2023 Fiscal Year Final Research Report

Proposal of a novel therapy for bullous keratopathy based on human-derived multiomics analysis

Research Project

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Project/Area Number	20K21663
Research Category	Grant-in-Aid for Challenging Research (Exploratory)
Allocation Type	Multi-year Fund
Review Section	Medium-sized Section 56:Surgery related to the biological and sensory functions and related fields
Research Institution	Tokyo Dental College
Principal Investigator	Takefumi Yamaguchi 東京歯科大学, 歯学部, 教授 (20383771)
Co-Investigator(Kenkyū-buntansha)	比嘉一成東京歯科大学, 歯学部, 講師 (60398782) 杉本昌弘東京医科大学, 医学部, 兼任教授 (30458963)
Project Period (FY)	2020-07-30 – 2024-03-31
Keywords	前房水 / 角膜内皮細胞 / 細胞老化
Outline of Final Research Achievements	In our previous study, we identified several biological pathways from multiomic analyses using refractory bullous keratopathy, which we named as "aqueous humor associated endotheliopathy". Based on these results, we hypothesized that NMN, a regulator of mitochondria and intracellular energy production, can alleviate corneal endothelial cell damage due to pathological aqueous humor. First, in DBA2J, a animal model of aqueous humor associated endotheliopathy, we repeated experiments of NMN-fed DBA2J for 1 month, and found that NMN decreased corneal endothelial damage. Second, we measured NAD/NADH levels in human aqueous humor and showed that the NAD/NADH levels were decreased in eyes with aqueous humor associated endotheliopathy. Third, in ex-vivo experiments using the aqueous humor from normal eyes and eyes with aqueous humor associated endotheliopathy, endothelial cell damage was increased in the cells that were cultured in aqueous humor from aqueous humor associated endotheliopathy.
Free Research Field	角膜移植
Academic Significance and Societal Importance of the Research Achievements	角膜内皮移植の発展によって水疱性角膜症の予後は劇的に改善したが、一部の水疱性角膜症では術後に角膜内皮細胞が減少し、移植片が早期に機能不全に陥るため何度も角膜移植を繰り返す必要がある。これは単に「角膜内皮細胞が減少し角膜浮腫をきたす」水疱性角膜症ではなく、「虹彩損傷・房水血管柵破綻を背景とする前房環境の病的変化による角膜内皮細胞の変性疾患」である。角膜提供が少ない我が国において多くの角膜を消費する本疾患概念の確立と病態解明は喫緊の課題である。本研究から前房環境の代謝異常の視点から「前房関連角膜内皮症」という疾患概念と、病態解析、治療法の開発につながる知見が得られ、今後の研究基盤が確立できた。