Ikeda, Shin-ichi

写真a

Affiliation

School of Medicine, Department of Ophthalmology (Shinanomachi)

Position

Project Senior Assistant Professor (Non-tenured)/Project Assistant Professor (Non-tenured)/Project Lecturer (Non-tenured)

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Career 【 Display / hide 】

  • 2008.04
    -
    2014.03

    Juntendo University Graduate School of Medicine, Department of Metabolism & Endocrinology, Post-doctoral fellow

  • 2014.04
    -
    2016.03

    Graduate School of Medicine, The University of Tokyo, Department of Gerontological Nursing/Wound Care Management, Assistant Professor

  • 2016.04
    -
    2022.10

    Keio University School of Medicine, Laboratory of Photobiology, Department of Ophthalmology, Assistant Professor

  • 2022.11
    -
    Present

    Keio University School of Medicine, Department of Ophtalmology, Lecturer

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Academic Degrees 【 Display / hide 】

  • Ph.D., University of Tsukuba, Coursework, 2009.03

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Research Areas 【 Display / hide 】

  • Life Science / Ophthalmology (Myopia Biology)

  • Life Science / Physiology

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Research Keywords 【 Display / hide 】

  • Extracellular Matrix

  • cell-cell-communication

  • Tissue remodeling

  • Myopia

  • Myopia Biology

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Papers 【 Display / hide 】

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

    Chen J., Ikeda S.I., Yang Y., Zhang Y., Ma Z., Liang Y., Negishi K., Tsubota K., Kurihara T.

    Molecular Medicine 30 ( 1 ) 25 2024.12

    ISSN  10761551

    　View Summary

    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.

  • Ginkgo biloba extracts improve choroidal circulation leading to suppression of myopia in mice.

    Jing Hou, Kiwako Mori, Shin-Ichi Ikeda, Heonuk Jeong, Hidemasa Torii, Kazuno Negishi, Toshihide Kurihara, Kazuo Tsubota

    Scientific reports 13 ( 1 ) 3772 - 3772 2023.12

    　View Summary

    Myopia is becoming more common across the world, necessitating the development of preventive methods. We investigated the activity of early growth response 1 (EGR-1) protein and discovered that Ginkgo biloba extracts (GBEs) activated EGR-1 in vitro. In vivo, C57BL/6 J mice were fed either normal or 0.0667% GBEs (200 mg/kg) mixed chow (n = 6 each), and myopia was induced with - 30 diopter (D) lenses from 3 to 6 weeks of age. Refraction and axial length were measured by an infrared photorefractor and an SD-OCT system, respectively. In lens-induced myopia mice, oral GBEs significantly improved refractive errors (- 9.92 ± 1.53 D vs. - 1.67 ± 3.51 D, p < 0.001) and axial elongation (0.22 ± 0.02 mm vs. 0.19 ± 0.02 mm, p < 0.05). To confirm the mechanism of GBEs in preventing myopia progression, the 3-week-old mice were divided into normally fed with either myopic-induced or non-myopic-induced groups and GBEs fed with either myopic-induced or non-myopic-induced groups (n = 10 each). Choroidal blood perfusion was measured with optical coherence tomography angiography (OCTA). In both non-myopic induced groups, compared to normal chow, oral GBEs significantly improved choroidal blood perfusion (8.48 ± 15.75%Area vs. 21.74 ± 10.54%Area, p < 0.05) and expression of Egr-1 and endothelial nitric oxide synthase (eNOS) in the choroid. In both myopic-induced groups, compared to normal chow, oral GBEs also improved choroidal blood perfusion (- 9.82 ± 9.47%Area vs. 2.29 ± 11.84%Area, p < 0.05) and was positively correlated with the change in choroidal thickness. These findings suggest that GBEs may inhibit the progression of myopia by improving choroidal blood perfusion.

  • Establishment of a novel ER-stress induced myopia model in mice.

    Longdan Kang, Shin-Ichi Ikeda, Yajing Yang, Heonuk Jeong, Junhan Chen, Yan Zhang, Kazuno Negishi, Kazuo Tsubota, Toshihide Kurihara

    Eye and vision (London, England) 10 ( 1 ) 44 - 44 2023.12

    ISSN  2326-0254

    　View Summary

    BACKGROUND: Recent studies have indicated a strong correlation between endoplasmic reticulum (ER) stress and myopia and that eyedrops containing the ER stress inducer tunicamycin (Tm) can induce myopic changes in C57BL/6 J mice. Therefore, this study aimed to create a new myopia model using Tm eyedrops and to explore the mechanism of ER stress-mediated myopia development. METHODS: Three-week-old C57BL/6 J mice were treated with different concentrations (0, 25, 50, and 100 μg/mL) and/or number of applications (zero, one, three, and seven) of Tm eyedrops. Refraction and axial length (AL) were measured before and one week after Tm treatment. Scleral collagen alterations were evaluated under polarised light after picrosirius red staining. ER stress-related indicators, such as the expression of collagen I and cleaved collagen were detected using Western blotting. RESULTS: Compared with the control group, mice administered eyedrops with 50 μg/mL Tm only once showed the greatest myopic shifts in refraction and AL elongation and reduced scleral expression of collagen I. Picrosirius red staining showed a lower percentage of bundled collagen in the Tm group. Expression of ER-stress indicators increased in the Tm groups. Furthermore, optimised administration of Tm induced matrix metalloproteinase-2 (MMP2) expression in the sclera, which plays a major role in collagen degradation. CONCLUSIONS: We have demonstrated that ER stress in the sclera is involved in myopia progression. Tm eyedrops induced myopic changes, loosening of the scleral collagen and decreased expression of collagen I. This process may be associated with ER stress in the sclera, which upregulates the expression of MMP2 leading to collagen degradation.

  • The orientation of choroidal macrophage polarization significantly influences the development of myopia in murine models

    Jing Hou, Shin-ichi Ikeda, Kiwako Mori, Heonuk Jeong, Hidemasa Torii, Kazuno Negishi, Kazuo Tsubota, Toshihide Kurihara

    (Cold Spring Harbor Laboratory)   2023.06

    　View Summary

    Abstract

    Myopia is a primary contributor to visual impairment and has emerged as a global public health concern. Evidence indicates that one of the main structural features of myopia is the corresponding decrease in choroidal thickness, and choroidal macrophages play an important role in maintaining the choroidal thickness. Nevertheless, the effect of choroidal macrophages on myopia remains unclear. Here, we discovered that the continuous intraperitoneal injection of clodronate liposomes depleted choroidal macrophages and leads to myopia, which confirmed that the presence of choroidal macrophages plays an important role in myopia development.

    Subsequently, based on the phenotypic characteristics of macrophages, experiments were designed to study the effects of different polarization directions of macrophages on myopia development. We found that lipopolysaccharides (LPS) injection can induce the polarization of choroidal M1 macrophages and result in myopia. Conversely, IL-4 or IL-13 injection causes choroidal M2 macrophage polarization and suppresses the progression of myopia. Additionally, we demonstrated that the opposite effects of M1 and M2 macrophages on myopia development may be related to their impacts on inflammation and oxidative stress response. These findings establish that choroidal macrophages are critically important in the development of myopia and provide new strategies for the development of myopic therapies.

  • Contralateral effect in progression and recovery of lens-induced myopia in mice

    Ma Z., Jeong H., Yang Y., Jiang X., Ikeda S.i., Negishi K., Kurihara T., Tsubota K.

    Ophthalmic and Physiological Optics 43 ( 3 ) 558 - 565 2023.05

    ISSN  02755408

    　View Summary

    Purpose: Apart from genetic factors, recent animal studies on myopia have focused on localised mechanisms. In this study, we aimed to examine the contralateral effects of monocular experimental myopia and recovery, which cannot be explained by a mere local mechanism. Methods: One eye of 3-week-old C57BL/6 male mice was fitted with a −30 dioptre (D) lens. The mice were distributed into two groups based on different conditions in the contralateral eye: either no lens (NLC) (n = 10) or a Plano lens on the contralateral eye (PLC) group (n = 6). Mice receiving no treatment on either eye were set as a control group (n = 6). Lenses were removed after 3 weeks of myopia induction. All mice were allowed to recover for 1 week in the same environment. Refractive status, axial length (AL) and choroidal thickness were measured before myopia induction, after 1 and 3 weeks of lens wear and after 1 week of recovery. Results: One week after removing the lenses, complete recovery was observed in the eyes that wore the −30 D lenses. In both the PLC and NLC groups, the refractive status showed a myopic shift after lens removal. Additionally, the choroid was significantly thinned in these eyes. The −30 D wearing eye showed a significant increase in AL after 3 weeks of lens wear. While the AL of the −30 D wearing eye ceased to grow after the lens was removed, the AL in the PLC and NLC contralateral eyes increased, and the binocular ALs gradually converged. Conclusions: Recovery of lens-induced myopia was observed in mouse models. In the fellow eyes, the effects, including thinning of the choroid and changes in refractive status, were triggered by contralateral visual cues.

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

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Reviews, Commentaries, etc. 【 Display / hide 】

  • Regulatory mechanism of pathological axial elongation thorough UPR pathway

    池田真一, 池田真一, 栗原俊英, 栗原俊英, 姜効炎, 姜効炎, 森紀和子, 森紀和子, 堅田侑作, 堅田侑作, 國見洋光, 國見洋光, 三輪幸裕, 三輪幸裕, 小沢信博, 小沢信博, 伊吹麻里, 伊吹麻里, 正田千穂, 正田千穂, 鳥居秀成, 鳥居秀成, 坪田一男, 坪田一男

    日本眼科学会雑誌 125 2021

    ISSN  0029-0203

  • 東京都内小中学生における最新の近視有病率と近視関連環境因子

    四倉絵里沙, 四倉絵里沙, 鳥居秀成, 鳥居秀成, 井ノ口美香子, 井ノ口美香子, 徳村光昭, 徳村光昭, 内野美樹, 中村共生, 兵頭麻里, 森紀和子, 森紀和子, 姜効炎, 池田真一, 池田真一, 近藤眞一郎, 近藤眞一郎, 根岸一乃, 栗原俊英, 栗原俊英, 坪田一男

    日本眼光学学会総会プログラム・抄録集 56th 2020

  • マウス近視モデルにおけるクロセチンの近視抑制効果

    森紀和子, 栗原俊英, 石田文子, 姜效炎, 池田真一, 鳥居秀成, 坪田一男

    日本眼科学会雑誌 123 2019

    ISSN  0029-0203

  • バイオレットライト照射はマウス近視モデルにおける近視進行を抑制する

    姜 效炎, 栗原 俊英, 森 紀和子, 池田 真一, 汪 楊淞, 鳥居 秀成, 坪田 一男

    日本眼科学会雑誌 ((公財)日本眼科学会)  122 ( 臨増 ) 185 - 185 2018.03

    ISSN  0029-0203

  • マウスレンズ誘導近視モデルにおける強膜リモデリングに関する細胞間クロストーク

    池田 真一, 姜 效炎, 田中 康久, 森 紀和子, 宮内 真紀, 鳥居 秀成, 坪田 一男, 栗原 俊英

    日本眼科学会雑誌 ((公財)日本眼科学会)  121 ( 臨増 ) 323 - 323 2017.03

    ISSN  0029-0203

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

  • Myopia development and scleral ER stress

    2020.04
    -
    2023.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, 池田 真一, Grant-in-Aid for Scientific Research (C), Principal investigator

    　View Summary

    近年アジア圏を中心に近視保有者が急増しており、メディアで報道されるなど注目されている。近視は眼球の前後の長さである眼軸長が伸長することで生じるが眼軸が長いほど視覚障害の割合が増加することからその進行を抑制することが重要であるが効果的な抑制法・治療法が現存しない。本研究は近視眼では強膜（白目部分）において小胞体ストレスが生じていること、その抑制により近視進行がほぼ抑制されることを見出した。これは強膜小胞体ストレスへの介入により効果的な近視抑制・治療法を生み出せる可能性を示唆している。本研究は強膜小胞体ストレスと近視進行の関係を明らかにしその抑制法を生み出そうとするものである。
    近視進行に強膜小胞体ストレスの関与を申請者は明らかにしているが、小胞体ストレスがどのように眼軸伸長に関与するのかどうかを検証するのが２０２０年度の目的であった。これに対して、小胞体ストレスによって活性化されるIRE1 (Inositol Response Element 1) 、ATF6 (Activating Transcription Factor 6)、PERK (PKR-like endoplasmic reticulum kinase)の３つのセンサータンパク質から始まるUnfolding Protein Response経路の阻害剤の点眼投与を近視誘導期間中に行った。その結果、阻害剤の単剤投与ではむしろ近視を促進することがありこのことはUPR経路の抑制により他経路が代償的に活性化されて近視進行を促進したと考えられた。そこで２種混合投与試験を行ったところPERKとATF6経路の同時阻害によって近視進行が抑制され、この２経路が近視進行に関わることが示唆された。また２経路のアゴニストの点眼投与は近視進行を誘導した。またテノン嚢下に高濃度のAAVを投与することで強膜において遺伝子発現をON/OFFに方法を確立した。その方法を用いて、IRE1, PERK, ATF6をCRISPER/Cas9システムによりノックダウンするとPERKのノックダウンでは近視化が認められたのに対して、ATF６のノックダウンは近視化を抑制することが明らかとなった。ATF6阻害剤の点眼投与は非近視誘導眼においても近視が誘導された事実とATF6ノックダウン実験による近視進行抑制の事実との矛盾は今後の検討課題であるが、PERK, ATF6経路が近視進行に関与することが強く示唆される結果である。
    本年度の目標は近視進行に関わる小胞体ストレス下流のシグナル経路を特定することであった。遺伝子改変動物を使った試験を想定していたが、マウスのクリーン度の問題で本学動物施設に導入することができなかったが、その点は阻害剤・活性化剤を用いた試験を代わりに施行したことでカバーされたどころかむしろ遺伝子改変マウス実験からは得られなかったであろう知見も得られた。また、テノン嚢下注射による遺伝子発現制御法の確立は年度内に行うことができた。以上の結果から予定通り進展していると考える。
    次年度はAAVによる強膜遺伝子制御法を用いて複数遺伝子のノックダウン実験を行う。また、近視進行に関わるATF6, PERKの標的遺伝子を見出すためin silico解析をまず行い、その後そこから得られた遺伝子の発現解析、および遺伝子の過剰発現・欠損実験を行う。

  • Effect of violet light on myopia progression

    2019.04
    -
    2020.03

    Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, 石田 文子, 栗原 俊英, 池田 真一, Grant-in-Aid for Scientific Research (C), No Setting

    　View Summary

    近視はアジア圏において急速に増加し、その保有率は60～90%であると試算されている。しかしその発症における分子機序は明らかではなく、そのため有効な治療法が存在しない。申請者らはヒト・ヒヨコを用いた試験で360nm-400nm領域光（バイオレットライト、VL）には近視進行抑制効果があること、また申請者らが開発したマウス近視誘導モデルにおいて近視強膜ではマクロファージの増加および繊維芽細胞増殖が生じることを見出した。強膜における細胞構成の変化が近視発症の分子機序であり、VLによる近視進行抑制は強膜における細胞増殖を抑制することで生じると仮説し、この仮説の検証を本研究の目的とする。
    近視はアジア圏を中心に急速に広がっているが、その発症・進行の分子機序および効果的な予防方法が存在しない。現在までに唯一エビデンスレベルが高い予防法として屋外活動あるが、申請者は太陽光に含まれる360nm~400nm領域の光（バイオレットライト）が近視進行抑制へ関与を示唆する知見を得ており、その近視進行抑制効果について検証した。申請者は夏、快晴、北向きの屋外太陽光に含まれるVLのエネルギーを基準にし、レンズ誘導近視マウスへの照射実験を行った結果、VLの照射はマウス近視モデルの近視進行を完全に抑えることが確認された。また、自然の太陽光の中にに豊富に存在する赤、緑、青色の光をVLと同じエネルギーでマウスに照射し、近視進行抑制効果を比較した結果、VLの近視抑制効果が一番強いことが確認された。以上により、屋外環境光に存在するVLはマウスの近視進行を抑制することができ、その抑制効果は波長特異的であることが証明された。
    また、近視は眼球の前後方向の長さである眼軸長が伸長することで生じるが、この眼球形態の変化に関して申請者は強膜に着目し病理学的組織学的な検討を詳細に進めたところ、近視強膜では、強膜線維芽細胞の粗面小胞体が膨張していることを見出した。これは小胞体ストレスが生じている際の一つの傍証であることから、近視強膜では小胞体ストレスが生じていること、それば眼軸伸長に関わっている可能性が考えられた。

  • 骨格筋における免疫学的微小環境と筋機能

    2016.04
    -
    2019.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, 池田 真一, Grant-in-Aid for Scientific Research (B), Principal investigator

    　View Summary

    Quality of skeletal muscle is determined not only muscle function but also life span of individual. However, the question of what is "quality of skeletal muscle" is not answered currently. From my previous study, I hypothesized component of extracellular matrix (ECM) in basal lamina covered a skeletal muscle fiber is the substance of "quality of skeletal muscle". I compared between "good skeletal muscle" such as trained muscle and "bad skeletal muscle" such as denervated or diabetic muscle using qPCR array and identified Lamb3 gene as a muscle quality control gene. Lamb3 gene is poorly expressed in normal skeletal muscle and strongly induced during muscle hypertrophy and muscle regeneration. Lamb3 activates Akt pathway, resulting in muscle regeneration and hypertrophy. These results suggested that muscle ECM is an important internal environment and their manipulation can control muscle quality.

  • 運動による筋の質・量の変化におけるマクロファージ中心仮説

    2013.04
    -
    2016.03

    科学研究費補助金, 池田真一, 基盤研究（C）, Research grant, Principal investigator

  • 運動によるインスリン感受性亢進における筋‐マクロファージ間コミュニケーション

    2011.04
    -
    2013.03

    科学研究費補助金, 池田真一, 若手研究（B）, Research grant, Principal investigator

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Memberships in Academic Societies 【 Display / hide 】

  • Japanese Association for Food Immunology, 

    2023.08
    -
    Present

  • Japan Myopia Society, 

    2020.04
    -
    Present

  • Japanese Ophthalmological Society, 

    2017.04
    -
    Present
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