Development of comprehensive therapeutic storategies for diabetic retinopathy

• Project/Area Number: 15H04995
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Ophthalmology
• Research Institution: Kyushu University
• Principal Investigator: Tasturo Ishibashi 九州大学, 大学病院, 病院長 (30150428)
• Co-Investigator(Kenkyū-buntansha): 池田 康博 九州大学, 医学研究院, 准教授 (20380389) ; 星野 友 九州大学, 工学研究院, 准教授 (40554689) ; 吉田 茂生 九州大学, 大学病院, 助手 (50363370) ; 中尾 新太郎 九州大学, 大学病院, 講師 (50583027)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000); Fiscal Year 2017: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2016: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2015: ¥10,790,000 (Direct Cost: ¥8,300,000、Indirect Cost: ¥2,490,000)
• Keywords: 糖尿病網膜症 / ROCK / ペリオスチン / 線維化 / 透過性 / 血管内皮細胞 / テネイシンC / 上皮間葉移行 / SARA / Smad2/3 / バリアー機能 / リパスジル / 網膜血管新生 / 血管透過性 / プラスチック抗体

Outline of Final Research Achievements

We aimed to establish a novel molecular targeting therapy based on two important pathological conditions, retinal fibrovascular memmbrane formation and macular edema in diabetic retinopathy. We have clarified the involvement of tenascin-C whose expression is specifically enhanced in retinal fibrovascular proliferation. In addition, RNAi tarageting tenascin-C showed significant inhibitory effect on retinal fibrovascular proliferation. On the other hand, inflammatory cytokine stimulation including MCP-1, IL-6, TNF-a was performed after pre-administration of ROCK-inhibitor, Lipasdir, to the cultured vascular endothelial cells. The inhibiton of ROCK pathway resulted in a decrease in transendothelial electric resistance and claudin-5 expression. These results indicated that Lipasdir may inhibit disruption of barrier function by supressing inflammatory cytokines other than VEGF.

Research Products

• [Journal Article] Internal limiting membrane peeling-dependent retinal structural changes after vitrectomy in rhegmatogenous retinal detachment. (2017)
  • Author(s): Hisatomi T, Tachibana T, Notomi S, Koyanagi Y, Murakami Y, Takeda A, Ikeda Y, Yoshida S, Enaida H, Murata T, Sakamoto T,Sonoda KH, Ishibashi T:
  • Journal Title: Retina Volume: 38（3） Issue: 3 Pages: 471-479
  • DOI: 10.1097/iae.0000000000001558
  • Peer Reviewed
• [Journal Article] Different distributions of M1 and M2 macrophages in a mouse model of laser-induced choroidal neovascularization. (2017)
  • Author(s): Zhou Y, Yoshida S, Kubo Y, Yoshimura T, Kobayashi Y, Nakama T, Yamaguchi M, Ishikawa K, Oshima Y, Ishibashi T:
  • Journal Title: Mol Med Rep Volume: 15(6) Issue: 6 Pages: 3949-3656
  • DOI: 10.3892/mmr.2017.6491
  • Peer Reviewed / Open Access
• [Journal Article] Risk Factors for Posterior Subcapsular Cataract in Retinitis Pigmentosa. (2017)
  • Author(s): Fujiwara K, Ikeda Y, Murakami Y, Funatsu J, Nakatake S, Tachibana T, Yoshida N, Nakao S, Hisatomi T, Yoshida S,Yoshitomi T, Ishibashi T, Sonoda KH:
  • Journal Title: Invest Ophthalmol Vis Sci Volume: 58(5) Issue: 5 Pages: 2534-2537
  • DOI: 10.1167/iovs.17-21612
  • Peer Reviewed
• [Journal Article] Optical coherence tomography angiography of the macular microvasculature changes in retinitis pigmentosa. (2017)
  • Author(s): Koyanagi Y, Murakami Y, Funatsu J, Akiyama M, Nakatake S, Fujiwara K, Tachibana T, Nakao S, Hisatomi T, Yoshida S,Ishibashi T, Sonoda KH, Ikeda Y:
  • Journal Title: Acta Ophthalmol Volume: 96(1) Issue: 1
  • DOI: 10.1111/aos.13475
  • Peer Reviewed
• [Journal Article] C-Reactive protein and progression of vision loss in retinitis pigmentosa. (2017)
  • Author(s): Murakami Y, Ikeda Y, Nakatake S, Fujiwara K, Tachibana T, Yoshida N, Notomi S, Hisatomi T, Yoshida S, Ishibashi T, Sonoda KH:
  • Journal Title: Acta Ophthalmol Volume: 96(2) Issue: 2
  • DOI: 10.1111/aos.13502
  • Peer Reviewed
• [Journal Article] Comparación de la efectividad de ranibizumab intravítreo para el tratamiento del edema macular diabético en ojos vitrectomizados y no vitrectomizados. (2017)
  • Author(s): Koyanagi Y, Yoshida S, Kobayashi Y, Kubo Y, Yamaguchi M, Nakama T,Nakao S, Ikeda Y, Ohshima Y, Ishibashi T, Sonoda K:
  • Journal Title: Ophthalmologica Volume: 238 Issue: Suppl. 1 Pages: 21-27
  • DOI: 10.1159/000477513
  • Peer Reviewed
• [Journal Article] One-Year Outcomes following Intravitreal Aflibercept for Polypoidal Choroidal Vasculopathy in Japanese Patients: The APOLLO Study. (2017)
  • Author(s): Oshima Y, Kimoto K, Yoshida N, Fujisawa K, Sonoda S, Kubota T,Murata T, Sakamoto T, Yoshida S, Sonoda KH, Ishibashi T:
  • Journal Title: Ophthalmologica Volume: 238 Issue: 3 Pages: 163-171
  • DOI: 10.1159/000477448
  • Peer Reviewed
• [Journal Article] Low-frequency coding variants in CETP and CFB are associated with susceptibility of exudative age-related macular degeneration in the Japanese population. (2016)
  • Author(s): Momozawa Y, Akiyama M, Kamatani Y, Arakawa S, Yasuda M, Yoshida S, Oshima Y, Mori R, Tanaka K, Mori K, Inoue S, Terasaki H, Yasuma T, Honda S, Miki A, Inoue M, Fujisawa K, Takahashi K, Yasukawa T, Yanagi Y, Kadonosono K, Sonoda KH, Ishibashi T, Takahashi A, Kubo M.
  • Journal Title: Hum Mol Genet. Volume: 25 Pages: 5027-5034
  • DOI: 10.1093/hmg/ddw335
  • Peer Reviewed / Open Access
• [Journal Article] Interleukin-12 inhibits pathological neovascularization in mouse model of oxygen-induced retinopathy. (2016)
  • Author(s): Zhou Y, Ishibashi T
  • Journal Title: Sci Rep. Volume: 6 Issue: 1 Pages: 28140-28140
  • DOI: 10.1038/srep28140
  • Peer Reviewed / Open Access
• [Journal Article] Tenascin-C promotes angiogenesis in fibrovascular membranes in eyes with proliferative diabetic retinopathy (2016)
  • Author(s): Kobayashi Y,Ishibashi T.
  • Journal Title: Mol Vis. Volume: 22 Pages: 436-45
  • Peer Reviewed / Open Access
• [Journal Article] Tenascin-C secreted by transdifferentiated retinal pigment epithelial cells promotes choroidal neovascularization via integrin αV. (2016)
  • Author(s): Kobayashi Y,Ishibashi T.
  • Journal Title: Lab Invest. Volume: 96 Issue: 11 Pages: 1178-1188
  • DOI: 10.1038/labinvest.2016.99
  • Peer Reviewed
• [Journal Article] Comparison of the Effectiveness of Intravitreal Ranibizumab for Diabetic Macular Edema in Vitrectomized and Nonvitrectomized Eyes. (2016)
  • Author(s): Koyanagi Y,Ishibashi T.
  • Journal Title: Ophthalmologica Volume: 236 Issue: 2 Pages: 67-73
  • DOI: 10.1159/000446992
  • Peer Reviewed
• [Journal Article] Vascular Normalization by ROCK Inhibitor: Therapeutic Potential of Ripasudil (K-115) Eye Drop in Retinal Angiogenesis and Hypoxia. (2016)
  • Author(s): Yamaguchi M, Nakao S, Arita R, Kaizu Y, Arima M, Zhou Y, Kita T, Yoshida S, Kimura K, Isobe T, Kaneko Y, Sonoda KH, Ishibashi T.
  • Journal Title: Invest Ophthalmol Vis Sci Volume: 57 Issue: 4 Pages: 2264-2276
  • DOI: 10.1167/iovs.15-17411
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] M2 Macrophages Enhance Pathological Neovascularization in the Mouse Model of Oxygen-Induced Retinopathy. (2015)
  • Author(s): Zhou Y, Yoshida S, Nakao S, Yoshimura T, Kobayashi Y, Nakama T, Kubo Y, Miyawaki K, Yamaguchi M, Ishikawa K, Oshima Y, Akashi K, Ishibashi T.
  • Journal Title: Invest Ophthalmol Vis Sci Volume: ５６ Pages: 4767-77
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The REVEAL Study: Ranibizumab Monotherapy or Combined with Laser versus Laser Monotherapy in Asian Patients with Diabetic Macular Edema. (2015)
  • Author(s): Ishibashi T, Li X, Koh A, Lai TY, Lee FL, Lee WK, Ma Z, Ohji M, Tan N, Cha SB, Shamsazar J, Yau CL; REVEAL Study Group.
  • Journal Title: Ophthalmology Volume: 122 Issue: 7 Pages: 1402-15
  • DOI: 10.1016/j.ophtha.2015.02.006
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Plasma Kallikrein-Kinin System as a VEGF-Independent Mediator of Diabetic Macular Edema. (2015)
  • Author(s): Kita T, Clermont AC, Murugesan N, Zhou Q, Fujisawa K, Ishibashi T, Aiello LP, Feener EP.
  • Journal Title: Diabetes Volume: 64 Issue: 10 Pages: 3588-99
  • DOI: 10.2337/db15-0317
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] 糖尿病網膜症：最近の話題 (2017)
  • Author(s): 石橋達朗
  • Organizer: 第1回大阪眼科アカデミー
  • Place of Presentation: 大阪市
  • Year and Date: 2017-02-25
  • Invited
• [Presentation] 糖尿病黄斑浮腫 (2017)
  • Author(s): 石橋達朗
  • Organizer: 第5回西東京Ophthalmic Seminar
  • Invited
• [Presentation] 糖尿病黄斑浮腫 (2017)
  • Author(s): 石橋達朗
  • Organizer: 第10回高知RETINAフォーラム
  • Invited
• [Presentation] 網膜色素変性に対する新しい治療法開発～遺伝子治療を中心に～ (2016)
  • Author(s): 石橋達朗
  • Organizer: 平成28年度 中国四国眼科医会講習会
  • Place of Presentation: 広島市
  • Year and Date: 2016-07-17
  • Invited
• [Presentation] 糖尿病網膜症：病態解明と治療の進歩 (2016)
  • Author(s): 石橋達朗
  • Organizer: 第100回秋田県眼科集談会
  • Place of Presentation: 秋田市
  • Year and Date: 2016-04-16
  • Invited
• [Presentation] 糖尿病網膜症：病態解明と治療の進歩 (2016)
  • Author(s): 石橋達朗
  • Organizer: 第10回九州眼科アカデミー
  • Place of Presentation: 福岡市
  • Year and Date: 2016-03-19
  • Invited
• [Presentation] 糖尿病網膜症の早期診断とあらたな分子標的に関する研究 (2015)
  • Author(s): 石橋達朗
  • Organizer: 平成27年度日本糖尿病合併症学会
  • Place of Presentation: 名古屋市
  • Year and Date: 2015-11-27
  • Invited
• [Presentation] 糖尿病網膜症：最近の話題 (2015)
  • Author(s): 石橋達朗
  • Organizer: 2015年度九州大学病院 総合診療科同門会
  • Place of Presentation: 福岡市
  • Year and Date: 2015-11-08
  • Invited
• [Presentation] 糖尿病網膜症：最近の話題 (2015)
  • Author(s): 石橋達朗
  • Organizer: 第20回東海黄斑疾患研究会
  • Place of Presentation: 名古屋市
  • Year and Date: 2015-08-06
  • Invited