萎縮型加齢黄斑変性のモデルマウス確立と、その病態の解明

2015 Fiscal Year Annual Research Report

• Project/Area Number: 25713056
• Research Institution: Nagoya University
• Principal Investigator: 兼子 裕規 名古屋大学, 医学(系)研究科(研究院), 助教 (20647458)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: 加齢黄斑変性 / 不飽和脂肪酸 / アミロイドβ / ヒスタミン受容体H4 / インターロイキン18 / プラズマ賦活液 / リノール酸 / malondialdehyde

Outline of Annual Research Achievements

本研究では当初より加齢黄斑変性のモデルマウス作製と、それを利用した病態解明を目的とした。
萎縮型加齢黄斑変性の純粋なモデルマウスを作成しようと試みたが、残念ながら滲出型モデルマウスとの明確な差別化はできなかった。その代わり、n-6系不飽和脂肪酸であるリノール酸負荷によってマウス血液中・網膜色素上皮中のmalondialdehydeが高濃度になることが確認された。In vitroの実験では、ヒト網膜色素上皮細胞の極性培養上にmalondialdehydeを添加したブタ視細胞を負荷すると、低濃度域では細胞障害が起きない代わりに血管内皮増殖因子(VEGF)濃度が上昇することが確認された。興味深いことに、高濃度malondialdehyde域では、ヒト網膜色素上皮細胞の細胞障害が確認されるとともに、VEGF分泌濃度が減少していった。これはちょうど、滲出型・萎縮型加齢黄斑変性の病態の違いを説明するうえで説得力のある変化だった。実際の加齢黄斑変性患者の組織を採取しmalondialdehyde濃度を測定したところ、滲出型でも萎縮型でも高濃度のmalondialdehydeが検出された。
これらのことから、in vivoでは高濃度リノール酸、in vitroではmalondialdehydeの負荷によって、加齢黄斑変性のモデルが作製できることが確認された。

Research Progress Status

27年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

27年度が最終年度であるため、記入しない。

Causes of Carryover

27年度が最終年度であるため、記入しない。

Expenditure Plan for Carryover Budget

27年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Human IgG1 antibodies suppress angiogenesis in a target-independent manner (2016)
  • Author(s): Bogdanovich S, Kim Y, Hirano Y, Baffi J, Tarallo V, Li S, Yasuma T, Arpitha P, Fowler B, Gelfand B, Tudisco L, Cicatiello V, Apicella I, De Falco S, Greco A, Brunetti A, Ruvo M, Sandomenico A, Nozaki M, Ogura Y, Kaneko H, Ijima R, Terasaki H, Ambati BK, Leusen J, Wright C, Ambati J
  • Journal Title: Signal Transduction and Targeted Therapy. Volume: 1 Pages: 1
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Malondialdehyde induces autophagy dysfunction and VEGF secretion in the retinal pigment epithelium in age-related macular degeneration. (2016)
  • Author(s): Ye F, Kaneko H*, Hayashi Y, Takayama K, Hwang SJ, Nishizawa Y, Kimoto R, Nagasaka Y, Tsunekawa T, Matsuura T, Yasukawa T, Kondo T, Terasaki H.
  • Journal Title: Free Radic Biol Med. Volume: 94 Pages: 121
  • DOI: 10.1016/j.freeradbiomed.2016.02.027
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Expression of Vascular Endothelial Growth Factor by Retinal Pigment Epithelial Cells Induced by Amyloid Beta is Depressed by an Endoplasmic Reticulum Stress Inhibitor (2016)
  • Author(s): Matsui A, Kaneko H*, Kachi S, Ye F, Hwang SJ, Katayama K, Nagasaka Y, Sugita T, Terasaki H.
  • Journal Title: Ophthalmic Res, Volume: 55 Pages: 37-44
  • DOI: 1159/000440885
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Plasma-activated medium suppresses choroidal neovascularization in mice: a new therapeutic concept for age-related macular degeneration (2015)
  • Author(s): Ye F, Kaneko H*, Nagasaka Y, Ijima R, Nakamura K, Nagaya M, Takayama K, Kajiyama H, Senga T, Tanaka H, Mizuno M, Kikkawa F, Hori M, Terasaki H
  • Journal Title: Sci Rep Volume: 5 Pages: 7705
  • DOI: 10.1038/srep07705.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Suppression of laser-induced choroidal neovascularization by the oral medicine targeting histamine receptor h4 in mice (2015)
  • Author(s): Ijima R, Kaneko H*, Ye F, Takayama K, Nagasaka Y, Kataoka K, Funahashi Y, Iwase T, Kachi S, Kato S, Terasaki H
  • Journal Title: Transl Vis Sci Technol Volume: 4 Pages: 6
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Macrophage- and RIP3-dependent inflammasome activation exacerbates retinal detachment-induced photoreceptor cell death (2015)
  • Author(s): Kataoka K, Matsumoto H, Kaneko H, Notomi S, Takeuchi K, Harry S, Atik A, Murakami Y, Kip C, Terasaki H, Miller J. Demetrios V.
  • Journal Title: Cell Death Dis Volume: 6 Pages: 1731
  • DOI: 10.1038/cddis.2015.73.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Significant Correlation between Retinal Venous Tortuosity and Aqueous Vascular Endothelial Growth Factor Concentration in Eyes with Central Retinal Vein Occlusion. (2015)
  • Author(s): Yasuda S, Kachi S, Kondo M, Ueno S, Kaneko H, Terasaki H.
  • Journal Title: PLoS One Volume: 10 Pages: 0134267
  • DOI: 10.1371/journal.pone.0134267
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Sex-Related Differences in Ocular Blood Flow of Healthy Subjects Using Laser Speckle Flowgraphy (2015)
  • Author(s): Yanagida K, Iwase T, Yamamoto K, Ra E, Kaneko H, Murotani K, Matsui S, Terasaki H
  • Journal Title: Invest Ophthalmol Vis Sci. Volume: 56 Pages: 4880-4890
  • DOI: 10.1167/iovs.15-16567
  • Peer Reviewed
• [Journal Article] Differences of Retinal Blood Flow Between Arteries and Veins Determined by Laser Speckle Flowgraphy in Healthy Subjects. (2015)
  • Author(s): Iwase T, Ra E, Yamamoto K, Kaneko H, Ito Y, Terasaki H
  • Journal Title: Medicine (Baltimore). Volume: 94 Pages: 1256
  • DOI: 10.1097/MD.0000000000001256.
  • Peer Reviewed
• [Journal Article] Surgical Videos with Synchronised Vertical 2-Split Screens Recording the Surgeons’ Hand Movement (2015)
  • Author(s): Kaneko H*, Ra E, Kawano K, Yasukawa T, Takayama K, Iwase T, Terasaki H.
  • Journal Title: Ophthalmologica Volume: 234 Pages: 243-246
  • DOI: 10.1159/000439119.
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Dry AMD: Potential Therapeutic Targets (2016)
  • Author(s): Hiroki Kaneko
  • Organizer: Asia-Pacific Academy of Ophthalmology Congress
  • Place of Presentation: Taipei, TAIWAN
  • Year and Date: 2016-03-24 – 2016-03-27
  • Int'l Joint Research / Invited
• [Presentation] Histamine receptor H4 as a new therapeutic target for age-related macular degeneration (2015)
  • Author(s): Hiroki Kaneko
  • Organizer: 13th Congress of the International Ocular Inflammation Society (IOIS)
  • Place of Presentation: San Francisco, USA
  • Year and Date: 2015-09-25 – 2015-09-27
  • Int'l Joint Research / Invited
• [Presentation] DICER1減少による萎縮型AMDの分子メカニズム (2015)
  • Author(s): 兼子 裕規
  • Organizer: 日本眼科学会総会2015
  • Place of Presentation: 北海道札幌市、ニトリ文化ホール
  • Year and Date: 2015-04-16 – 2015-04-19
  • Invited