Roll of Cellular Senescence in the Pathogenesis of Aniridia

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K09696
• 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: Osaka University
• Principal Investigator: KAWASAKI SATOSHI 大阪大学, 大学院医学系研究科, 招へい教員 (60347458)
• Co-Investigator(Kenkyū-buntansha): 馬場 耕一 大阪大学, 大学院医学系研究科, 寄附講座教授 (00436172)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 無虹彩症 / PAX6 / 細胞老化 / p53 / 角膜上皮細胞

Outline of Final Research Achievements

Aniridia is a disease caused by genetic mutation of a single allele of the PAX6 gene and is associated with age-related diseases such as cataracts, corneal ring fatigue, and glaucoma in addition to congenital anomalies. Human iPS cells (PAX6+/- iPS cells) in which a loss-of-function mutation was introduced into one allele of the PAX6 gene using gene editing technology were generated, and ocular-like structures were induced in vitro and gene expression was examined to investigate the association between the PAX6 gene and senescence. It was unveiled that the expression of the TP63 gene, one of the core transcription factor network of corneal epithelial cells, was decreased. It was speculated that the downregulation of PAX6 gene levels disrupts the core transcription factor network, resulting in the downregulation of TP63 gene expression, and ultimately in the upregulation of p53 function, leading to cellular senescence.

Free Research Field

医歯薬学

Academic Significance and Societal Importance of the Research Achievements

無虹彩症では白内障、緑内障、角膜輪部機能不全が若年で起こることは知られてきたが、これまでに無虹彩症で老化が促進しているという報告はなく、また無虹彩症でなぜ白内障や角膜輪部疲弊症といった老化形質が若年で生じるのかという疑問に明確に答えた報告も存在しない。本研究の結果から無虹彩症においては、PAX6遺伝子量の低下によって角膜上皮細胞のコア転写因子ネットワークが破綻してTP63遺伝子の発現低下を来し、最終的に細胞老化を来すことが示唆された。本研究の結果により、無虹彩症患者の後天異常である白内障、緑内障、角膜輪部機能不全については治療介入の可能性が示唆され、将来的な医療シーズとなるものと考えられた。