A new therapeutic approach of preeclampsia with lysophospholipids

• Project/Area Number: 23791825
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Obstetrics and gynecology
• Research Institution: Nagoya University
• Principal Investigator: KOTANI Tomomi 名古屋大学, 医学部附属病院, 講師 (70359751)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2013: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2012: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2011: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 胎児発育不全 / 絨毛浸潤 / S1P / LPA / EVT / 卵膜 / Ｓ１Ｐ / ＬＰＡ / ＥＶＴ / 浸潤 / autotaxin

Research Abstract

The subtypes of receptors of lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) were expressed in EVT at early gestation. LPA3, S1P1 and S1P3 promoted migration of EVT, but S1P2 suppressed that in EVT cell lines. LPA induced invasion of EVT via activation of ERK, STAT-3, and Akt. S1P1 and S1P3 induced the expression of MMP-9, but S1P2 reduced it. The expression pattern of S1PR subtypes was dependent on cell density. In high cell concentration, S1P2 was mainly expressed, but S1P1 and S1P3 were dominantly expressed in low cell concentration. The antagonist of S1P2 (JTE-013) significantly induced migration of EVT. In pregnant ICR mouse, peritoneal injection of JTE-013 had no effect on the development of placenta and fetus, but injection of FTY720 (S1P1 and 3 antagonist) significantly reduced the weight of placenta and fetus, compared with control. Thus, antagonists or agonists of LPA or S1P could be a new therapeutic drug for fetal growth retardation, and preeclampsia.

Research Products

• [Journal Article] Altered expression of enzymes regulating the activity of endothelin-1 in the lower segment of the human amnion during labor (2013)
  • Author(s): Kotani T, Iwase A, Tsuda H, et al (他8名)
  • Journal Title: Biol Reprod Volume: 89(3) Pages: 52-52
  • Peer Reviewed
• [Journal Article] Increased expression of sphingosine kinase in the amnion during labor (2013)
  • Author(s): Erkhembaatar LO, Kotani T, Sumigama S, et al (他9名)
  • Journal Title: Placenta Volume: 34(4) Pages: 353-9
  • Peer Reviewed
• [Journal Article] 胎児発育不全と胎盤 (2013)
  • Author(s): 小谷友美, 炭竈誠二, 津田弘之ら(他3名)
  • Journal Title: 産婦人科の実際 Volume: Vol.62 (8) Pages: 1065-1072
• [Journal Article] Altered expression of enzymes regulating the activity of endothelin-1 in the lower segment of the human amnion during labor. (2013)
  • Author(s): Kotani T, Iwase A, Tsuda H, Mano Y, Yamamoto E, Nakano T, Hasegawa Y, Li H, Sumigama S, Itakura A, Kikkawa F.
  • Journal Title: Biok Reprod Volume: 89 Issue: 3 Pages: 1-7
  • DOI: 10.1095/biolreprod.113.108480
  • Peer Reviewed
• [Journal Article] Increased expression of sphingosine kinase in the amnion during labor. (2013)
  • Author(s): Erkhembaatar LO, Kotani T, Sumigama S, Tsuda H, Mano Y, Hua L, Hasegawa Y, Wang J, Sugiyama C, Nakahara T, Iwase A, Kikkawa F.
  • Journal Title: Placneta Volume: 34 Pages: 353-359
  • Peer Reviewed
• [Journal Article] High expression of N-acetylglucosaminyltransferase IVa promotes invasion of choriocarcinoma (2012)
  • Author(s): Niimi K, Yamamoto E, Kotani T, et al (他7名)
  • Journal Title: Br J Cancer Volume: 107(12) Pages: 1969-77
  • Peer Reviewed
• [Journal Article] A case report of placental mesenchymal dysplasia with an increased VEGF-D expression (2012)
  • Author(s): Kotani T, Sumigama S, Tsuda H, et al (他9名)
  • Journal Title: Placenta Volume: 33(10) Pages: 888-91
  • Peer Reviewed
• [Journal Article] The loss of endoglin promotes the invasion of extravillous trophoblasts (2011)
  • Author(s): Mano Y, Kotani T, Shibata K, et al (他7名)
  • Journal Title: Endocrinology Volume: 152(11) Pages: 4386-94
  • Peer Reviewed
• [Journal Article] The loss of endoglin promotes the invasion of extravillous trophoblasts. (2011)
  • Author(s): Mano Y, Kotani T, Shibata K, Matsumura H, Tsuda H, Sumigama S, Yamamoto E, Iwase A, Senga T, Kikkawa F.
  • Journal Title: Endocrinology. Volume: 152 Pages: 4386-4394
  • Peer Reviewed
• [Journal Article] Maternal mental disorders and pregnancy outcomes: a clinical study in a Japanese population. (2011)
  • Author(s): Hironaka M, Kotani T, Sumigama S, Tsuda H, Mano Y, Hayakawa H, Tanaka S, Ozaki N, Tamakoshi K, Kikkawa F.
  • Journal Title: J Obstet Gynaecol Res. Volume: 37 Issue: 10 Pages: 1283-1289
  • DOI: 10.1111/j.1447-0756.2010.01512.x
  • Peer Reviewed
• [Presentation] 炎症に起因する早産におけるエンドセリン(ET)-1を制御する酵素の発現バランスについて (2014)
  • Author(s): 小谷友美ら(他10名)
  • Organizer: 第66回日本産婦人科学会学術講演会
  • Place of Presentation: 東京国際フォーラム(東京都千代田区)
  • Year and Date: 2014-04-20
• [Presentation] The new insights of preterm labor with chorioaminonitis(CAM) (2014)
  • Author(s): Tomomi Kotani et al. (他7名)
  • Organizer: 2014 SGI 61^<st> Annual Scientific meeting
  • Place of Presentation: イタリア、フィレンチェ
  • Year and Date: 2014-03-28
• [Presentation] 炎症に起因する早産におけるエンドセリン（ＥＴ)-1を制御する酵素の発現バランスについて (2014)
  • Author(s): 小谷友美、炭竈誠二、津田弘之、眞野由紀雄、中野知子、今井健史、諸井博明、
  • Organizer: 第66回日本産科婦人科学会学術講演会
  • Place of Presentation: 東京国際フォーラム(千代田区）
• [Presentation] The new insights of preterm labor with chorioamnionitis (CAM) (2014)
  • Author(s): Tomomi Kotani, Seiji Sumigama, Hiroyuki Tsuda, Yukio Mano, Tomoko Nakano, Shima Hirako, Hua Li, Fumitaka Kikkawa
  • Organizer: 2014 SGI 61st Annual Scientific Meeting
  • Place of Presentation: フィレンツェ(イタリア）
• [Presentation] The involvement of enzymes which activate and inactivate endothelin-1 (ET-1) in human labor onset (2012)
  • Author(s): Tomomi Kotani, Seiji Sumigama, Hiroyuki Tsuda, Yukio Mano, Tomoko Nakano, Kaoru Nimi, Sawako Fujiwara, Satoshi Matsukawa, Yuriko Watanabe, Li Hua, Fumitaka Kikkawa
  • Organizer: IFPA2012
  • Place of Presentation: 広島
• [Presentation] The new mediators of human labour-onset (2012)
  • Author(s): Tomomi Kotani, Tomoko Nakano, Yuriko Watanabe, Yukio Mano, Hiroyuki Tsuda, Li hua,
  • Organizer: COGI
  • Place of Presentation: リスボン
• [Presentation] 絨毛浸潤の調節について (2011)
  • Author(s): 小谷友美ら(他7名)
  • Organizer: 第19回日本胎盤学会学術集会
  • Place of Presentation: 東京ステーションコンファレンス(東京都千代田区)
  • Year and Date: 2011-10-01
• [Presentation] リゾリン脂質による絨毛浸潤機能の調節作用 (2011)
  • Author(s): 小谷友美ら(他10名)
  • Organizer: 第63回日本産婦人科学会学術講演会
  • Place of Presentation: 大阪国際会議場(大阪市)
  • Year and Date: 2011-08-29
• [Presentation] 絨毛浸潤の調節について
  • Author(s): 小谷友美
  • Organizer: 第19回日本胎盤学会学術集会
  • Place of Presentation: 東京ステーションコンファレンス
• [Presentation] リゾリン脂質による絨毛浸潤機能の調節作用
  • Author(s): 小谷友美
  • Organizer: 第63回日本産婦人科学会学術講演会
  • Place of Presentation: 大阪国際会議場
• [Remarks]
  • URL: http://www.med.nagoya-u.ac.jp/obgy/research/obstetrics/