Myopia development and scleral ER stress

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K09834
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56060:Ophthalmology-related
• Research Institution: Keio University
• Principal Investigator: Ikeda Shin-ichi 慶應義塾大学, 医学部(信濃町), 特任助教 (50534898)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 近視 / 強膜 / 小胞体ストレス

Outline of Final Research Achievements

Here, we show that endoplasmic reticulum (ER) stress in sclera is an essential regulator of axial elongation in myopia development through activation of both PERK and ATF6 axis followed by scleral collagen remodelling. Mice with lens-induced myopia (LIM) showed ER stress in sclera. Pharmacological interventions for ER stress could induce or inhibit myopia progression. LIM activated all IRE1, PERK and ATF6 axis, and pharmacological inhibition of both PERK and ATF6 suppressed myopia progression, which was confirmed by knocking down above two genes via CRISPR/Cas9 system. LIM changed the expression of scleral collagen genes responsible for ER stress. Furthermore, collagen fibre thinning and expression of dysregulated collagens in LIM were ameliorated by 4-PBA administration. We demonstrate that scleral ER stress and PERK/ATF6 pathway controls axial elongation during the myopia development in vivo model and 4-PBA eye drop is promising drug for myopia suppression/treatment.

Free Research Field

眼科学　細胞生物学

Academic Significance and Societal Importance of the Research Achievements

近視はアジア圏を中心に急増している。眼球が前後方向に伸長することが近視の本体であるがその伸長により後眼部に物理的な負荷が加わることで視覚障害につながることが報告されてから眼軸伸長への介入の必要性が認識されるようになったが、効果的な方法は現存しない。本研究により見出された強膜小胞体ストレスへの介入は極めて効率的に眼軸伸長、近視進行を抑制したことから本研究を元とした薬剤開発は急増する近視に歯止めをかける可能性があり、社会的に非常に意義深い研究成果が得られた。