Investigating a novel cell death signaling in retinal pigment epithelium

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K09758
• 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: The University of Tokyo
• Principal Investigator: Ueta Takashi 東京大学, 医学部附属病院, 助教 (90631573)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 網膜色素上皮 / 過酸化脂質 / 抗酸化酵素 / glutathione peroxidase 4

Outline of Final Research Achievements

Glutathione peroxidase 4 (GPx4) is a unique enzyme that can directly detoxify phospholipid peroxides in cell membranes. When mice in which GPx4 was specifically deleted in the retinal pigment epithelium (RPE) (GPx4 cKO mice) were created using flox mice and AAV-Cre vectors, they exhibited accumulation of lipid peroxide metabolites and rapid RPE degeneration. Examination using optical coherence tomography, immunohistochemistry, and electron microscopy showed that the pathological image resembled that of dry age-relatd macular degeneration (AMD). It has become clear that lipid peroxide accumulation in the RPE can lead to severe RPE degeneration, as observed in late-stage AMD.

Free Research Field

眼科

Academic Significance and Societal Importance of the Research Achievements

網膜色素上皮は視機能の維持に重要であるため、その異常は加齢黄斑変性を含む種々の網膜変性疾患につながり、重篤な視機能低下を来たす可能性がある。これらの疾患の治療開発研究を行う上での問題点の１つとして、有用な動物モデルが少ない点が挙げられる。本研究ではGPx4という細胞膜にできた過酸化脂質を解毒する酵素に着目し、GPx4を網膜色素上皮特異的に欠損させたマウスを作製したところ、加齢黄斑変性によく似た眼症状を呈した。今後の治療開発研究を行う上で有用なマウスモデルと考えられるとともに、過酸化脂質の蓄積により重篤な網膜色素上皮変性を来たしうることが示された。