Elucidating the pathophysiology of placental insufficiency for the novel treatment of the disease

• Project/Area Number: 19K24044
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0906:Surgery related to the biological and sensory functions and related fields
• Research Institution: The University of Tokyo
• Principal Investigator: Sayama Seisuke 東京大学, 医学部附属病院, 助教 (00775041)
• Project Period (FY): 2019-08-30 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 妊娠高血圧腎症 / 胎児発育不全 / 赤血球 / 妊娠高血圧症候群 / 胎盤輸送 / アミノ酸トランスポーター / 胎盤

Outline of Research at the Start

胎盤機能不全に伴う周産期疾患（胎児発育不全(FGR)や妊娠高血圧腎症(PE)）発症の分子病態機序の解明を目指す。申請者らは、マウスの知見として、母獣の赤血球の酸素運搬能の低下が胎盤の低酸素状態を惹起し、母児間の栄養輸送機構を阻害し、FGRの発症に関与することを明らかとした(Sayama S., Blood, under revision)。マウスでの知見をヒトFGR/PE症例で検討し、病態機序における重要性および治療的可能性を検証する。

Outline of Final Research Achievements

We analyzed the relationship between fetal growth restriction (FGR) and preeclampsia (PE) with erythrocytes by using a mouse model which lacks ENT1 on the erythrocyte cell membrane showing lowered oxygen binding capacity. These mice showed FGR phenotype, which was possibly due to hypoxia in the placenta and down regulated amino acid transporter in the placenta. Based on these findings, we investigated whether the erythrocyte oxygen binding capacity has a role in the pathogenesis of FGR/PE.

Academic Significance and Societal Importance of the Research Achievements

胎児発育不全や妊娠高血圧腎症による早産や新生児死亡、母体死亡を減らすためにはその疾患の原因を解明する必要があるが、多くは謎に包まれたままである。母体赤血球という切口で同疾患の原因を解明するのは全く新しい方法で、画期的な原因解明や治療に繋がる可能性を秘めた研究である。

Research Products

• [Journal Article] Maternal erythrocyte ENT1?mediated AMPK activation counteracts placental hypoxia and supports fetal growth (2020)
  • Author(s): Sayama Seisuke、Song Anren、Brown Benjamin C.、Couturier Jacob、Cai Xiaoli、Xu Ping、Chen Changhan、Zheng Yangxi、Iriyama Takayuki、Sibai Baha、Longo Monica、Kellems Rodney E.、D’Alessandro Angelo、Xia Yang
  • Journal Title: JCI Insight Volume: 5 Issue: 10
  • DOI: 10.1172/jci.insight.130205
  • Peer Reviewed / Open Access
• [Presentation] 妊娠高血圧腎症の病態生理と子宮腺筋症が及ぼす周産期疾患について (2021)
  • Author(s): 佐山晴亮
  • Organizer: 第36回日本生殖免疫学会総会
  • Invited
• [Presentation] ENT1 mediated maintenance of maternal erythrocytes’ oxygen delivering capacity plays crucial roles in placental oxygenation and adequate fetal growth (2020)
  • Author(s): Seisuke Sayama
  • Organizer: 日本産婦人科学会
• [Presentation] Maternal erythrocyte ENT1-mediated oxygen delivery is necessary for adequate placental oxygenation and fetal growth (2019)
  • Author(s): Seisuke Sayama
  • Organizer: 国際生殖免疫学会
  • Int'l Joint Research
• [Presentation] Maternal erythrocyte ENT1-mediated AMPK activation and oxygen delivery: a missing component counteracting placental hypoxia, dysfunction, and fetal growth restriction. (2019)
  • Author(s): Seisuke Sayama
  • Organizer: American society of Hematology
  • Int'l Joint Research
• [Presentation] 胎盤におけるアミノ酸輸送機構と胎児発育 (2019)
  • Author(s): 佐山晴亮
  • Organizer: 胎盤学会
  • Invited
• [Presentation] 赤血球の酸素運搬能の低下は、胎盤のアミノ酸輸送機構を阻害し胎児発育不全の発症に関与する (2019)
  • Author(s): 佐山晴亮
  • Organizer: 妊娠高血圧学会