Investigation of placental adenosine signaling in the pathogenesis of preeclampsia

• Project/Area Number: 16H06266
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Obstetrics and gynecology
• Research Institution: The University of Tokyo
• Principal Investigator: Iriyama Takayuki 東京大学, 医学部附属病院, 講師 (10570442)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥22,620,000 (Direct Cost: ¥17,400,000、Indirect Cost: ¥5,220,000); Fiscal Year 2018: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2017: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2016: ¥10,920,000 (Direct Cost: ¥8,400,000、Indirect Cost: ¥2,520,000)
• Keywords: 妊娠高血圧腎症

Outline of Final Research Achievements

We found that ⅰ）transcription factor X plays key roles in the enhancement of placental adenosine signaling leading to preeclampsia(PE).ⅱ) agent X with the effects to ameliorate endothelial dysfunction shows therapeutic potentials for PE. ⅲ) elevation of HIF-2α in trophoblasts underlies the downregulation of PlGF expression in PE. ⅳ) elevation of LIGHT leading to the increased sFlt-1 expression implies the pathogenic link between the development of PE in hydatidiform mole.

Academic Significance and Societal Importance of the Research Achievements

妊娠高血圧腎症（PE)は、妊娠中の高血圧を主徴とする疾患であり、母児の周産期罹病の主因であるが、その発症と病態形成の詳細な分子機序はいまだ不明な点が多い。本研究においては、PEにおいて増強した胎盤でのアデノシンシグナルの分子機序の一端を明らかとし、アデノシンシグナルおよび血管内皮障害を標的とした治療的な可能性を示す結果を得た。PEに対する病態に即した有効な治療法は存在せず、PE病態の分子機序の解明および治療法の開発は喫緊の課題である。臨床への応用を含め、本研究がその一歩となる可能性を秘めている。

Research Products

• [Journal Article] Tokishakuyakusan, a traditional Japanese medicine (Kampo) mitigates iNKT cell-mediated pregnancy loss in mice (2018)
  • Author(s): Nagamatsu Takeshi、Fujii Tatsuya、Schust Danny J.、Tsuchiya Naoko、Tokita Yohei、Hoya Mari、Akiba Naoya、Iriyama Takayuki、Kawana Kei、Osuga Yutaka、Fujii Tomoyuki
  • Journal Title: American Journal of Reproductive Immunology Volume: 80 Issue: 4
  • DOI: 10.1111/aji.13021
  • Peer Reviewed
• [Journal Article] Elevation of maternal serum sFlt-1 in pregnancy with mirror syndrome caused by fetal cardiac failure (2018)
  • Author(s): Katoh Yoshihisa、Seyama Takahiro、Mimura Nobuko、Furuya Hitomi、Nakayama Toshio、Iriyama Takayuki、Nagamatsu Takeshi、Osuga Yutaka、Fujii Tomoyuki
  • Journal Title: Oxford Medical Case Reports Volume: 2018 Issue: 3
  • DOI: 10.1093/omcr/omx112
  • Peer Reviewed
• [Journal Article] Atomoxetine, a selective norepinephrine reuptake inhibitor, improves short-term histological outcomes after hypoxic-ischemic brain injury in the neonatal male rat. (2018)
  • Author(s): Toshimitsu M, Kamei Y, Ichinose M, Seyama T, Imada S, Iriyama T, Fujii T.
  • Journal Title: Int J Dev Neurosci Volume: - Issue: 1 Pages: 34-45
  • DOI: 10.1016/j.ijdevneu.2018.03.011
  • Peer Reviewed
• [Journal Article] Impact of Th1/Th2 cytokine polarity induced by invariant NKT cells on the incidence of pregnancy loss in mice (2018)
  • Author(s): Hoya Mari、Nagamatsu Takeshi、Fujii Tatsuya、Schust Danny J.、Oda Hiroko、Akiba Naoya、Iriyama Takayuki、Kawana Kei、Osuga Yutaka、Fujii Tomoyuki
  • Journal Title: American Journal of Reproductive Immunology Volume: 79 Issue: 3
  • DOI: 10.1111/aji.12813
  • Peer Reviewed
• [Journal Article] Pretreatment with magnesium sulfate attenuates white matter damage by preventing cell death of developing oligodendrocytes. (2018)
  • Author(s): Seyama T, Kamei Y, Iriyama T, Imada S, Ichinose M, Toshimitsu M, Fujii T, Asou H.
  • Journal Title: J Obstet Gynaecol Res. Volume: 44 Issue: 4 Pages: 601-607
  • DOI: 10.1111/jog.13568
  • Peer Reviewed
• [Journal Article] Enhanced HIF2α expression during human trophoblast differentiation into syncytiotrophoblast suppresses transcription of placental growth factor (2017)
  • Author(s): Fujii Tatsuya、Nagamatsu Takeshi、Morita Kazuki、Schust Danny J.、Iriyama Takayuki、Komatsu Atsushi、Osuga Yutaka、Fujii Tomoyuki
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 12455-12455
  • DOI: 10.1038/s41598-017-12685-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Shifting of HIF subtypes expression during syncytialization is associated with the regulation of VEGF family molecules in human trophoblast cells (2018)
  • Author(s): Fujii T et.al
  • Organizer: 平成31年度 日本産科婦人科学会学術講演会
• [Presentation] LIGHT elevation underlies sFlt-1 overproduction in hydatidiform mole ：An implication for the pathogenic link between molar pregnancy and preeclampsia (2018)
  • Author(s): Matsui H et.al
  • Organizer: 平成31年度 日本産科婦人科学会学術講演会
• [Presentation] 妊娠高血圧腎症における炎症性サイトカインの役割の検討～治療標的・予知マーカーとしての可能性の探求～ (2017)
  • Author(s): 入山高行
  • Organizer: 日本産科婦人科学会学術講演会
• [Presentation] 胎盤での過剰なアデノシグナルを介した妊娠高血圧腎症の発症機序の解明 (2016)
  • Author(s): 入山高行
  • Organizer: 日本妊娠高血圧学会
  • Place of Presentation: 埼玉県大宮市
  • Invited
• [Presentation] 妊娠高血圧腎症の病態形成における自己抗体の関与 (2016)
  • Author(s): 入山高行
  • Organizer: 日本生殖免疫学会
  • Place of Presentation: 兵庫県神戸市
  • Invited
• [Book] Preeclampsia -Basic, Genomic, and Clinical (2018)
  • Author(s): Iriyama T
  • Total Pages: 290
  • Publisher: Springer Nature
• [Book] Preeclampsia Basic, Genomic, and Clinical (2018)
  • Author(s): Shigeru Saito and et.al.
  • Total Pages: 290
  • Publisher: Springer Nature
  • ISBN: 9789811058912