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Damage of retinal ganglion cells : Mechanism of the cell death in the local and central nervous system and protection and regeneration of the neural cells.

Research Project

Project/Area Number 18209053
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Ophthalmology
Research InstitutionThe University of Tokyo

Principal Investigator

ARAIE Makoto  The University of Tokyo, 医学部・附属病院, 教授 (00092122)

Co-Investigator(Kenkyū-buntansha) AIHARA Makoto  東京大学, 医学部・附属病院, 講師 (80222462)
TOMIDOKORO Atsuo  東京大学, 医学部・附属病院, 講師 (80227628)
KASHIWAGI Kenji  山梨大学, 医学部・附属病院, 准教授 (30194723)
HARA Hideaki  岐阜薬科大学, 薬学部, 教授 (20381717)
KATO Satoru  金沢大学, 医学(系)研究科, 教授 (10019614)
Project Period (FY) 2006 – 2008
Project Status Completed (Fiscal Year 2008)
Budget Amount *help
¥49,400,000 (Direct Cost: ¥38,000,000、Indirect Cost: ¥11,400,000)
Fiscal Year 2008: ¥9,620,000 (Direct Cost: ¥7,400,000、Indirect Cost: ¥2,220,000)
Fiscal Year 2007: ¥19,240,000 (Direct Cost: ¥14,800,000、Indirect Cost: ¥4,440,000)
Fiscal Year 2006: ¥20,540,000 (Direct Cost: ¥15,800,000、Indirect Cost: ¥4,740,000)
Keywords脳・神経 / 網膜神経節細胞 / 緑内障 / 神経保護 / 神経再生 / 高次機能障害 / 高次細胞障害
Research Abstract

(1) マウス、ラット眼を用いた緑内障性神経細胞障害のin vitro での解析 : 各種ストレス(酸化ストレス、低酸素ストレス、グルタミン酸負荷)によるRGC 障害に対する保護作用を各種薬剤(β遮断薬、Baxinhibitory peptide、フラボノイド)について検討した。(2)マウス眼を用いた緑内障性神経細胞障害のin vivo での解析 : 網膜神経節細胞(RGC)に特異的蛍光を発するCFP マウスの眼底撮影により網膜細胞を直接観察し、虚血再灌流による神経細胞死を生体内で評価できた。マウスの加齢に伴うRGC の自然減少を検討した。(3)マウス及び猿緑内障モデル眼の中枢神経系における機能及び構造の解析 : サル緑内障眼では脳内で障害を受けたマイクログリアに集積する末梢方ベンゾジアゼピンのトレーサーの集積とc-fos 遺伝子の発現などの変化を脳内で検討した。マウスではNMDA 投与7 日以降に、対側のLGN において特異的にNeuN 陽性細胞の細胞体の収縮が認められた。(4)金魚とマウスでの視神経障害時に発現する遺伝子・分子の解析 : 視神経が再生可能な魚の損傷網膜から再生関連分子を見つけ、その再生に果す役割を調べると共に視神経が再生できないラットの眼球に導入し、その再生効果を検証した。IGF-1、プルプリン、トランスグルタミネースといった分子が金魚の視神経再生に重要な役割を果すことが分かった。これら再生分子の挙動をラット損傷モデルで調べた所、金魚とは異なり、むしろ活性或いは発現が損傷後速やかに消退・消失した。そこでこれら再生分子をラット網膜内へ蛋白、遺伝子レベルで導入した所in vitro、in vivo 両面でラットの視神経再生を促進し有用であることが証明された。(5)網膜幹細胞、間葉系幹細胞を用いたRGC 再生の検討 : 網膜幹細胞、間葉系幹細胞を用いたRGC 再生の検討 : 骨髄間葉系幹細胞の分泌する因子が、培養されたにおいて視細胞前駆細胞に保護的に作用することを見いだした。RCS ラットにおいて骨髄間葉系幹細胞の網膜下移植により、形態学的、機能的に網膜変性が抑制されることが判明した。さらに、骨髄幹細胞が錐体視細胞、桿体視細胞の両方に対して保護効果があることが判明した。

Report

(4 results)
  • 2008 Annual Research Report   Final Research Report ( PDF )
  • 2007 Annual Research Report
  • 2006 Annual Research Report
  • Research Products

    (34 results)

All 2009 2008 2007 2006 Other

All Journal Article (20 results) (of which Peer Reviewed: 15 results) Presentation (13 results) Book (1 results)

  • [Journal Article] Effects of Bax-inhibiting Peptides in Retinal Ganglion Cell Death Induced by Glutamate or Oxidative Stress In2009

    • Author(s)
      Chen YN, Aihara M, Mao W, Yamada H, Matsuyama S, Araie M
    • Journal Title

      Vitro Brain Res 1148

      Pages: 28-37

    • Related Report
      2008 Final Research Report
    • Peer Reviewed
  • [Journal Article] Effect of an inducer of BiP, a molecular chaperone, on endoplasmic reticulum(ER)stress-induced retinal cell death2009

    • Author(s)
      nokuchi Y, Nakajima Y, Shimazawa M, Kurita T, Kubo M, Saito A, Sajiki H, Kudo T, Aihara M, Imaizumi K, Araie M, Hara H.
    • Journal Title

      Invest Opthamol Vis Sci 50

      Pages: 334-344

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Effects of prostanoid EP agonists on mouse intraocular pressure.2009

    • Author(s)
      Saeki T, Ota T, Aihara M, Araie M.
    • Journal Title

      nvest Opthamol Vis Sci 50

      Pages: 2201-2208

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Imaging Mouse Retinal Ganglion Cells and Their Loss in vivo by a Fundus Camera in the Normal and Ischemia-Reperfusion Model2008

    • Author(s)
      Murata H, Aihara M, Chen YN, Ota T, Numaga J, Araie M
    • Journal Title

      Invest Ophthalmol Vis Sci 49

      Pages: 5546-5552

    • Related Report
      2008 Final Research Report
    • Peer Reviewed
  • [Journal Article] Lysyl oxidase-like 1 gene polymorphisms in Japanese patients with primary open angle glaucoma and exfoliation syndrome2008

    • Author(s)
      F MABUCHI, Y SAKURADA, K KASHIWAGI, Z YAMAGATA, H IIJIMA, S TSUKAHARA
    • Journal Title

      Molecular Vision 14

      Pages: 1303-1308

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Long-term Effects of Latanoprost Monotherapy on Intraocular Pressure in Japanese Glaucoma Patients2008

    • Author(s)
      K. KASHIWAGI, T TSUMYEA, S TSUKAHARA
    • Journal Title

      J Glaucoma 17

      Pages: 662-666

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Imaging mouse retinal ganglion cells and their loss in vivo by a fundus camera in the normal and ischemia-reperfusion model.2008

    • Author(s)
      Murata H, Aihara M, Chen YN, Ota T, Numaga J, Araie M.
    • Journal Title

      Invest Opthamol Vis Sci 49

      Pages: 5546-52

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Effects of beta-adrenergic receptor antagonists on oxidative stress in purified rat retinal ganglion cells2007

    • Author(s)
      Yu ZK, Chen YN, Aihara M, Mao W, Uchida S, Araie M
    • Journal Title

      Mol Vis 13

      Pages: 833-90

    • Related Report
      2008 Final Research Report
    • Peer Reviewed
  • [Journal Article] Involvement of ER stress in retinal cell death2007

    • Author(s)
      Shimazawa M, Inokuchi Y, Ito Y, Murata H, Aihara M, Miura M, Araie M and Hara H
    • Journal Title

      Mol Vis 13

      Pages: 578-587

    • Related Report
      2008 Final Research Report
    • Peer Reviewed
  • [Journal Article] Involvement of double-stranded RNA-dependent protein kinase in ER stress-induced retinal neuron damage2007

    • Author(s)
      Shimazawa M, Ito Y, Inokuchi Y, and Hara H
    • Journal Title

      Invest Ophthalmol Vis Sci 48

      Pages: 3729-3736

    • Related Report
      2008 Final Research Report
    • Peer Reviewed
  • [Journal Article] Hypoxia-lnduced Retinal Ganglion Cell Death and the Neuroprotective Effects of Beta-adrenergic Antagonists2007

    • Author(s)
      Yi-Ning Chen, Hideyuki Yamada, Wei Mao, Shigemi Matsuyama, Makoto Aihara, Makoto Araie.
    • Journal Title

      Brain Res 7

      Pages: 28-37

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Purpurin expression in the zebrafish retina during early development and after optic nervelesion in adults2007

    • Author(s)
      Tanaka, M., Murayama, D., Nagashima, M., Higashi, T., Mawatari, K.,
    • Journal Title

      Brain Res 1153

      Pages: 34-42

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Upregulation of IGF-I in the goldfishr etinal ganglion cells during the early stage of optic enrve regeneration2007

    • Author(s)
      Koriyama, Y., Homma, K., Sugitani, K, , Higuchi, Y., Matsukawa, T.,
    • Journal Title

      Neurochem.Int 50

      Pages: 749-756

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Early downregulation of IGF-I decides the fate of rat retinal ganglion cells after optic nerve injury.2007

    • Author(s)
      Homma K, Koriyama Y, Mawatari K, Higuchi Y, Kosaka J, Kato S.
    • Journal Title

      Neurochemistry International (in press)

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Upregulation of IGF-I in the goldfish retinal ganglion cells during the early stage of optic nerve regeneration.2007

    • Author(s)
      Koriyama Y, Homma K, Sugitani K, Higuchi Y, Matsukawa T, Murayama D, Kato S.
    • Journal Title

      Neurochemistry International, 2007, (in press)

    • NAID

      120001450995

    • Related Report
      2006 Annual Research Report
  • [Journal Article] stranded RNA-dependent proteinkinase protects against cell damage induced by ER stress2006

    • Journal Title

      Neurosci. Lett 409

      Pages: 192-195

    • Related Report
      2008 Final Research Report
    • Peer Reviewed
  • [Journal Article] Upregulation of retinal transglutaminase during the axonal elongation stage of goldfish optic nerve regeneration.2006

    • Author(s)
      Sugitani K, Matsukawa T, Koriyama Y, Shintani T, Nakamura T, Noda M, Kato S.
    • Journal Title

      Neuroscience 142

      Pages: 1081-1092

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Neuroprotective effect of latanoprost on rat retinal ganglion cells.2006

    • Author(s)
      Kudo H, Nakazawa T, Shimura M, Takahashi H, Fuse N, Kashiwagi K, Tamai M.
    • Journal Title

      Graefes Arch Clin Exp Ophthalmol. 244

      Pages: 1003-1009

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Role of apoptosis signal-regulating kinase 1 in stress-induced neural cell apoptosis in vivo.2006

    • Author(s)
      Harada C, Nakamura K, Namekata K, Okumura A, Mitamura Y, Iizuka Y, Kashiwagi K, Yoshida K, Ohno S, Matsuzawa A, Tanaka K, Ichijo H, Harada T.
    • Journal Title

      Am J Pathol. 168

      Pages: 261-269

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Nitric oxide-cGMP signaling regulates axonal elongation during optic nerve regeneration in the goldfish in vitro and in vivo

    • Author(s)
      Koriyama Y, yasuda R, Homma K, Mawatari K,Nagashima M, Sugitani K, Matsukawa T, Kato S
    • Journal Title

      J. Neurochem (in press)

    • NAID

      120001450994

    • Related Report
      2008 Final Research Report
    • Peer Reviewed
  • [Presentation] マウス正常眼における網膜神経節細胞の減少率2009

    • Author(s)
      村田博史、相原-、新家 眞
    • Organizer
      第113回日本眼科学会総会
    • Place of Presentation
      東京都
    • Year and Date
      2009-04-16
    • Related Report
      2008 Annual Research Report
  • [Presentation] CFP発現マウスを用いた視神経におけるレチノトピー2009

    • Author(s)
      鶴我英和、村田博史、相原一、新家 眞
    • Organizer
      第113回日本眼科学会総会
    • Place of Presentation
      東京都
    • Year and Date
      2009-04-16
    • Related Report
      2008 Annual Research Report
  • [Presentation] Modification of Glutamate Transporters in Rat Mullar cells Under Centrifugal force pressure2008

    • Author(s)
      T HAN, T Furuya, K Kashiwagi
    • Organizer
      ARVO
    • Place of Presentation
      米国
    • Year and Date
      2008-04-28
    • Related Report
      2008 Annual Research Report
  • [Presentation] グルタミン酸トランスポーターの網膜神経節細胞への影響2008

    • Author(s)
      古屋 敏江、播 智迎、柏木 賢治
    • Organizer
      第112回日本眼科学会総会
    • Place of Presentation
      横浜市
    • Year and Date
      2008-04-18
    • Related Report
      2008 Annual Research Report
  • [Presentation] CFP発現マウスを用いた眼圧依存性網膜神経節細胞障害の評価2008

    • Author(s)
      鶴我英和、村田博史、相原一、新家 眞
    • Organizer
      第112回日本眼科学会総会
    • Place of Presentation
      横浜市
    • Year and Date
      2008-04-18
    • Related Report
      2008 Annual Research Report
  • [Presentation] フラボノイドの網膜神経節細胞保護効果2008

    • Author(s)
      毛い、佐伯忠志朗、陳逸寧、相原一、新家 眞
    • Organizer
      第112回日本眼科学会総会
    • Place of Presentation
      横浜市
    • Year and Date
      2008-04-18
    • Related Report
      2008 Annual Research Report
  • [Presentation] A retinol binding protein, purpurin protects injury-induced apoptosis and regenerateaXons in rat CNS neurons2008

    • Author(s)
      Koriyama Y, Saito J, Matsukawa T, Kato S
    • Organizer
      WashingtonDC
    • Place of Presentation
      Neuroscience 2008 USA
    • Related Report
      2008 Final Research Report
  • [Presentation] Involvement of endoplasmic reticulum stress in retinal cell death2007

    • Author(s)
      Suemori S, Shimazawa M, Yamamoto T, Hara H
    • Organizer
      The ARVO Annual Meeting
    • Place of Presentation
      Fort Lauderdale, Florida
    • Related Report
      2008 Final Research Report
  • [Presentation] 網膜細胞死における小胞体誘導シャペロンの関与2007

    • Author(s)
      井口勇太、嶋澤雅光、中島佳美、工藤喬、今泉和則、原英彰
    • Organizer
      第80 回日本薬理学会年会
    • Place of Presentation
      名古屋
    • Related Report
      2008 Final Research Report
  • [Presentation] PDGFR・受容体の神経保護効果2007

    • Author(s)
      金本 尚志, 水上 皆, 谷本 誠治, 木内 良明
    • Organizer
      第27回日本眼薬理学会
    • Place of Presentation
      岐阜市
    • Related Report
      2007 Annual Research Report
  • [Presentation] 虚血再灌流モデルを用いた生体内網膜神経節細胞の経時的変化の評価2006

    • Author(s)
      村田博史, 陳逸寧, 太田貴史, 相原一, 新家眞
    • Organizer
      第17回日本緑内障学会
    • Place of Presentation
      熊本
    • Related Report
      2008 Final Research Report
  • [Presentation] pitavastatin(NK104)のラット網膜神経節細胞保護効果2006

    • Author(s)
      毛蔚, 陳逸寧, 相原一, 新家眞. Et.al.
    • Organizer
      第26回眼薬理学会
    • Place of Presentation
      福井
    • Related Report
      2008 Final Research Report
  • [Presentation] pitavastatin のラット網膜神経節細胞保護効果2006

    • Author(s)
      毛蔚, 陳逸寧, 相原一, 新家眞. Et.al.
    • Organizer
      Ophthalmoneuroprotection
    • Place of Presentation
      東京
    • Related Report
      2008 Final Research Report
  • [Book] Model Organisms in Spinal Cord Regeneration2007

    • Author(s)
      Kato, S, Koriyama, Y, Matsukawa, T, Sugitani, K.
    • Total Pages
      18
    • Publisher
      Wiley-VCH, Weinheim
    • Related Report
      2006 Annual Research Report

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Published: 2006-04-01   Modified: 2016-04-21  

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