Functional Analyses of epigenetic molecules associated with early induced transcription factors in angiogenesis

2019 Fiscal Year Final Research Report

• Project/Area Number: 17H03614
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Medical genome science
• Research Institution: The University of Tokyo
• Principal Investigator: KANKI YASUHARU 東京大学, アイソトープ総合センター, 助教 (00534869)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 血管新生 / エピジェネティクス / VEGF

Outline of Final Research Achievements

This study was initiated with the aim of identifying candidate molecules of new drugs that do not inhibit physiological angiogenesis but inhibit pathological angiogenesis involved in malignant solid tumor growth and progression. Based on multi-omics analysis of human vascular endothelial cells stimulated with vascular endothelial growth factor (VEGF), we identified two epigenomic modification-related molecules, PTIP and PCGF3, as candidate targets. Next, we generated vascular endothelial cell-specific Pcgf3 knockout mice, which resulted in the inhibition of angiogenesis. This study not only identified the first epigenome-associated factor in angiogenesis, but its inhibition also resulted in reduction of angiogenesis in vivo, making it a promising candidate for future anti-angiogenic drugs.

Free Research Field

血管生物学

Academic Significance and Societal Importance of the Research Achievements

本研究成果により、遺伝子の一過性の転写に抑制系タンパク質複合体PRC1.3の関与があるという従来にない機構を示すことができ、この点において学術的意義の高い研究となった。一方で、生理的な血管新生を阻害せずに、病的血管新生を阻害する候補となるエピゲノム関連因子を同定した。現在、臨床では抗血管新生阻害薬は抗がん剤のみならず、糖尿病性網膜症、加齢黄斑変性症など、多岐にわたる。悪性腫瘍や生活習慣病悪化によるQOLの低下が、医療経済の圧迫の要因の一つであることを鑑みると、本研究成果を生かした創薬は、わが国だけではなく、他の先進国でもインパクトのある結果となる。