Development of novel approach for prevention of preterm birth by inhibiting cervical ripening using anti-inflammatory proteins

• Project/Area Number: 18K09220
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56040:Obstetrics and gynecology-related
• Research Institution: The University of Tokyo
• Principal Investigator: Nagamatsu Takeshi 東京大学, 医学部附属病院, 准教授 (60463858)
• 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: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 早産 / 妊娠 / 頸管熟化 / 抗炎症蛋白 / 炎症制御 / プロテアーゼ / 子宮頸管熟化 / SLPI / プログラニュリン / 抗プロテアーゼ

Outline of Final Research Achievements

In this study, we aimed to investigate the involvement of two anti-inflammatory proteins, progranulin (PGRN) and secretory leukocyte protease inhibitor (SLPI), in the regulation of cervical ripening and to gain new insights for the treatment of preterm birth. Analysis of mouse models of preterm birth and clinical specimens revealed that PGRN and SLPI were produced abundantly at the cervix and fetal membrane. Expression patterns at the cervix were different between PGRN and SLPI depending on the causes of preterm birth. Anti-inflammatory and anti-protease properties are shared among PGRN and SLPI, but they might play distinct roles in the regulation of cervical ripening.

Academic Significance and Societal Importance of the Research Achievements

プロゲステロン作用不全と感染炎症は早産の代表的な背景機序である。しかし、臨床的にその双方を鑑別して治療の個別化に結び付けることはできていない。本研究の結果から妊婦の頸管において、PGRNおよびSLPIは異なる発現制御を受けており、そうした早産の背景原因の鑑別のためのバイオマーカー候補となりうることが示唆された。また特に、SLPIは早産の背景要因に関わらず病的頸管熟化の阻止に働くことが期待でき、子宮頸管熟化抑制という新規の着眼点からの早産治療の候補となりうる。

Research Products

• [Journal Article] Secretory leukocyte protease inhibitor and progranulin as possible regulators of cervical remodeling in pregnancy (2021)
  • Author(s): Samejima Taiki、Nagamatsu Takeshi、Akiba Naoya、Fujii Tatsuya、Sayama Seisuke、Kawana Kei、Taguchi Ayumi、Kumasawa Keiichi、Iriyama Takayuki、Osuga Yutaka、Fujii Tomoyuki
  • Journal Title: Journal of Reproductive Immunology Volume: 143 Pages: 103241-103241
  • DOI: 10.1016/j.jri.2020.103241
• [Journal Article] Impact of additional risk factors on the incidence of preterm delivery among pregnant women diagnosed with short cervix (2020)
  • Author(s): Samejima Taiki、Nagamatsu Takeshi、Iriyama Takayuki、Nakayama Toshio、Seyama Takahiro、Sayama Seisuke、Kumasawa Keiichi、Komatsu Atsushi、Kawana Kei、Osuga Yutaka、Fujii Tomoyuki
  • Journal Title: Taiwanese Journal of Obstetrics and Gynecology Volume: 59 Issue: 2 Pages: 195-199
  • DOI: 10.1016/j.tjog.2020.01.005
  • Peer Reviewed / Open Access
• [Journal Article] Ultrasonographic vascularity assessment for predicting future severe hemorrhage in retained products of conception after second-trimester abortion (2019)
  • Author(s): Akiba Naoya、Iriyama Takayuki、Nakayama Toshio、Seyama Takahiro、Sayama Seisuke、Kumasawa Keiichi、Komatsu Atsushi、Yabe Shinichiro、Nagamatsu Takeshi、Osuga Yutaka、Fujii Tomoyuki
  • Journal Title: The Journal of Maternal-Fetal & Neonatal Medicine Volume: ahead of print Issue: 4 Pages: 1-7
  • DOI: 10.1080/14767058.2019.1610739
  • Peer Reviewed
• [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] 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] Molecular Mechanisms to Regulate Trophoblast Cell Functions and Cervical (2018)
  • Author(s): 永松 健
  • Journal Title: 日本産科婦人科学会雑誌ACTA OBST GYNAEC JPN Volume: 70 Pages: 2604-2614
• [Presentation] Regulation of cervical ripening by anti-inflammatory mediators in preterm labor and term delivery (2019)
  • Author(s): Takeshi Nagamatsu
  • Organizer: The 14th World Congress of International Society for Immunology of Reproduction
  • Int'l Joint Research / Invited
• [Presentation] Progranulin and secretory leukocyte protease inhibitor as key mediators in cervical ripening (2019)
  • Author(s): Akiba Naoya, Takeshi Nagamatsu 他
  • Organizer: 第71回日本産科婦人科学会学術集会
• [Presentation] 学術奨励賞受賞講演 絨毛細胞機能および子宮頸管熟化を制御する分子システムと妊娠維持機構 (2018)
  • Author(s): 永松 健
  • Organizer: 第70回 日本産科婦人科学会学術集会
  • Invited
• [Presentation] The association of progranulin expression controlled by progesterone with cervical maturation (2018)
  • Author(s): Taiki Samejima, Takeshi Nagamatsu, Takayuki Iriyama, Yutaka Osuga, Tomoyuki Fujii
  • Organizer: 第70回 日本産科婦人科学会学術集会
• [Presentation] Secretory leukocyte protease inhibitor as a key regulator of cervical maturation (2018)
  • Author(s): Takeshi Nagamatsu
  • Organizer: The 38th Annual Meeting of the American Society for reproductive Immunology
  • Int'l Joint Research / Invited
• [Presentation] Progranulin as a key mediator in cervical ripening (2018)
  • Author(s): Naoya Akiba,Takeshi Nagamatsu,Keiichi Kumasawa, Takayuki Iriyama, Yutaka Osuga, Tomoyuki Fujii
  • Organizer: Congress of European Society for Reproductive Immunology 2018
• [Presentation] Progranulinによる頸管熟化制御機構-Essential role of progranulin in the regulation of cervical remodeling (2018)
  • Author(s): 秋葉 直也, 永松 健, 鮫島 大輝, 熊澤 恵一, 瀬山 貴博, 中山 敏男, 入山 高行, 大須賀 穣, 藤井 知行
  • Organizer: 第33回日本生殖免疫学会