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Roll of Cellular Senescence in the Pathogenesis of Aniridia

Research Project

Project/Area Number 21K09696
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 56060:Ophthalmology-related
Research InstitutionOsaka 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
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2023: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2022: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords無虹彩症 / PAX6 / 細胞老化 / p53 / 角膜上皮細胞
Outline of Research at the Start

無虹彩症は先天的に虹彩の無形成ないし低形成、黄斑低形成などを呈し、また後天性にも白内障、角膜輪部疲弊症、緑内障 などを発症する。白内障、角膜輪部疲弊症、緑内障は加齢性疾患であることから、PAX6遺伝子量の減少が細胞老化を促進し、結果として組織老化を招いている可能性がある。我々は ヒトの無虹彩症のin vitro病態モデルとして、PAX6遺伝子の片アリルに機能喪失型変異を導 入したヒトiPS細胞を作製した。本研究では、このin vitro病態モデルを用いて、無虹彩症の角膜上皮と水晶体において組織老化が促進しているかどうかを明らかにする。

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.

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。

Report

(3 results)
  • 2023 Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • Research Products

    (1 results)

All 2021

All Presentation (1 results)

  • [Presentation] GENERATION OF AN IN VITRO DISEASE MODEL OF ANIRIDIA BY INTRODUCING HETEROZYGOUS LOSS-OF-FUNCTION MUTATION OF PAX6 GENE IN HUMAN IPS CELLS2021

    • Author(s)
      Satoshi Kawasaki , Kohji Ohmoto , Kohji Nishida
    • Organizer
      International Society for Stem Cell Research
    • Related Report
      2021 Research-status Report

URL: 

Published: 2021-04-28   Modified: 2025-01-30  

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