Signaling pathways which affect expression of the transcription factors associated with the patent ductus arteriosus

• Project/Area Number: 18K07889
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Tokyo Women's Medical University
• Principal Investigator: Hayama Emiko 東京女子医科大学, 医学部, 非常勤講師 (00349698)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 動脈管 / 酸素感受性 / 転写因子 / シグナル伝達 / 胎児発達

Outline of Final Research Achievements

Increase of oxygen concentration in blood induces postnatal ductus arteriosus (DA) vasoconstriction, initiating functional closure. DA gets programmed for the postnatal closure as developmental maturation, involving proliferation and migration of DA smooth muscle to form neointima, increase of extracellular matrix, development of smooth muscle contraction system, and oxygen sensing ability.
In this study, rabbit full-term fetal DA was exposed to high or low oxygen circumstances, and the RNA sequencing was applied to detect difference of their mRNA expression. Oxygen modified DA signal transduction systems, including the cAMP signal and MAPK pathways, angiogenesis, cellular proliferation, smooth muscle constriction, epigenetic modification, transformation, interaction of extracellular matrix molecules with cells, oxidative phosphorylation, and apoptosis. DA also responds immunologically against the inflammation induced by the oxygen treatment.

Academic Significance and Societal Importance of the Research Achievements

動脈管が胎生期に開存していることは生命維持に必須であり、生後は閉じないと心不全に陥る。酸素を感受して閉鎖する動脈管には、特徴的なシグナル伝達及び遺伝子制御機構が存在する。未熟児動脈管を収縮する薬は、現在プロスタグランジン生成を抑制するCOX阻害剤（インドメタシン等）のみである。酸素感受能を含む動脈管の多様なシグナル伝達システムを明らかにできれば、動脈管の成熟を促進し、収縮・機能的閉鎖へと導く方策も考案できることから、未熟児動脈管開存症を治療する創薬ターゲットの発見が期待できる。