Establishment of new pathological concept by elucidation of epigenetic control mechanism in diabetic retinopathy

Research Project

Project/Area Number	16K11282
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Research Field	Ophthalmology
Research Institution	University of Fukui
Principal Investigator	Takamura Yoshihiro 福井大学, 学術研究院医学系部門, 准教授 (00283193)
Co-Investigator(Kenkyū-buntansha)	稲谷大福井大学, 学術研究院医学系部門, 教授 (40335245) 沖昌也福井大学, 学術研究院工学系部門, 教授 (60420626)
Project Period (FY)	2016-04-01 – 2020-03-31
Project Status	Completed (Fiscal Year 2019)
Budget Amount *help	¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000) Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000) Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000) Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000) Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Keywords	虚血性網膜疾患 / エピジェネティクス / VEGF / サイトカイン / 血管新生 / メチル化 / 虚血 / 糖尿病網膜症
Outline of Final Research Achievements	As a model organism for retinal ischemic disease, a hyperoxia-induced mouse model (OIR) was created. P7 was defined as a physiological angiogenesis sample, and P17 OIR was defined as a pathological angiogenesis sample. As a result of microarray analysis, 4 genes of Aqp1, Btg1, Cxcr4, and F3 were extracted as those showing changes only under physiological conditions, and Adm was extracted as those showing changes only under pathological conditions. Kdm3a involved in histone demethylation was found in the 1321 probe whose expression level was confirmed to change at P17, which is the peak of pathological angiogenesis. These results suggest that, among hypoxia-responsive genes, changes in the expression level may be used properly depending on the situation, between physiological and pathological angiogenesis.
Academic Significance and Societal Importance of the Research Achievements	これまでの眼科領域では、正常と病的血管新生どちらの状況においても血管新生の誘導は低酸素応答であり、転写制御の違いについては注目されてこなかった。本結果から低酸素応答の遺伝子の中でも、発現量の変化は状況に応じて「使い分け」されている可能性が示唆された。この病態の仕組みにおける解明をさらに進めることで、生理的な血管の機能性を保存しつつ、病的な発現機構のみを制御する新たな治療戦略の構築が可能となることが期待できる。