Retinal Vascular Regeneration by Rectifying Angiogenic Directions

• Project/Area Number: 22689046
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Ophthalmology
• Research Institution: Kobe University
• Principal Investigator: UEMURA Akiyoshi 神戸大学, 大学院・医学研究科, 特命助教 (30373278)
• Co-Investigator(Renkei-kenkyūsha): FUKUSHIMA Yoko 神戸大学, 大学院・医学研究科, 研究員 (70647031)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥25,740,000 (Direct Cost: ¥19,800,000、Indirect Cost: ¥5,940,000); Fiscal Year 2012: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2011: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2010: ¥15,210,000 (Direct Cost: ¥11,700,000、Indirect Cost: ¥3,510,000)
• Keywords: 血管新生 / 内皮細胞 / 糸状仮足 / Sema3E / PlexinD1 / RhoJ / Arhgef15 / VEGF / VEGFR2 / Cdc42 / セマフォリン3E / プレキシンD1 / 網膜血管新生 / 虚血性網膜症

Research Abstract

We attempted to develop a modality by which angiogenic directions are rectified in ischemic retinopathy. During development, binding of neuron-derived Sema3E to endothelial PlexinD1 activated RhoJ, thereby retracting disoriented angiogenesis. In a mouse model of ischemic retinopathy, intravitreal injections of Sema3E protein selectively prevented disoriented angiogenesis without affecting retinal vascular regeneration. Theses results present a new paradigm of vascular regeneration therapy that guides new blood vessels toward the ischemic retinas.

Research Products

• [Journal Article] Arhgef15 promotes retinal angiogenesis by mediating VEGF-induced Cdc42 activation and potentiating RhoJ inactivation in endothelial cells. (2012)
  • Author(s): Kusuhara S., Fukushima Y., Fukuhara S., Jakt L.M., Okada M., Shimizu Y., Hata M., Nishida K., Negi A., Hirashima M., Mochizuki N., Nishikawa S. and Uemura A.
  • Journal Title: PLoS One Volume: 7 Issue: 9 Pages: e45858-e45858
  • DOI: 10.1371/journal.pone.0045858
  • Peer Reviewed
• [Journal Article] Angiopoietin-2 differentially regulates angiogenesis through Tie2 and integrin signaling (2012)
  • Author(s): Felcht M, Luck R, Schering A, Seidel P, Srivastava K, Hu J, Bartol A, Kienast Y, Vettel C, Loos EK, Kutschera S, Bartels S, Appak S, Besemfelder E, Terhardt D, Chavakis E, Wieland T, Klein C, Thomas M, Uemura A, Goerdt S, Augustin HG
  • Journal Title: J Clin Invest Volume: 122 Pages: 1991-2005
  • Peer Reviewed
• [Journal Article] Endosomal sorting by Semaphorin 4A in retinal pigment epithelium supports photoreceptor survival (2012)
  • Author(s): Toyofuku T, Nojima S, Ishikawa T, Takamatsu H, Tsujimura T, Uemura A, Matsuda J, Seki T, Kumanogoh A
  • Journal Title: Genes Dev Volume: 26 Pages: 816-829
  • Peer Reviewed
• [Journal Article] The sphingosine-1-phosphate transporter Spns2 expressed on endothelial cells regulates lymphocyte trafficking in mice (2012)
  • Author(s): Fukuhara S, Simmons S, Kawamura S, Inoue A, Orba Y, Tokudome T, Sunden Y, Arai Y, Moriwaki K, Ishida J, Uemura A, Kiyonari H, Abe T, Fukamizu A, Hirashima M, Sawa H, Aoki J, Ishii M, Mochizuki N
  • Journal Title: J Clin Invest Volume: 122 Pages: 1416-1426
  • Peer Reviewed
• [Journal Article] FGD5 mediates pro-angiogenic action of vascular endothelial growth factor in human vascular endothelial cells (2012)
  • Author(s): Kurogane Y, Miyata M, Kubo Y, Nagamatsu Y, Kundu RK, Uemura A, Ishida T, Quertermous T, Hirata K, Rikitake Y
  • Journal Title: Arterioscler Thromb Vasc Biol Volume: 32 Pages: 988-996
  • Peer Reviewed
• [Journal Article] Endosomal sorting by Semaphorin 4A in retinal pigment epithelium supports photoreceptor survival. (2012)
  • Author(s): Toyofuku T, Nojima S, Ishikawa T, Takamatsu H, Tsujimura T, Uemura A, Matsuda J, Seki T, Kumanogoh A
  • Journal Title: Genes Dev Volume: 26 Issue: 8 Pages: 816-829
  • DOI: 10.1101/gad.184481.111
  • Peer Reviewed
• [Journal Article] Angiopoietin-2 differentially regulates angiogenesis through Tie2 and integrin signaling. (2012)
  • Author(s): Felcht M, （他18名）, Uemura A, Goerdt S, Augustin HG
  • Journal Title: J Clin Invest Volume: 122 Issue: 6 Pages: 1991-2005
  • DOI: 10.1172/jci58832
  • Peer Reviewed
• [Journal Article] The sphingosine-1-phosphate transporter Spns2 expressed on endothelial cells regulates lymphocyte trafficking in mice (2012)
  • Author(s): Fukuhara S, et al
  • Journal Title: J Clin Invest Volume: (印刷中)(掲載確定)
  • Peer Reviewed
• [Journal Article] FGD5 mediates proangiogenic action of vascular endothelial growth factor in human vascular endothelial cells (2012)
  • Author(s): Kurogane Y, et al
  • Journal Title: Arterioscler Thromb Vasc Biol Volume: (印刷中)(掲載確定)
  • Peer Reviewed
• [Journal Article] selectively suppresses disoriented angiogenesis in ischemic retinopathy in mice (2011)
  • Author(s): Fukushima Y, Okada M, Kataoka H, Hirashima M, Yoshida Y, Mann F, Gomi F, Nishida K, Nishikawa S, Uemura A
  • Journal Title: J Clin Invest Volume: 121 Pages: 1974-1985
  • Peer Reviewed
• [Journal Article] Sema3E-PlexinD1 signaling selectively suppresses disoriented angiogenesis in ischemic retinopathy in mice. (2011)
  • Author(s): Fukushima Y, Okada M, Kataoka H, Hirashima M, Yoshida Y, Mann F, Gomi F, Nishida K, Nishikawa S, Uemura A.
  • Journal Title: J Clin Invest. Volume: (印刷中)
  • NAID: 40019951919
  • Peer Reviewed
• [Journal Article] Inhibition of semaphorin as a novel strategy for therapeutic angiogenesis (2010)
  • Author(s): Moriya J, Minamino T, Tateno K, Okada S, Uemura A, Shimizu I, Yokoyama M, Nojima A, Okada M, Koga H, Komuro I
  • Journal Title: Circ Res Volume: 106 Pages: 391-398
  • Peer Reviewed
• [Journal Article] 網膜血管新生におけるガイダンス分子の役割 (2010)
  • Author(s): 植村明嘉
  • Journal Title: 日本臨床 Volume: 68 Pages: 349-353
• [Journal Article] 網膜における生理的血管発生と病的血管新生 (2010)
  • Author(s): 植村明嘉
  • Journal Title: 実験医学 Volume: 28 Pages: 2825-2830
• [Journal Article] MRP4 knockdown enhances migration, suppresses apoptosis, and produces aggregated morphology in human retinal vascular endothelial cells. (2010)
  • Author(s): Tagami M, Kusuhara S, Imai H, Uemura A, Honda S, Tsukahara Y, Negi A.
  • Journal Title: Biochem Biophys Res Commun. Volume: 400 Pages: 593-598
  • Peer Reviewed
• [Journal Article] Pharmacological treatment of retinopathy of prematurity : anti-angiogenic or pro-angiogenic? (2010)
  • Author(s): Uemura A.
  • Journal Title: Expert Rev Ophthalmol. Volume: 5 Pages: 123-127
• [Journal Article] EphrinB2-EphB4 signals regulate formation and maintenance of funnel-shaped valves in corneal lymphatic capillaries
  • Author(s): Katsuta H, Fukushima Y, Maruyama K, Hirashima M, Nishida K, Nishikawa S, Uemura A
  • Journal Title: nvest Ophthalmol Vis Sci Volume: (in press)
  • Peer Reviewed
• [Presentation] RhoJ integrates VEGF and Sema3E signals in angiogenic endothelial cells. (2013)
  • Author(s): Uemura A
  • Organizer: 26th Spring Congress of the Korean Diabetes Association & 1st Korea-Japan Diabetes Forum
  • Place of Presentation: 韓国
  • Invited
• [Presentation] Mouse retinal angiogenesis as a model system of diabetic retinopathy (2012)
  • Author(s): Uemura A
  • Organizer: 2012 International Conference on Diabetes and Metabolism
  • Place of Presentation: 韓国
  • Year and Date: 2012-11-08
• [Presentation] 網膜症における血管新生 (2012)
  • Author(s): 植村明嘉
  • Organizer: 第27回日本糖尿病合併症学会シンポジウム
  • Place of Presentation: 福岡
  • Year and Date: 2012-11-02
• [Presentation] The small GTPase RhoJ mediates Sema3E-induced contraction of 2nd endothelial cells (2012)
  • Author(s): Uemura A
  • Organizer: Pacific Society of Vascular Biology
  • Place of Presentation: 韓国
  • Year and Date: 2012-10-31
• [Presentation] Arhgef15 promotes angiogenesis by mediating VEGF-induced Cdc42 activation and potentiating RhoJ inactivation in endothelial cells. (2012)
  • Author(s): Uemura A
  • Organizer: 17th International Vascular Biology Meeting
  • Place of Presentation: ドイツ
  • Year and Date: 2012-09-17
• [Presentation] RhoJ regulates endocytic trafficking of VEGFR2 and PlexinD1 in endothelial cells (2012)
  • Author(s): Uemura A
  • Organizer: 7th International Kloster Seeon Angiogenesis Meeting
  • Place of Presentation: ドイツ
  • Year and Date: 2012-06-04
• [Presentation] 眼内血管新生病の治療における新規創薬標的分子の同定 (2012)
  • Author(s): 植村明嘉
  • Organizer: 第89回日本生理学会大会シンポジウム
  • Place of Presentation: 松本
  • Year and Date: 2012-03-30
• [Presentation] Identification of novel drug target molecules for the treatment of ocular neoangiogenesis (2012)
  • Author(s): 植村明嘉
  • Organizer: 第89回日本生理学会大会
  • Place of Presentation: 松本文化会館(長野県)(招待講演)
  • Year and Date: 2012-03-30
• [Presentation] RhoJ mediates Sema3E-induced contraction of endothelial cells (2012)
  • Author(s): Uemura A
  • Organizer: Keystone Symposia. Angiogenesis: Advances in Basic Science andTherapeutic Applications
  • Place of Presentation: 米国
  • Year and Date: 2012-01-17
• [Presentation] RhoJ Mediates Sema3E-Induced Contraction of Endothelial Cells (2012)
  • Author(s): Uemura A
  • Organizer: Keystone Symnposia. Angiogenesis
  • Place of Presentation: Snowbird Resort Snowbird, Utah USA
  • Year and Date: 2012-01-17
• [Presentation] Mouse retinal angiogenesis as a model system of diabetic retinopathy. (2012)
  • Author(s): Uemura A
  • Organizer: International Conference on Diabetes and Metabolism
  • Place of Presentation: 韓国
  • Invited
• [Presentation] RhoJ regulates endocytic trafficking of VEGFR2 and PlexinD1 in endothelial cells. (2012)
  • Author(s): Uemura A
  • Organizer: 7th International Kloster Seeon Angiogenesis Meeting
  • Place of Presentation: ドイツ
• [Presentation] Arhgef15 promotes angiogenesis by mediating VEGF-induced Cdc42 activation and potentiating RhoJ inactivation in endothelial cells (2012)
  • Author(s): Uemura A
  • Organizer: 17th International Vascular Biology Meeting
  • Place of Presentation: ドイツ
• [Presentation] RhoJによる内皮細胞運動の制御 (2012)
  • Author(s): 植村明嘉
  • Organizer: 第21回日本血管生物医学会
  • Place of Presentation: 大阪
  • Invited
• [Presentation] 網膜症における血管新生 (2012)
  • Author(s): 植村明嘉
  • Organizer: 第27回日本糖尿病合併症学会
  • Place of Presentation: 福岡
  • Invited
• [Presentation] Identification of G protein-related genes in angiogenic endothelial cells (2011)
  • Author(s): 植村明嘉
  • Organizer: 第19回日本血管生物医学会シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2011-12-09
• [Presentation] Identification of G protein-related genes in angiogenic endothelial cells (2011)
  • Author(s): 植村明嘉
  • Organizer: 第19回日本血管生物医学会
  • Place of Presentation: 東京ステーションコンファレンス(東京都)(招待講演)
  • Year and Date: 2011-12-09
• [Presentation] 網膜血管の再生 (2011)
  • Author(s): 植村明嘉
  • Organizer: 第50回日本網膜硝子体学会総会シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2011-12-04
• [Presentation] 網膜血管の再生 (2011)
  • Author(s): 植村明嘉
  • Organizer: 第50回日本網膜硝子体学会総会
  • Place of Presentation: 東京国際フォーラム(東京都)(招待講演)
  • Year and Date: 2011-12-04
• [Presentation] The small GTPase RhoJ mediates Sema3E-induced contraction of endot helial cells (2011)
  • Author(s): Uemura A
  • Organizer: The Second Pacific Symposium on Vascular Biology
  • Place of Presentation: Shilla Hotel(韓国)(招待講演)
  • Year and Date: 2011-10-31
• [Presentation] Sema3E-PlexinD1 signaling selectively suppresses disoriented angiogenesis in ischemic retinopathy 9th in mice (2011)
  • Author(s): Uemura A
  • Organizer: Korea-Japan Joint Symposium on Vascular Biology
  • Place of Presentation: 韓国
  • Year and Date: 2011-08-26
• [Presentation] Sema3E-PlexinD1 signaling selectively suppresses disoriented angiogenes is in ischemic retinopathy in mice (2011)
  • Author(s): Uemura A
  • Organizer: The 9^<th> Korea-Japan Joint Symposium on Vascular Biology
  • Place of Presentation: Shilla Hotel(韓国)(招待講演)
  • Year and Date: 2011-08-26
• [Presentation] 新生血管内皮細胞に発現する新規遺伝子の同定 (2011)
  • Author(s): 植村明嘉
  • Organizer: 第115回日本眼科学会総会
  • Place of Presentation: 東京国際フォーラム(東京都)(招待講演)
  • Year and Date: 2011-05-12
• [Presentation] Restoration of angiogenic directions in ischemic retinopathy (2011)
  • Author(s): 植村明嘉
  • Organizer: 第36回日本微小循環学会シンポジウム
  • Place of Presentation: 名古屋市立大学病院(愛知県)(招待講演)
• [Presentation] 糖尿病網膜症における血管再生療法の開発 (2010)
  • Author(s): 植村明嘉
  • Organizer: 第2回京都糖尿病眼合併症フォーラム
  • Place of Presentation: 芝蘭会館(京都府)(招待講演)
  • Year and Date: 2010-09-10
• [Presentation] How to promote regeneration of functional capillaries in the ischemic retina (2010)
  • Author(s): Uemura A
  • Organizer: World Ophthalmology Congress
  • Place of Presentation: ドイツ
  • Year and Date: 2010-06-07
• [Presentation] How to promote regeneration of functional capillaries in the ischemic retina. (2010)
  • Author(s): Uemura A.
  • Organizer: World Ophthalmology Congress
  • Place of Presentation: ベルリン(ドイツ)(招待講演)
• [Presentation] Sema3E-PlexinD1 signaling facilitates vascular regeneration by selectively suppressing disoriented angiogenesis in a mouse model of ischemic retinopathy. (2010)
  • Author(s): Uemura A, Hirashima M, Yoshida Y, Mann F, Nishikawa S
  • Organizer: 6^<th> International Kloster Seeon Meeting 'Angiogenesis'
  • Place of Presentation: ゼーオン市(ドイツ)
• [Presentation] Sema3E-PlexinD1 signaling facilitates vascular regeneration in ischemic retina by selectively suppressing disoriented angiogenesis. (2010)
  • Author(s): Uemura A, Fukushima Y, Nishikawa S
  • Organizer: ARVO Annual Meeting
  • Place of Presentation: フォートローダーデール市(米国)
• [Book] 血管新生研究の最先端 (2013)
  • Author(s): 植村明嘉
  • Publisher: 医薬ジャーナル社
• [Book] 血管新生研究の最先端「Semaphorin-Plexin」 (2013)
  • Author(s): 植村明嘉
  • Publisher: 医薬ジャーナル社
• [Book] 血管生物医学事典 (2011)
  • Author(s): 植村明嘉
  • Publisher: 朝倉書店
• [Book] 血管生物医学事典分担執筆(「網膜血管の発生」) (2011)
  • Author(s): 植村明嘉
  • Publisher: 朝倉書店
• [Book] 血管生物医学事典分担執筆(「Semaphorin」) (2011)
  • Author(s): 植村明嘉
  • Publisher: 朝倉書店
• [Book] Encyclopedia of the Eye, Vol4 (2010)
  • Author(s): Uemura A
  • Publisher: Oxford: Academic Press
• [Book] Encyclopedia of the Eye, Vol.4 (2010)
  • Author(s): Uemura A
  • Publisher: Academic Press
• [Book] 眼のサイエンス 視覚の不思議 (2010)
  • Author(s): 植村明嘉
  • Publisher: 文光堂
• [Patent(Industrial Property Rights)] 新規な血管新生調節因子の利用 (2011)
  • Inventor(s): 植村明嘉、福嶋葉子、福原茂朋、望月直樹、西川伸一
  • Industrial Property Rights Holder: 植村明嘉、福嶋葉子、福原茂朋、望月直樹、西川伸一
  • Industrial Property Number: 2011-238012
  • Filing Date: 2011-10-28