Role of prostanoid in demyelination and remyelination.

• Project/Area Number: 17K08604
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General pharmacology
• Research Institution: Kitasato University
• Principal Investigator: Kojima Fumiaki 北里大学, 医療衛生学部, 准教授 (30550545)
• Co-Investigator(Kenkyū-buntansha): 市川 尊文 北里大学, 医療衛生学部, 教授 (30245378)
• Project Period (FY): 2017-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: プロスタノイド / 多発性硬化症 / 遺伝子欠損マウス

Outline of Final Research Achievements

We investigated the role of microsomal prostaglandin E synthase-1 (mPGES-1) in demyelination and motor dysfunction induced by cuprizone, one of the well-established models of multiple sclerosis (MS). Demyelination in the brain was induced in mPGES-1 knock-out (KO) and wild-type (WT) mice by feeding ad libitum with a powdered diet containing cuprizone. Cuprizone up-regulated the expression of mPGES-1 in the brain of WT mice. Interestingly, mPGES-1 KO mice exhibited lower degree of demyelination and reduced motor dysfunction compared to WT mice. These data indicate that mPGES-1 and its derived prostaglandin E2 (PGE2) might contribute to the pathophysiology of MS and open possible novel therapeutic approaches for MS.

Academic Significance and Societal Importance of the Research Achievements

本研究によって得られた成果は、MSの病態形成機構の解明ならびに効果的な治療法の開発に資することが期待される。最近では、脱髄は、脊髄損傷やアルツハイマー病などの神経変性疾患、統合失調症・鬱病・自閉症といった様々な精神疾患にも関与していることが次々と報告されている。本研究成果は、MS以外の脱髄疾患の病態解明と新たな治療法の開発にも有用な情報を提供できる可能性がある。

Research Products

• [Journal Article] Facilitation of colonic T cell immune responses is associated with an exacerbation of dextran sodium sulfate?induced colitis in mice lacking microsomal prostaglandin E synthase-1 (2022)
  • Author(s): Kojima Fumiaki、Sekiya Hiroki、Hioki Yuka、Kashiwagi Hitoshi、Kubo Makoto、Nakamura Masaki、Maehana Shotaro、Imamichi Yoshitaka、Yuhki Koh-ichi、Ushikubi Fumitaka、Kitasato Hidero、Ichikawa Takafumi
  • Journal Title: Inflammation and Regeneration Volume: 42 Issue: 1 Pages: 1-24
  • DOI: 10.1186/s41232-021-00188-1
  • Peer Reviewed / Open Access
• [Journal Article] Panton-Valentine Leukocidin Induces Cytokine Release and Cytotoxicity Mediated by the C5a Receptor on Rabbit Alveolar Macrophages (2021)
  • Author(s): Shinya Harada, Hayato Kawada, Shotaro Maehana, Hidehito Matsui, Makoto Kubo, Fumiaki Kojima, Hidero Kitasato, Masato Katagiri.
  • Journal Title: Japanese Journal of Infectious Diseases Volume: 74 Issue: 4 Pages: 352-358
  • DOI: 10.7883/yoken.JJID.2020.657
  • NAID: 130008066545
  • ISSN: 1344-6304, 1884-2836
  • Year and Date: 2021-07-31
  • Peer Reviewed
• [Journal Article] Complete genome sequencing and comparative genomic analysis of KPC-2-producing Klebsiella pneumoniae isolated from a hospital sewage water in Japan. (2021)
  • Author(s): Ryotaro Eda, Shotaro Maehana, Aki Hirabayashi, Masaki Nakamura, Takashi Furukawa, Shinsuke Ikeda, Kouji Sakai, Fumiaki Kojima, Kazunari Sei, Masato Suzuki, Hidero Kitasato.
  • Journal Title: J Glob Antimicrob Resist. Volume: 24 Pages: 180-182
  • DOI: 10.1016/j.jgar.2020.12.007
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Natural factories that manufacture antimicrobial resistance genes: quadruple blaGES-carrying plasmids in Aeromonas and Pseudomonas species. (2021)
  • Author(s): Shotaro Maehana, Ryotaro Eda, Aki Hirabayashi, Nagi Niida, Masaki Nakamura, Takashi Furukawa, Shinsuke Ikeda, Fumiaki Kojima, Kouji Sakai, Kazunari Sei, Hidero Kitasato, Masato Suzuki.
  • Journal Title: Int J Antimicrob Agents. Volume: 28 Issue: 5 Pages: 106327-106327
  • DOI: 10.1016/j.ijantimicag.2021.106327
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] LRRK2 Inhibition Ameliorates Dexamethasone-Induced Glucose Intolerance <i>via</i> Prevents Impairment in GLUT4 Membrane Translocation in Adipocytes (2020)
  • Author(s): Motoki Imai, Fumitaka Kawakami, Makoto Kubo, Makoto Kanzaki, Hiroko Maruyama, Rei Kawashima, Tatsunori Maekawa, Yoshifumi Kurosaki, Fumiaki Kojima, Takafumi Ichikawa.
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 43 Issue: 11 Pages: 1660-1668
  • DOI: 10.1248/bpb.b20-00377
  • NAID: 130007934043
  • ISSN: 0918-6158, 1347-5215
  • Year and Date: 2020-11-01
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Histamine depolarizes rat intracardiac ganglion neurons through the activation of TRPC non-selective cation channels. (2020)
  • Author(s): Aya Sato, Shiho Arichi, Fumiaki Kojima, Toru Hayashi, Tatsuko Ohba, Dennis Lawrence Cheung, Kei Eto, Madoka Narushima, Hideji Murakoshi, Yoshihiro Maruo, Yuichi Kadoya, Junichi Nabekura, Hitoshi Ishibashi.
  • Journal Title: Eur J Pharmacol. Volume: 886 Pages: 173536-173536
  • DOI: 10.1016/j.ejphar.2020.173536
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Inhibition of Interleukin-6 Signaling Attenuates Aortitis, Left Ventricular Hypertrophy and Arthritis in Interleukin-1 Receptor Antagonist Deficient Mice. (2020)
  • Author(s): Yoshiko Hada, Haruhito A. Uchida, Tomoyuki Mukai, Fumiaki Kojima, Masashi Yoshida, Hidemi Takeuchi, Yuki Kakio, Nozomu Otaka,Yoshitaka Morita, Jun Wada.
  • Journal Title: Clin. Sci. (Lond). Volume: 134 Issue: 20 Pages: 2771-2787
  • DOI: 10.1042/cs20201036
  • NAID: 120007168219
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Real-time visualization of intratumoral necrosis using split-luciferase reconstitution by protein trans-splicing. (2020)
  • Author(s): Go Kagiya Ayaka Sato Ryohei Ogawa Masanori Hatashita Mana Kato Makoto Kubo Fumiaki Kojima Fumitaka Kawakami Yukari Nishimura Naoya Abe Fuminori Hyodo.
  • Journal Title: Mol Ther Oncolytics. Volume: 20 Pages: 48-58
  • DOI: 10.1016/j.omto.2020.12.001
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prostaglandin F2α Facilitates Platelet Activation by Acting on Prostaglandin E2 Receptor Subtype EP3 and Thromboxane A2 Receptor TP in Mice (2019)
  • Author(s): Kashiwagi Hitoshi、Yuhki Koh-ichi、Imamichi Yoshitaka、Kojima Fumiaki、Kumei Shima、Tasaki Yoshikazu、Narumiya Shuh、Ushikubi Fumitaka
  • Journal Title: Thrombosis and Haemostasis Volume: 119 Issue: 08 Pages: 1311-1320
  • DOI: 10.1055/s-0039-1688906
  • Peer Reviewed
• [Journal Article] Interleukin-24 Transduction Modulates Human Prostate Cancer Malignancy Mediated by Regulation of Anchorage Dependence (2019)
  • Author(s): MAEHANA SHOTARO、MATSUMOTO YUTA、KOJIMA FUMIAKI、KITASATO HIDERO
  • Journal Title: Anticancer Research Volume: 39 Issue: 7 Pages: 3719-3725
  • DOI: 10.21873/anticanres.13520
  • Peer Reviewed / Open Access
• [Journal Article] Prostaglandin F2α facilitates platelet activation by acting on prostaglandin E2 receptor subtype EP3 and thromboxane A2 receptor TP in mice. (2019)
  • Author(s): Hitoshi Kashiwagi, Koh-ichi Yuhki, Yoshitaka Imamichi, Fumiaki Kojima, Shima Kumei, Shuh Narumiya, Fumitaka Ushikubi.
  • Journal Title: Thrombosis and Haemostasis. Volume: in press
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prostaglandin I2 suppresses the development of diet-induced nonalcoholic steatohepatitis in mice (2018)
  • Author(s): Kumei Shima、Yuhki Koh-Ichi、Kojima Fumiaki、Kashiwagi Hitoshi、Imamichi Yoshitaka、Okumura Toshikatsu、Narumiya Shuh、Ushikubi Fumitaka
  • Journal Title: The FASEB Journal Volume: 32 Issue: 5 Pages: 2354-2365
  • DOI: 10.1096/fj.201700590r
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Roles of prostanoids in the regulation of platelet function. (2018)
  • Author(s): Hitoshi Kashiwagi, Koh-ichi Yuhki, Yoshitaka Imamichi, Fumiaki Kojima, Shima Kumei, Shuh Narumiya, Fumitaka Ushikubi.
  • Journal Title: Thromb Haemost Res. Volume: 2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cigarette Smoke Extract Inhibits Platelet Aggregation by Suppressing Cyclooxygenase Activity (2017)
  • Author(s): Kashiwagi Hitoshi、Yuhki Koh-ichi、Imamichi Yoshitaka、Kojima Fumiaki、Kumei Shima、Higashi Tsunehito、Horinouchi Takahiro、Miwa Soichi、Narumiya Shuh、Ushikubi Fumitaka
  • Journal Title: TH Open Volume: 01 Issue: 02 Pages: e122-e129
  • DOI: 10.1055/s-0037-1607979
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] mPGES1-Dependent Prostaglandin E2(PGE2) Controls Antigen-Specific Th17 and Th1 Responses by Regulating T Autocrine and Paracrine PGE2Production (2017)
  • Author(s): Maseda Damian、Johnson Elizabeth M.、Nyhoff Lindsay E.、Baron Bridgette、Kojima Fumiaki、Wilhelm Ashley J.、Ward Martin R.、Woodward Jerold G.、Brand David D.、Crofford Leslie J.
  • Journal Title: The Journal of Immunology Volume: 200 Issue: 2 Pages: 725-736
  • DOI: 10.4049/jimmunol.1601808
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] ウサギ肺胞マクロファージ（AM）を用いたPanton-Valentine leukocidin（PVL）の作用 (2021)
  • Author(s): 原田真也, 川田逸人, 前花祥太郎, 松井秀仁, 久保 誠, 小島史章, 北里英郎, 片桐真人
  • Organizer: 第61回日本呼吸器学会学術講演会
• [Presentation] 放射線による腫瘍内低酸素細胞アポトーシスの可視化とその経時変化 (2021)
  • Author(s): 青柳美希、小川良平、畑下昌範、兵藤文紀、久保誠、小島史章、川上文貴、鍵谷豪.
  • Organizer: 北里大学バイオサイエンスフォーラム
• [Presentation] T細胞免疫系の制御を介した膜型プロスタグランジンE合成酵素-1のデキストラン硫酸ナトリウム誘発腸炎に対する保護的役割 (2021)
  • Author(s): 日置優花、関谷広樹、三島絵梨香、北浦咲耶子、久保誠、北里英郎、市川尊文、小島史章.
  • Organizer: 145回 薬理学会関東部会
• [Presentation] Action of Panton-Valentine leukocidin on rabbit alveolar macrophages. (2021)
  • Author(s): 原田真也、川田逸人、前花祥太郎、松井秀仁、久保 誠、小島史章、北里英郎、片桐真人、横場正典.
  • Organizer: The 25th Congress of the Asian Pacific Society of Respirology.
  • Int'l Joint Research
• [Presentation] 腸管炎症・免疫系におけるプロスタグランジンE合成酵素の役割 (2021)
  • Author(s): 小島史章
  • Organizer: 第13回 北里大学医療衛生学部附属再生医療細胞デザイン研究施設シンポジウム
• [Presentation] Inhibition of Interleukin-6 Signaling Attenuates Aortitis and Cardiomyocyte Hypertrophy in Interleukin-1 Receptor Antagonist Deficient Mice. (2020)
  • Author(s): Yoshiko Hada, Haruhito A. Uchida, Tomoyuki Mukai, Fumiaki Kojima, Nozomu Otaka, Hidemi Takeuchi, Masashi Yoshida, Yoshitaka Morita, Yoichiro Iwakura, Jun Wada.
  • Organizer: Arteriosclerosis, Thrombosis and Vascular Biology / Peripheral Vascular Disease (ATVB|PVD) 2020 Scientific Sessions (ATVB/PVD 2020)
  • Int'l Joint Research
• [Presentation] Role of the microsomal prostaglandin E synthase-1 in cuprizone-induced demyelination and motor dysfunction. (2020)
  • Author(s): Fumiaki Kojima, Hiroki Sekiya, Hayato Kawada, Hitoshi Kashiwagi, Yoshitaka Imamichi, Koh-ichi Yuhki, Fumitaka Ushikubi, Hidero Kitasato, Takafumi Ichikawa.
  • Organizer: 第93回 日本薬理学会年会
• [Presentation] The prostaglandin E2-EP4 system protects the liver in Concanavalin A-induced hepatitis. (2020)
  • Author(s): Yoshitaka Imamichi, Koh-ichi Yuhki, Hitoshi Kashiwagi, Shima Kumei, Katsura Nakanishi, Fumiaki Kojima, Shuh Narumiya, Fumitaka Ushikubi.
  • Organizer: 第93回 日本薬理学会年会
• [Presentation] Inhibition of Interleukin-6 Signaling on Aortitis in Interleukin-1 Receptor Antagonist Deficient Mice. (2019)
  • Author(s): Yoshiko Hada, Haruhito A. Uchida, Tomoyuki Mukai, Fumiaki Kojima, Nozomu Otaka, Yasuhiro Onishi, Yoshitaka Morita, Yoichiro Iwakura, Jun Wada.
  • Organizer: Arteriosclerosis, Thrombosis and Vascular Biology / Peripheral Vascular Disease (ATVB|PVD) 2019 Scientific Sessions (ATVB/PVD 2019)
  • Int'l Joint Research
• [Presentation] プロスタノイド生合成系に着目した炎症性腸疾患の病態形成機序の解明 (2019)
  • Author(s): 小島史章
  • Organizer: 第32回北里大学大学院医療系研究科研究フォーラム
• [Presentation] Role of the prostaglandin E2-EP4 system in Concanavalin A-induced hepatitis (2019)
  • Author(s): Yoshitaka Imamichi1, Ko-ichi Yuhki, Hitoshi Kashiwagi, Shima Kumei, Fumiaki Kojima, Katsura Nakanishi, Shuh Narumiya, Fumitaka Ushikubi
  • Organizer: 日本薬理学会年会
• [Presentation] Up-regulation of colonic Th1/Th17 cytokines is associated with increased severity of experimental colitis in mice lacking microsomal prostaglandin E synthase-1. (2018)
  • Author(s): Hiroki Sekiya, Masaki Nakamura, Shotaro Maehana, Hitoshi Kashiwagi, Yoshitaka Imamichi, Koh-ichi Yuhki, Fumitaka Ushikubi, Takafumi Ichikawa, Hidero Kitasato, Fumiaki Kojima.
  • Organizer: 18th World Congress of Basic and Clinical Pharmacology.
  • Int'l Joint Research
• [Presentation] Potentiating effect of prostaglandin F2a on platelet aggregation in mice. (2018)
  • Author(s): Hitoshi Kashiwagi, Koh-ichi Yuhki, Yoshitaka Imamichi, Fumiaki Kojima, Shima Kumei, Shuh Narumiya, Fumitaka Ushikubi.
  • Organizer: 18th World Congress of Basic and Clinical Pharmacology.
  • Int'l Joint Research
• [Presentation] 炎症性腸疾患における膜型プロスタグランジンE合成酵素-1の役割 (2018)
  • Author(s): 関谷広樹、守田なつみ、中村仁美、青木 結、久保 誠、市川尊文、北里英郎、小島史章
  • Organizer: 北里大学バイオサイエンスフォーラム
• [Presentation] 炎症性腸疾患における膜型プロスタグランジンE合成酵素－1の役割 (2017)
  • Author(s): 関谷広樹、河喜多智美、鈴木沙織、京極美帆、倉本大輔、市川尊文、北里英郎、小島史章
  • Organizer: 薬理学会関東部会
• [Presentation] トリニトロベンゼンスルホン酸誘発腸炎モデルにおける膜型プロスタグランジンE合成酵素-1の保護的役割 (2017)
  • Author(s): 関谷広樹、河喜多智美、中村正樹、前花祥太郎、市川尊文、北里英郎、小島史章
  • Organizer: 炎症再生医学会
• [Presentation] デキストラン硫酸ナトリウム誘発腸炎モデルにおけるTh1/Th17系の制御を介したmPGES-1/PGE2系の保護的役割 (2017)
  • Author(s): 関谷広樹、市川尊文、北里英郎、小島史章
  • Organizer: 炎症再生医学会
• [Presentation] 炎症性腸疾患におけるTh17/Th1系の制御を介した膜型プロスタグランジンE合成酵素-1の保護的役割 (2017)
  • Author(s): 関谷広樹、鈴木沙織、京極美帆、倉本大輔、市川尊文、北里英郎、小島史章
  • Organizer: 北里大学バイオサイエンスフォーラム
• [Presentation] 炎症性腸疾患様マウスモデルを用いた膜型プロスタグランジンE合成酵素-1の役割 (2017)
  • Author(s): 関谷広樹、鈴木沙織、京極美帆、倉本大輔、市川尊文、北里英郎、小島史章
  • Organizer: 日本炎症性腸疾患学会