相関の血糖変動状態による変化

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    2018.04, ロート製薬株式会社, 低酸素応答を基軸としたトランスレーショナルリサーチの推進

  • 2016年度日本抗加齢医学会研究奨励賞

    2016.06, 日本抗加齢医学会, 低酸素応答の加齢黄斑変性における役割

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Memberships in Academic Societies 【 Display / hide

  • The Japanese Society for Photomedicine and Photobiology, 

  • 日本ロービジョン学会, 

  • 日本人類遺伝学会, 


Committee Experiences 【 Display / hide

  • 2022.11

    Associate Editor for Neurodegeneration, Frontiers in Neuroscience

  • 2022.10

    眼科 外来医長, 慶應義塾大学病院