2019 Fiscal Year Final Research Report
Investigation of epigenetic mechanisms associated with anti-VEGF drug tolerance
| Project/Area Number |
17K11469
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Ophthalmology
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| Research Institution | St. Marianna University School of Medicine |
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Principal Investigator |
Takagi Hitoshi 聖マリアンナ医科大学, 医学部, 教授 (70283596)
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| Co-Investigator(Kenkyū-buntansha) |
北岡 康史 聖マリアンナ医科大学, 医学研究科, 教授 (10367352)
塩野 陽 聖マリアンナ医科大学, 医学部, 講師 (20737598)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Keywords | jmjd1a / epigenetic regulation |
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| Outline of Final Research Achievements |
Anti-VEGF treatment is effective for vascular-leakage in diabetic retinopathy and age-related macular degeneration. Drug tolerance has, however, been reported. The H3K9 histone demethylase Jmjd1a has been reported as a potential regulator of VEGF production through HIF1 modification. In the present study, no remarkable differences were observed between wild type mouse and Jmjd1a knockout mouse in developmental retinal vasculature. On the other hand, distinct suppression of retinal neovascularization was observed in knockout mouse rather than wild type mouse in oxygen-induced retinal neovascular model. These finding suggests that epigenetic modification with histone demethylase reaction regulate VEGF effects in retinal vasculature under hypoxic condition. The epigenetic regulation might be associated with anti-VEGF drug tolerance.
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| Free Research Field |
糖尿病網膜症
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| Academic Significance and Societal Importance of the Research Achievements |
黄斑浮腫や脈絡膜新生血管に対し血管内皮増殖因子(VEGF)阻害治療が有効であるが、症例ごとの反応の違いや薬剤耐性が報告されている。遺伝子自体の変化を介さず遺伝子クロマチン凝集や転写後遺伝子の安定化などエピジェネティクスと呼ばれる遺伝子調節メカニズムが個体差や反応性の違いに影響すると注目されている。VEGFによる網膜血管形成ではDNAヒストンメチル化を抑制すると正常な網膜血管の発生には影響せず、低酸素下では血管新生が抑制された。低酸素下ではエピジェネティクス制御がVEGF作用を修飾していることが示唆され、今後VEGF阻害治療の薬剤耐性の解決や有効性向上にその関与の検討が有用となる可能性がある。
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