Role of Neurovascular unit regulated by amacrine cells in refractory inflammatory eye diseases

• Project/Area Number: 16K11330
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Ophthalmology
• Research Institution: Tokyo Medical University
• Principal Investigator: Usui Yoshihiko 東京医科大学, 医学部, 講師 (50408142)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: ぶどう膜炎 / Neurovascular unit / ぶどう膜網膜炎 / アマクリン細胞 / 黄斑浮腫 / 難治性眼炎症性疾患 / microRNA / 液性因子 / 眼炎症疾患

Outline of Final Research Achievements

Because retinal amacrine cells and horizontal cells are present in the vicinity of intraretinal capillaries in the intermediate and deep plexuses, the amacrine cells and horizontal cells interact with the capillaries in the intermediate and deep plexuses of the retina and may contribute to stabilization of the vasculature. BRB failure causes damage to capillaries in the inner plexus of the retina due to functional failure of amacrine cells and horizontal cells present in the inner plexus of the retina. These are speculated to result in edema and visual function deterioration in inflammatory eye diseases.

Academic Significance and Societal Importance of the Research Achievements

Neurovascular unitは網膜疾患病態解明でも治療の面でも重要であり、神経および血管障害をきたす眼炎症性疾患では、アマクリンニューロンが制御するNeurovascular unit全体を治療標的とし、網膜血管の破綻を救済するneurovascular protectionという新たなコンセプトで、難治性眼炎症疾患以外の様々な網膜疾患（糖尿病網膜症、網膜静脈閉塞症、加齢黄斑変性症、未熟児網膜症など）の治療法も開発される可能性がある。

Research Products

• [Int'l Joint Research] スクリプス研究所(米国)
• [Journal Article] Corneal lymphangiogenesis ameliorates corneal inflammation and edema in late stage of bacterial keratitis. (2019)
  • Author(s): Narimatsu A, Hattori T, Koike N et al.
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 2984-2984
  • DOI: 10.1038/s41598-019-39876-x
  • Peer Reviewed / Open Access
• [Journal Article] Absence of Posterior Vitreous Detachment Is a Risk Factor of Severe Bleb-Related Endophthalmitis (2019)
  • Author(s): Umazume Kazuhiko、Suzuki Jun、Usui Yoshihiko、Maruyama Katsuhiko、Wakabayashi Yoshihiro、Goto Hiroshi
  • Journal Title: Journal of Ophthalmology Volume: 2019 Pages: 1-5
  • DOI: 10.1155/2019/1585830
  • Peer Reviewed / Open Access
• [Journal Article] miR-30a-5p inhibition promotes interaction of Fas+ endothelial cells and FasL+ microglia to decrease pathological neovascularization and promote physiological angiogenesis (2019)
  • Author(s): Murinello Salome、Usui Yoshihiko、Sakimoto Susumu、Kitano Maki、Aguilar Edith、Friedlander H. Maura、Schricker Amelia、Wittgrove Carli、Wakabayashi Yoshihiro、Dorrell Michael I.、Westenskow Peter D.、Friedlander Martin
  • Journal Title: Glia Volume: 67 Issue: 2 Pages: 332-344
  • DOI: 10.1002/glia.23543
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Punctate retinal pigment epitheliopathy and choroidopathy after radiotherapy with chemotherapy (2018)
  • Author(s): Usui Yo, Mizusawa T, Goto H
  • Journal Title: JAMA Ophthalmology Volume: 136 Issue: 8 Pages: e181754-e181754
  • DOI: 10.1001/jamaophthalmol.2018.1754
  • Peer Reviewed / Open Access
• [Journal Article] Evaluation of efficacy of infliximab for retinal vasculitis and extraocular symptoms in Beh?et disease (2018)
  • Author(s): Umazume Akihiko、Kezuka Takeshi、Usui Yoshihiko、Suzuki Jun、Goto Hiroshi
  • Journal Title: Japanese Journal of Ophthalmology Volume: 62 Issue: 3 Pages: 390-397
  • DOI: 10.1007/s10384-018-0589-2
  • Peer Reviewed
• [Journal Article] VEGF regulates local complement activity in the eye and kidney. (2017)
  • Author(s): Keir L, Firth R, Aponik L, Feitelberg D, Sakimoto S, Aguilar E, Welsh G, Richards A, Usui Y, Satchell S, Kuzmuk V, Goult J, Bull K, Sharma R, Bharti K, Westenskow PD, Michael I, Saleem M, Friedlander M.
  • Journal Title: J Clin Invest Volume: 1 Issue: 1 Pages: 199-214
  • DOI: 10.1172/jci86418
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CD44 expression in endothelial colony forming cells regulates neurovascular trophic effect. (2017)
  • Author(s): Sakimoto S, Marchetti V, Edith E, Lee K, Usui Y, Murinello S, Bucher F, Trombley JK, Fallon R, Wagey R, Peters C, Scheppke EL, Westenskow PD, Friedlander M.
  • Journal Title: JCI Insight Volume: 2 Issue: 2
  • DOI: 10.1172/jci.insight.89906
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Propionibacterium acnesas a possible pathogen of granuloma in patients with ocular sarcoidosis (2017)
  • Author(s): Goto Hiroshi、Usui Yoshihiko、Umazume Akihiko、Uchida Keisuke、Eishi Yoshinobu
  • Journal Title: British Journal of Ophthalmology Volume: 101 Issue: 11 Pages: 1510-1513
  • DOI: 10.1136/bjophthalmol-2016-309248
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Aqueous immune mediators in malignant uveal melanomas in comparison to benign pigmented intraocular tumors. (2017)
  • Author(s): Usui Y, Tsubota K, Agawa T, Ueda S, Umazume K, Okunuki Y, Kezuka T, Yamakawa N, Goto H.
  • Journal Title: Graefes Arch Clin Exp Ophthalmol Volume: 255 Issue: 2 Pages: 393-399
  • DOI: 10.1007/s00417-016-3541-5
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] 黄斑浮腫の病因 血液-網膜関門およびNeurovascular unitの破綻の観点より (2017)
  • Author(s): 臼井嘉彦
  • Journal Title: 眼科 Volume: 59 Pages: 399-405
  • NAID: 40021194111
• [Journal Article] Comprehensive polymerase chain reaction assay for detection of pathogenic DNA in lymphoproliferative disorders of the ocular adnexa. (2016)
  • Author(s): Usui Y, Rao NA, Takase H, Tsubota K, Umazume K, Diaz-Aguilar D, Kezuka T, Mochizuki M, Goto H, Sugita S.
  • Journal Title: Sci Rep Volume: 6 Issue: 1 Pages: 36621-36621
  • DOI: 10.1038/srep36621
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] 炎症病態における網膜神経―血管相互作用の障害 (2019)
  • Author(s): 臼井嘉彦
  • Organizer: 第123回日本眼科学会総会
  • Invited
• [Presentation] 免疫反応の場としての網膜～免疫学的アプローチを主軸とした難治性網膜硝子体疾患の病態解明～ (2017)
  • Author(s): 臼井嘉彦
  • Organizer: 第121回日本眼科学会総会
  • Invited
• [Presentation] 基礎から極める網膜血管機能解析 網膜血管における制御機構 ～Neurovascular unitの観点より～ (2017)
  • Author(s): 臼井嘉彦
  • Organizer: 第121回日本眼科学会総会
  • Invited
• [Presentation] 黄斑部毛細血管拡張症における網膜マイクログリアの役割 (2017)
  • Author(s): 臼井嘉彦、栗原俊英、崎元晋、後藤浩、Martin Friedlander
  • Organizer: 第５６回日本網膜硝子体学会
• [Presentation] β-catenin in retinal amacrine and horizontal interneurons is important for maintain stability of the retinal vasculature. (2016)
  • Author(s): Yoshihiko Usui, Toshihide Kurihara, Hiroshi Goto, Martin Friedlander
  • Organizer: 日本網膜硝子体学会
  • Place of Presentation: ベルサール渋谷
  • Year and Date: 2016-12-02
  • Invited
• [Presentation] Retinal microglia are critical for subretinal neovascularization in a murine model of macular telangiectasia (2016)
  • Author(s): Usui Y, Kurihara T, Goto H, Friedlander M.
  • Organizer: ISER
  • Place of Presentation: 東京
  • Year and Date: 2016-09-25
  • Int'l Joint Research / Invited
• [Presentation] β-catenin in retinal interneurons is important for maintain stability of the retinal microvasculature. (2016)
  • Author(s): Usui Y, Westenskow PD, Kurihara T, Aguilar E, Paris LP, Sakimoto S, Murinello S, Bucher F, Feitelberg D, Friedlander M.
  • Organizer: ARVO
  • Place of Presentation: シアトル
  • Year and Date: 2016-04-30
  • Int'l Joint Research