Generation of dry age-related macular degeneration model mouse and elucidation of the pathogenesis

• Project/Area Number: 25713056
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Partial Multi-year Fund
• Research Field: Ophthalmology
• Research Institution: Nagoya University
• Principal Investigator: Kaneko Hiroki 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
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥26,260,000 (Direct Cost: ¥20,200,000、Indirect Cost: ¥6,060,000); Fiscal Year 2015: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2014: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2013: ¥19,370,000 (Direct Cost: ¥14,900,000、Indirect Cost: ¥4,470,000)
• Keywords: 加齢黄斑変性 / 脈絡膜新生血管 / 不飽和脂肪酸 / malondialdehyde / アミロイドβ / ヒスタミン受容体H4 / プラズマ照射液 / リノール酸 / インターロイキン18 / プラズマ賦活液 / 網膜色素上皮 / 萎縮型加齢黄斑変性 / 地図状変性 / 過酸化脂質

Outline of Final Research Achievements

Amyloid β induced vascular endothelial growth factor (VEGF) and endoplasmic reticulum (ER) stress marker up-regulation in retinal pigment epithelium (RPE). ER stress inhibitor blocked VEGF secretion. When large amount of linoleic acid was administered in mice, malondialdehyde (MDA) was accumulated in RPE and blood. MDA was also detected in the RPE and blood from the patients with AMD. In the administration of MDA in cultured human RPE cells, low concentrations of MDA induced VEGF up-regulation without inducing RPE damage, whereas high concentrations of MDA induced VEGF down-regulation and RPE degeneration. This change suggested the difference of wet- and dry-AMD.
We verified the expression of histamine receptor H4 (HRH4) in the choroidal neovascularization (CNV) and the vitreous injection or oral administration of the anti-HRH4 medicine reduced CNV. Plasma-activated medium irradiated with low temperature plasma also reduced CNV in mice.

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: 1-1
  • 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: 23 Pages: 121-134
  • DOI: 10.1016/j.freeradbiomed.2016.02.027
  • NAID: 120005866829
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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
  • 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): F. Ye, H. Kaneko, Y. Nagasaka, R. Ijima, K. Nakamura, M. Nagaya, K. Takayama, H. Kajiyama, T. Senga, H. Tanaka, M. Mizuno, F. Kikkawa, M. Hori, and H. Terasaki
  • Journal Title: Sci Rep Volume: 5 Issue: 1 Pages: 7705-7705
  • DOI: 10.1038/srep07705
  • Peer Reviewed / Open Access
• [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: 6-6
  • 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, Sweigard JH, Atik A, Murakami Y, Connor KM, Terasaki H, Miller JW, Vavvas DG
  • Journal Title: Cell Death Dis. Volume: 6 Issue: 4 Pages: 1731-1731
  • DOI: 10.1038/cddis.2015.73
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [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 Issue: 7 Pages: 0134267-0134267
  • DOI: 10.1371/journal.pone.0134267
  • Peer Reviewed / Open Access
• [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 Issue: 8 Pages: 4880-90
  • DOI: 10.1167/iovs.15-16567
  • Peer Reviewed / Open Access
• [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 Issue: 33 Pages: 1-8
  • DOI: 10.1097/md.0000000000001256
  • Peer Reviewed / Open Access
• [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 Issue: 4 Pages: 243-6
  • DOI: 10.1159/000439119
  • Peer Reviewed / Open Access
• [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: 6-6
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] IL-18 is not therapeutic for neovascular age-related macular degeneration. (2014)
  • Author(s): Hirano Y, Yasuma T, Mizutani T, Fowler BJ, Tarallo V, Yasuma R, Kim Y, Bastos-Carvalho A, Kerur N, Gelfand BD, Bogdanovich S, He S, Zhang X, Nozaki M, Ijima R, Kaneko H, Ogura Y, Terasaki H, Nagai H, Haro I, Ambati BK, Hinton DR, Ambati J.
  • Journal Title: Nat Med. Volume: 20 Issue: 12 Pages: 1372-1372
  • DOI: 10.1038/nm.3671
  • Peer Reviewed
• [Journal Article] DICER1/Alu RNA dysmetabolism induces Caspase-8-mediated cell death in age-related macular degeneration. (2014)
  • Author(s): Kim Y, Tarallo V, Kerur N, Yasuma T, Gelfand BD, Bastos-Carvalho A, Hirano Y, Yasuma R, Mizutani T, Fowler BJ, Li S, Kaneko H, Bogdanovich S, Ambati BK, Hinton DR, Hauswirth WW, Hakem R, Wright C, Ambati J.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 111 Issue: 45 Pages: 16082-16082
  • DOI: 10.1073/pnas.1403814111
  • Peer Reviewed
• [Journal Article] Interleukin-18 induces retinal pigment epithelium degeneration in mice. (2014)
  • Author(s): Ijima R, Kaneko H, Ye F, Nagasaka Y, Takayama K, Kataoka K, Kachi S, Iwase T, Terasaki H.
  • Journal Title: Invest Ophthalmol Vis Sci Volume: 55 Issue: 10 Pages: 6673-6673
  • DOI: 10.1167/iovs.14-15367
  • 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
  • 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
  • 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
  • Invited