Elucidation of a role of age-related lipid accumulation on Bruch's membrane in the pathogenesis of age-related macular degeneration

• Project/Area Number: 16K11293
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Ophthalmology
• Research Institution: Nagoya City University
• Principal Investigator: Yasukawa Tsutomu 名古屋市立大学, 大学院医学研究科, 准教授 (00324632)
• Co-Investigator(Kenkyū-buntansha): 小椋 祐一郎 名古屋市立大学, 大学院医学研究科, 教授 (70191963) ; 平野 佳男 名古屋市立大学, 大学院医学研究科, 講師 (40405163) ; 堂前 純子 中部大学, 応用生物学部, 教授 (70227700)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 加齢黄斑変性 / 網膜色素上皮 / ブルッフ膜 / 脂質 / リポフスチン / ノックアウトマウス / 光障害 / 慢性炎症 / 眼科 / 細胞生物学 / マウス

Outline of Final Research Achievements

In order to elucidate the role of lipid deposition under retinal pigment epithelium (RPE) from the 30s in the pathogenesis of age-related macular degeneration (AMD), black shadows in the fundus observed in DR / DL mode of confocal scanning ophthalmoscope (F10, Nidek, Aichi, Japan) were observed. These shadows were related to age and smoking status, which are well known as a risk of AMD, suggesting that these shadows might represent lipid deposits.
Next, apoE knockout mice showed lipid deposition under RPE with aging. The relationship of lipid deposition (apoE expression) to vascular endothelial growth factor expression, size of laser induced choroidal neovascular in young and old mice suggested that deposited lipids might be related to the pathogenesis of AMD.

Academic Significance and Societal Importance of the Research Achievements

AMDは環境や遺伝素因など多因子が関与する疾患であるが、高度の脂質沈着がAMD発症を直接予測する所見である可能性があり、AMD発症と沈着脂質の程度や分布の関連性について検討することで、AMDの発症リスクを推定することができれば、社会的意義が大きい。
今後、apoEノックアウトマウスの眼底をF10で観察し、黒い陰影が沈着脂質であることを動物実験で実証する。その他、ABCA1ノックアウトマウスなどのコレステロール沈着マウスなども使って実験を行い、免疫組織学的手法と、電子顕微鏡検査も用いて、AMDの病態解明を行う。これにより、AMD発症予防や悪化予防の脂質関連の新薬候補を見いだせる可能性がある。

Research Products

• [Journal Article] Fundus autofluorescence and retinal sensitivity in fellow eyes of age-related macular degeneration in Japan (2019)
  • Author(s): Yasukawa Tsutomu、Mori Ryusaburo、Sawa Miki、Shinojima Ari、Hara Chikako、Sekiryu Tetsuju、Oshima Yuji、Saito Masaaki、Sugano Yukinori、Kato Aki、Ashikari Masayuki、Hirano Yoshio、et al.
  • Journal Title: PLOS ONE Volume: 14 Issue: 2 Pages: e0213161-e0213161
  • DOI: 10.1371/journal.pone.0213161
  • Peer Reviewed / Open Access
• [Journal Article] In vitro drusen model - three-dimensional spheroid culture of retinal pigment epithelial cells. (2018)
  • Author(s): Usui H, Nishiwaki A, Landiev L, Kacza J, Eichler W, Wako R, Kato A, Takase N, Kuwayama S, Ohashi K, Yafai Y, Bringmann A, Kubota A, Ogura Y, Seeger J, Wiedemann P, Yasukawa T.
  • Journal Title: Journal of Cell Science Volume: 132 Issue: 4
  • DOI: 10.1242/jcs.215798
  • Peer Reviewed / Open Access
• [Journal Article] Genome-wide association study suggests four variants influencing outcomes with ranibizumab therapy in exudative age-related macular degeneration. (2018)
  • Author(s): Akiyama M, Takahashi A, Momozawa Y, Arakawa S, Miya F, Tsunoda T, Ashikawa K, Oshima Y, Yasuda M, Yoshida S, Enaida H, Tan X, Yanagi Y, Yasukawa T, Ogura Y, Nagai Y, Takahashi K, Fujisawa K, Inoue M, Arakawa A, Tanaka K, Yuzawa M, Kadonosono K, Sonoda KH, Ishibashi T, Kubo M.
  • Journal Title: J Hum Genet Volume: 63 Issue: 10 Pages: 1083-1091
  • DOI: 10.1038/s10038-018-0493-0
  • Peer Reviewed
• [Journal Article] Flattening of retinal pigment epithelial detachments after pneumatic displacement of submacular hemorrhages secondary to age-related macular degeneration (2018)
  • Author(s): Kimura Masayo、Yasukawa Tsutomu、Shibata Yu、Kato Aki、Hirano Yoshio、Uemura Akiyoshi、Yoshida Munenori、Ogura Yuichiro
  • Journal Title: Graefe's Archive for Clinical and Experimental Ophthalmology Volume: 256 Issue: 10 Pages: 1823-1829
  • DOI: 10.1007/s00417-018-4059-9
  • Peer Reviewed
• [Journal Article] Tissue Plasminogen Activator as an Antiangiogenic Agent in Experimental Corneal Neovascularization in Rabbits (2018)
  • Author(s): Arai Kon-ichi、Yasukawa Tsutomu、Kato Aki、Kubota Ayae、Usui Hideaki、Takase Noriaki、Kuwayama Soichiro、Ogura Yuichiro
  • Journal Title: Ophthalmic Res Volume: 59 Issue: 3 Pages: 170-175
  • DOI: 10.1159/000487054
  • Peer Reviewed
• [Journal Article] A multicenter randomized controlled study of antioxidant supplementation with lutein for chronic central serous chorioretinopathy. (2017)
  • Author(s): Shinojima A, Sawa M, Sekiryu T, Oshima Y, Mori R, Hara C, Sugano Y, Kato A, Asato H, Yuzawa M, Gomi F, Ogura Y, Ishibashi T, Nanri T, Yasukawa T.
  • Journal Title: Ophthalmologica Volume: 237 Issue: 3 Pages: 159-166
  • DOI: 10.1159/000455807
  • Peer Reviewed
• [Journal Article] Evaluation of peripheral fundus autofluorescence in eyes with wet age-related macular degeneration. (2016)
  • Author(s): Suetsugu T, Kato A, Yoshida M, Yasukawa T, Nishiwaki A, Hasegawa N, Usui H, Ogura Y.
  • Journal Title: Clin Ophthalmol Volume: 10 Pages: 2497-2503
  • DOI: 10.2147/opth.s120402
  • Peer Reviewed / Open Access
• [Journal Article] Low-frequency coding variants in CETP and CFB are associated with susceptibility of exudative age-related macular degeneration in the Japanese population. (2016)
  • Author(s): Momozawa Y, Akiyama M, Kamatani Y, Arakawa S, Yasuda M, Yoshida S, Oshima Y, Mori R, Tanaka K, Mori K, Inoue S, Terasaki H, Yasuma T, Honda S, Miki A, Inoue M, Fujisawa K, Takahashi K, Yasukawa T, Yanagi Y, Kadonosono K, Sonoda KH, Ishibashi T, Takahashi A, Kubo M.
  • Journal Title: Hum Mol Genet. Volume: 25 Pages: 5027-5034
  • DOI: 10.1093/hmg/ddw335
  • Peer Reviewed / Open Access
• [Journal Article] Tissue plasminogen activator as an anti-angiogenic agent in experimental laser-induced choroidal neovascularization in mice. (2016)
  • Author(s): Ozone D, Mizutani T, Nozaki M, Ohbayashi M, Hasegawa N, Kato A, Yasukawa T, Ogura Y.
  • Journal Title: Invest Ophthalmic Vis Sci Volume: 57 Issue: 13 Pages: 5348-5354
  • DOI: 10.1167/iovs.16-19617
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Investigation of the etiology of central serous chorioretinopathy using en face OCT and indocyanine green angiography. (2016)
  • Author(s): Shinojima A, Fujita K, Mori R, Kawamura A, Yuzawa M, Yasukawa T.
  • Journal Title: Ophthalmologic Volume: 236 Issue: 2 Pages: 100-107
  • DOI: 10.1159/000448342
  • Peer Reviewed
• [Journal Article] Densitometry of choroidal vessels in eyes with and without central serous chorioretinopathy by wide-field indocyanine green angiography. (2016)
  • Author(s): Hirahara S, Yasukawa T, Kominami A, Nozaki M, Ogura Y.
  • Journal Title: Am J Ophtahlmol Volume: 166 Pages: 103-111
  • DOI: 10.1016/j.ajo.2016.03.040
  • Peer Reviewed
• [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] Combination therapy with intravitreal tissue plasminogen activator and ranibizumab for subfoveal type 2 choroidal neovascularization (2016)
  • Author(s): 68. Kachi I, Yasukawa T, Kato A, Takase N, Morita H, Kubota A, Hirano Y, Uemura A, Ogura Y.
  • Journal Title: Jpn J Ophthalmol Volume: 60 Issue: 3 Pages: 179-186
  • DOI: 10.1007/s10384-016-0434-4
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Preretinal glial membrane with Rock activation after internal limiting membrane peeling (2019)
  • Author(s): Usui H, Kato A, Shimizu H, Terasaki H, Ogura Y, Yasukawa T.
  • Organizer: 第34回アジア太平洋眼科学研究会議（APAO）
  • Int'l Joint Research
• [Presentation] Mechanism of macular hole closure by internal limiting membrane peeling (2019)
  • Author(s): Yasukawa T.
  • Organizer: 2019年ベイル硝子体手術会議
  • Int'l Joint Research / Invited
• [Presentation] Combination therapy of intravitreal tissue plasminogen activator and ranibizumab for type 2 choroidal neovascularization: a pilot study. (2016)
  • Author(s): Yasukawa T, Ogura Y.
  • Organizer: 30th meeting of the Club Jules Gonin
  • Place of Presentation: Bordeaux (France)
  • Year and Date: 2016-07-06
  • Int'l Joint Research
• [Presentation] Visual outcomes of polypoidal choroidal vasculopathy with or without prompt treatment. (2016)
  • Author(s): Masko S, Yasukawa T, Hirahara S, Fujino S, Kato A, Nishiwaki A, Yoshida M, Ogura Y.
  • Organizer: ARVO
  • Place of Presentation: Seattle, WA (USA)
  • Year and Date: 2016-05-01
  • Int'l Joint Research