Gene network analysis of placental function regulators and a seed gene, ezrin

• Project/Area Number: 25860396
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Applied pharmacology
• Research Institution: Keio University
• Principal Investigator: NISHIMURA Tomohiro 慶應義塾大学, 薬学部, 講師 (40453518)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2014: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 胎児発育不全 / 血液胎盤関門 / 遺伝子ネットワーク / 胎児成長不全 / エズリン / ヒポタウリン / 遺伝子ネットワーク解析 / トランスポーター / 胎盤

Outline of Final Research Achievements

Placental function plays important roles in the fetal growth. Ezrin is a regulatory gene for plasma membrane proteins in the placenta, and deficiency of ezrin induces fetal growth retardation (FGR). This study aimed to clarify a gene network between ezrin and the other genes responsible for FGR by means of informatics and experiments in order to understand the molecular mechanism of the ezrin-mediated FGR. Network analysis showed no direct relationship between ezrin and the known FGR-related genes, indicating that ezrin-mediated FGR includes the novel molecular mechanism. We further analyzed protein interaction between Ezrin and a hypotaurine transporter, SLC6A13 in the placenta, since Ezrin knockout fetal mice showed deficiency of hypotaurine. Ezrin and SLC6A13 are co-localized on the plasma membrane in the labyrinth zone of mouse placenta. These results indicate that a novel interaction between Ezrin and SLC6A13 is important for fetal growth.

Research Products

• [Journal Article] Organic anion transporter 4-mediated transport of olmesartan at basal plasma membrane of human placental barrier (2015)
  • Author(s): Noguchi S, Nishimura T, Fujibayashi A, Maruyama T, Tomi M, Nakashima E.
  • Journal Title: J Pharm Sci Volume: 104 Issue: 9 Pages: 3128-3135
  • DOI: 10.1002/jps.24434
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Protective effect of hypotaurine against oxidative stress-induced cytotoxicity in rat placental trophoblasts (2015)
  • Author(s): Nishimura T, Duereh M, Sugita Y, Yoshida Y, Higuchi K, Tomi M, Nakashima E.
  • Journal Title: Placenta Volume: 36 Issue: 6 Pages: 693-698
  • DOI: 10.1016/j.placenta.2015.02.014
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Fetal growth retardation and lack of hypotaurine in ezrin knockout mice. (2014)
  • Author(s): Nishimura T, Higuchi K, Sai Y, Sugita Y, Yoshida Y, Tomi M, Wada M, Wakayama T, Tamura A, Tsukita S, Soga T, Nakashima E.
  • Journal Title: PLoS ONE Volume: 9(8) Issue: 8 Pages: e105423-e105423
  • DOI: 10.1371/journal.pone.0105423
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Role of protein kinase A in regulating steroid sulfate uptake for estrogen production in human placental choriocarcinoma cells (2014)
  • Author(s): Tomi M, Miyata Y, Noguchi S, Nishimura S, Nishimura T, Nakashima E.
  • Journal Title: Placenta Volume: 35 Issue: 8 Pages: 658-660
  • DOI: 10.1016/j.placenta.2014.06.003
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] System amino acid transporter SNAT2 shows subtype-specific affinity for betaine and hyperosmotic inducibility in placental trophoblasts. (2014)
  • Author(s): Nishimura T, Yagi R, Usuda M, Oda K, Yamazaki M, Suda S, Takahashi Y, Okazaki F, Sai Y, Higuchi, K, Maruyama T, Tomi M, Nakashima E
  • Journal Title: Biochim Biophys Acta. Volume: VOL. 1838 Issue: 5 Pages: 1306-12
  • DOI: 10.1016/j.bbamem.2014.01.004
  • Peer Reviewed
• [Journal Article] Evaluation of rat in vivo fetal-to-maternal transfer clearances of various xenobiotics by umbilical perfusion. (2013)
  • Author(s): Nishimura T, Takanohashi T, Tomi M, Horikoshi M, Higuchi K, Sai Y, Nakashima E.
  • Journal Title: J Pharm Sci Volume: 102(9) Issue: 9 Pages: 3356-3363
  • DOI: 10.1002/jps.23551
  • Peer Reviewed
• [Journal Article] Estrogen receptor α induction by mitoxantrone increases Abcg2 expression in placental trophoblast cells. (2013)
  • Author(s): Oda K, Nishimura T, Higuchi K, Ishido N, Ochi K, Iizasa H, Sai Y, Tomi M, Nakashima E.
  • Journal Title: J Pharm Sci Volume: 102 Issue: 9 Pages: 3364-3372
  • DOI: 10.1002/jps.23549
  • Peer Reviewed
• [Presentation] Distribution of hypotaurine transporter, Slc6a13, in placental trophoblasts during mid to late pregnancy (2014)
  • Author(s): Nishimura T, Araki H, Takaki Y, Tomi M, Nakashima E
  • Organizer: 19th North American ISSX Meeting / 29th JSSX Meeting
  • Place of Presentation: San Francisco
  • Year and Date: 2014-10-19 – 2014-10-23
• [Presentation] Slc6a13の胎盤における発現分布とヒポタウリン取込み輸送による酸化ストレスからの細胞保護 (2014)
  • Author(s): 西村友宏、小島和晃、高木良也、荒木光、登美斉俊、中島恵美
  • Organizer: 第９回トランスポーター研究会年会
  • Place of Presentation: 名古屋
  • Year and Date: 2014-06-14 – 2014-06-15
• [Presentation] ヒポタウリントランスポーターSlc6a13の胎盤における発現と細胞保護作用 (2014)
  • Author(s): 西村 友宏、荒木 光、小島 和晃、登美 斉俊、中島 恵美
  • Organizer: 日本薬剤学会第２９年会
  • Place of Presentation: 大宮
  • Year and Date: 2014-05-20 – 2014-05-22
• [Presentation] Hypotaurine transporter contributes to cytoprotection in placental trophoblasts from oxidative stress (2014)
  • Author(s): Nishimura T, Tomi M, Nakashima E
  • Organizer: 5th Asia Pasific International Society for the Study of Xenoiotics (ISSX) Meeting
  • Place of Presentation: Tienjin
  • Year and Date: 2014-05-09 – 2014-05-12
• [Presentation] Cytoprotective properties of hypotaurine by scavenging hydroxyl radicals in placental trophoblast cells. (2013)
  • Author(s): Araki H, Duereh M, Nishimura T, Sugita Y, Higuchi K, Tomi M, Nakashima E.
  • Organizer: International Federation of Placenta Associations(IFPA)2013
  • Place of Presentation: Whistler, Canada
• [Presentation] Rat in vivo fetal-to-maternal transfer clearances of various xenobiotics by umbilical perfusion. (2013)
  • Author(s): Nishimura T, Tomi M, Nakashima E.
  • Organizer: International Society for the Study of Xenobiotics, 10th International ISSX Meeting
  • Place of Presentation: Toronto, Canada
• [Presentation] Uptake and antioxidative effect of hypotaurine in the placenta. (2013)
  • Author(s): Araki H, Duereh M, Sugita Y, Higuchi K, Nishimura T, Tomi M, Nakashima E.
  • Organizer: Asian Federation for Pharmaceutical Sciences 2013
  • Place of Presentation: Jeju, Republic of Korea
• [Presentation] ヒポタウリンの胎盤での生理的濃度維持における細胞膜輸送の寄与および活性酸素除去作用. (2013)
  • Author(s): 西村友宏、杉田友紀、Mariam Duereh、登美斉俊、中島恵美.
  • Organizer: 日本薬剤学会第28年会
  • Place of Presentation: 名古屋