Immunosuppressive role of lysophosphatidylserine and its evaluation as drug targets

• Project/Area Number: 25293010
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Biological pharmacy
• Research Institution: Tohoku University
• Principal Investigator: Aoki Junken 東北大学, 薬学研究科(研究院), 教授 (20250219)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000); Fiscal Year 2015: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2014: ¥10,140,000 (Direct Cost: ¥7,800,000、Indirect Cost: ¥2,340,000); Fiscal Year 2013: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
• Keywords: リゾホスファチジルセリン / GPCR / 作動薬 / 免疫抑制 / 脂質メディエーター / 自己免疫疾患 / 質量分析 / 生理活性脂質

Outline of Final Research Achievements

Previously we isolated two GPCR, P2Y10 and GPR174, as specific receptor for lysophospholipid mediator, lysophosphatidylserine (LysoPS). In this study, by analyzing knockout mice of P2Y10 and GPR174, we tried to identify the pathophysiological roles of LysoPS through these receptors. In addition, we tried to create specific agonist as drug candidates. First we found that both P2Y10 and GPR174 KO mice showed enlarged lymphonodes and spleen with enhanced proliferation of T and B lymphocytes. By chemically modifying each chemical group of LysoPS, we succeeded in identifying specific agonists for each receptor, which showed 1,000 times more activity than LysoPS.

Research Products

• [Journal Article] Structure-Activity Relationships of Lysophosphatidylserine Analogs as Agonists of G-Protein-Coupled Receptors GPR34, P2Y10, and GPR174 (2015)
  • Author(s): Masaya Ikubo, Asuka Inoue, Sho Nakamura, Sejin Jung, Misa Sayama, Yuko Otani, Akiharu Uwamizu, Keisuke Suzuki, Takayuki Kishi, Akira Shuto, Jun Ishiguro, Michiyo Okudaira, Kuniyuki Kano, Kumiko Makide, Junken Aoki, and Tomohiko Ohwada
  • Journal Title: Journal of Medicinal Chemistry Volume: 58 Issue: 10 Pages: 4204-4219
  • DOI: 10.1021/jm5020082
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Iida Y, Sunami E, Yamashita H, Hiyoshi M, Ishihara S, Yamaguchi H, Inoue A, Makide K, Tsuno NH, Aoki J, Kitayama J, Watanabe T (2015)
  • Author(s): Phosphatidylserine-specific phospholipase A1 (PS-PLA1) expression in colorectal cancer correlates with tumor invasion and hematogenous metastasis
  • Journal Title: Anticancer Res Volume: 35 Pages: 1459-1464
  • Peer Reviewed
• [Journal Article] Lysophosphatidylserine has Bilateral Effects on Macrophages in the Pathogenesis of Atherosclerosis (2015)
  • Author(s): Nishikawa M, Kurano M, Ikeda H, Aoki J, Yatomi Y
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 22 Issue: 5 Pages: 518-526
  • DOI: 10.5551/jat.25650
  • NAID: 130004704381
  • ISSN: 1340-3478, 1880-3873
  • Peer Reviewed / Open Access
• [Journal Article] Lysophosphatidylserine analogues differentially activate three LysoPS receptors (2015)
  • Author(s): Akiharu Uwamizu, Asuka Inoue, Kensuke Suzuki, Michiyo Okudaira, Akira Shuto, Yuji Shinjo, Jun Ishiguro, Kumiko Makide, Masaya Ikubo, Sho Nakamura, Sejin Jung, Misa Sayama, Yuko Otani, Tomohiko Ohwada and Junken Aoki
  • Journal Title: Journal of biochemistry Volume: 157 Issue: 3 Pages: 151-160
  • DOI: 10.1093/jb/mvu060
  • Peer Reviewed / Open Access
• [Journal Article] Novel lysophosphoplipid receptors: their structure and function. (2014)
  • Author(s): Makide K, Uwamizu A, Shinjo Y, Ishiguro J, Okutani M, Inoue A, Aoki J.
  • Journal Title: J. Lipid Res. Volume: 55 Issue: 10 Pages: 1986-95
  • DOI: 10.1194/jlr.r046920
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Separation and quantification of 2-acyl-1-lysophospholipids and 1-acyl-2-lysophospholipids in biological samples by LC-MS/MS. (2014)
  • Author(s): Okudaira M, Inoue A, Shuto A, Nakanaga K, Kano K, Makide K, Saigusa D, Tomioka Y, Aoki J.
  • Journal Title: J. Lipid Res. Volume: 55 Issue: 10 Pages: 2178-2192
  • DOI: 10.1194/jlr.d048439
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] GPR34 as a lysophosphatidylserine receptor (2013)
  • Author(s): Makide K and Aoki J
  • Journal Title: J. Biochem. Volume: 153 Issue: 4 Pages: 327-329
  • DOI: 10.1093/jb/mvt010
  • Peer Reviewed
• [Presentation] リゾリン脂質の GPCR への結合様式解明のための誘導体合成 (2016)
  • Author(s): 佐山 美紗, ジョン セジン, 中村 翔, 井久保 仁也, 尾谷 優子, 上水 明治, 岸 貴之, 井上 飛鳥, 巻出 久美子, 青木 淳賢, 広川 貴次, 大和田 智彦
  • Organizer: 日本薬学会
  • Place of Presentation: 横浜パシフィコ
  • Year and Date: 2016-03-26
• [Presentation] CRISPR/Cas9システムを用いたLysoPS受容体 TKO マウスの作製 (2015)
  • Author(s): 新上 雄司, 井上 飛鳥, 巻出 久美子, 中島 修, 青木 淳賢
  • Organizer: BMB2015
  • Place of Presentation: 神戸国際会議場
  • Year and Date: 2015-12-01
• [Presentation] LysoPS受容体のサブタイプ選択的アゴニストの開発 (2015)
  • Author(s): 上水 明治, 井上 飛鳥, 井久保 仁也, 中村 翔, ジョン セジン, 佐山 美紗, 岸 貴之, 巻出 久美子, 尾谷 優子, 大和田 智彦, 青木 淳賢
  • Organizer: BMB2015
  • Place of Presentation: 神戸国際会議場
  • Year and Date: 2015-12-01
• [Presentation] Novel GPCRs for lysophosphatidylserine; their structure and function (2015)
  • Author(s): Junken Aoki
  • Organizer: PLM2015
  • Place of Presentation: 東京
  • Year and Date: 2015-02-10 – 2015-02-12
• [Presentation] Novel Receptors for lysophosphatidylserine; their structure and function (2014)
  • Author(s): Junken Aoki
  • Organizer: FEPS2014 (Federation of European Physiological Societies 2014)
  • Place of Presentation: Budapest (ハンガリー)
  • Year and Date: 2014-08-26 – 2014-08-29
• [Presentation] 免疫系を制御する新たな脂質メディエーターリゾホスファチシジルセリン (2014)
  • Author(s): 青木淳賢
  • Organizer: 第35回再生・炎症学会、
  • Place of Presentation: 沖縄
  • Year and Date: 2014-07-02 – 2014-07-04
• [Presentation] TGFα切断アッセイのハイスループットスクリーニングへの応用 (2014)
  • Author(s): 上水明治、井上飛鳥、青木 淳賢
  • Organizer: 日本薬学会
  • Place of Presentation: 熊本
• [Presentation] LysoPS は GPR174 を介して IL-2 産生を抑制する (2013)
  • Author(s): 新上 雄司、北村 一、石黒 純、奥谷 倫世、井上 飛鳥、巻出 久美子、井久保 仁也、大和田 智彦、青木 淳賢
  • Organizer: 日本生化学会
  • Place of Presentation: 横浜
• [Presentation] LysoPSの検出系の確立と生体内におけるLysoPSの検出 (2013)
  • Author(s): 奥平倫世、井上飛鳥、三枝大輔、富岡佳久、巻出久美子、青木淳賢
  • Organizer: 日本脂質生化学会
  • Place of Presentation: 松島、宮城
• [Presentation] リゾホスファチジルセリンは活性化リンパ球の増殖を抑制する (2013)
  • Author(s): 石黒 純、北村 一、首藤 啓明、新上 雄司、井上 飛鳥、巻出 久美子、青木 淳賢
  • Organizer: 日本生化学会
  • Place of Presentation: 横浜
• [Presentation] コンカナバリンA誘導肝炎におけるリゾホスファチジルセリンの機能解析 (2013)
  • Author(s): 鈴木 健介、奥谷 倫世、井上 飛鳥、巻出 久美子、青木 淳賢
  • Organizer: 日本生化学会
  • Place of Presentation: 横浜