新規スレオニン含有リン脂質のマスト細胞における機能と産生機構の解明

• Project/Area Number: 19659014
• Research Category: Grant-in-Aid for Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Biological pharmacy
• Research Institution: Tohoku University
• Principal Investigator: 青木 淳賢 Tohoku University, 大学院・薬学研究科, 教授 (20250219)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥3,300,000 (Direct Cost: ¥3,300,000); Fiscal Year 2008: ¥1,600,000 (Direct Cost: ¥1,600,000); Fiscal Year 2007: ¥1,700,000 (Direct Cost: ¥1,700,000)
• Keywords: リゾホスファチジルスレオニン / 受容体 / 産生酵素 / ノックアウトマウス / リゾボスファチジルセリン / マスト細胞 / 脱顆粒反応 / ヒスタミン / リゾホスファチジルセリン

Research Abstract

マスト細胞は、細胞表面のIgE受容体に結合したIgEが抗原により架橋されると脱顆粒し、ヒスタミンなどのケミカルメディエーターを放出することにより、様々なアレルギー疾患に関与している。リゾリン脂質の一種であるリゾホスファチジルセリン(lysoPS)はラット腹腔マスト細胞(RPMC)のIgEと抗原により惹起される脱顆粒反応を著しく促進する作用を有することが知られているが、その作用機構については不明な点が多く残されている。我々はこれまでに様々なlysoPS誘導体を有機化学的に作製合成し、マスト細胞上に存在するlysoPS受容体のリガンド認識性について検討した結果、極性頭部にスレオニンを持つリゾリン脂質、リゾホスファチジルスレオニン(lysoPT)がlysoPSよりも十〜数十倍強い脱顆粒促進活性を有することリゾホスファチジルスレオニン(lysoPT)を見出した。一方、マスト細胞上にはlysoPSに反応性を示すGタンパク質共役型受容体GPR34が発現していることが最近報告され、たが、lysoPSによる脱顆粒促進作用がGPR34を介しているかについては不明であった可能性が示唆された。そこで今回、GPR34のlysoPT応答性を調べたところlysoPTはGPR34に一切反応しなかった。このことから、lysoPSによる脱顆粒促進作用にはGPR34が関与しないこと、マスト細胞にはGPR34と異なるもう一つの未知lysoPS受容体の少なくとも二つのlysoPS受容体が存在することがわかった。GPR34に対するKOマウスの作製に成功した。

Research Products

• [Journal Article] Protection against oxidative stress-induced hepatic injury by intracellular type II PAF-acetylhydrolase by metabolism of oxidized phospholipids in vivo (2009)
  • Author(s): Nakamura, K., Igarashi, K., Ohkawa, R., Okubo, S., Yokota, H., Kishimoto, T., Ide, K., Masuda, A., Yamamoto, T., Saito, N., Kurokawa, M., Tsuji, S., Okudaira, S., Ikeda, H., Aoki, J., and Yatomi, Y.
  • Journal Title: J Biol. Chem (In press)
  • Peer Reviewed
• [Journal Article] Analysis of serum and urinary lysophospholipase D/autotaxin in nephrotic syndrome (2009)
  • Author(s): Makide, K., Kitamura, H., Sato, Y., Okutani, M., and Aoki, J
  • Journal Title: POLM (In press)
  • Peer Reviewed
• [Journal Article] Embryo Spacing and Implantation Timing Are Differentially Regulated by LPA3-Mediated Lysophosphatidic Acid Signaling in Mice (2009)
  • Author(s): Endo, T., Kano, K., Motoki, R., Hama, K., Okudaira, S., Ishida, M., Ogiso, H., Tanalca,M., Matsuki, N., Taguchi, R., Kanai, M., Shibasaki, M., Arai, H., and Aoki, J.
  • Journal Title: J. Biochem (In press)
  • Peer Reviewed
• [Journal Article] Validation of an autotaxin enzyme immunoassay in human serum samples and its application to hypoalbuminemia differentiation (2008)
  • Author(s): Makide, K., Kano, K., Kitamura, H., Arima, N., and Aoki, J
  • Journal Title: Tanpakushitsu Kakusan Koso 54 Pages: 29-39
• [Journal Article] Phospholipase A(1) assays using a radiolabeled substrate and mass spectrometry (2008)
  • Author(s): Ohuchi, H., Hamada, A., Matsuda, H., Takagi, A., Tanaka, M., Aoki, J., Arai, H., and Noji, S.
  • Journal Title: Dev. Dyn 237 Pages: 3280-3294
  • Peer Reviewed
• [Journal Article] Serum lysophospholipase D/autotaxin may be a new nutritional assessment marker : study on prostate cancer patients (2008)
  • Author(s): Nakasaki, T., Tanaka, T., Okudaira, S., Hirosawa, M., Umemoto, E., Otani, K., Jin, S., Bai, Z., Hayasaka, H., Fukui, Y., Aozasa, K., Fujita, N., Tsuruo, T., Ozono, K., Aoki, J., and Miyasaka, M
  • Journal Title: Am J pathol 173 Pages: 1566-1576
  • Peer Reviewed
• [Journal Article] Protection against oxidative stress-induced hepatic injury by intracellular type II PAF-acetylhydrolase by metabolism of oxidized phospholipids in vivo. (2008)
  • Author(s): Kono N, Inoue T, Yoshida Y, Sato H, Matsusue T, Itabe H, Niki E, Aoki J, Arai H.
  • Journal Title: J. Biol. Chem. 283 Pages: 1628-1636
  • Peer Reviewed
• [Journal Article] Analysis of serum and urinary lysophospholipase D/autotaxin in nephrotic syndrome. (2008)
  • Author(s): Nakamura K, Nangaku M, Ohkawa R, Okubo S, Yokota H, Ikeda H, Aoki J, Yatomi Y.
  • Journal Title: Clin. Chem. Lab. Med. 46 Pages: 150-151
  • Peer Reviewed
• [Journal Article] Validation of an autotaxin enzyme immunoassay in human samples and its application to hypoalbuminemia differentiation. (2008)
  • Author(s): Nakamura K, Igarashi K, Ide K, Ohkawa R, Okubo S, Yokota H, Masuda A, Oshima N, Takeuchi T, Nangaku M, Okudaira S, Arai H, Ikeda H, Aoki J, Yatomi Y.
  • Journal Title: Clin. Chim. Acta 388 Pages: 51-58
  • Peer Reviewed
• [Journal Article] Embryo Spacing and Implantation Timing Are Differentially Regulated by LPA3-Mediated Lysophosphatidic Acid Signaling in Mice. (2007)
  • Author(s): Hama K, Aoki J, Inoue A, Endo T, Amano T, Motoki R, Kanai M, Ye X, Chun J, Matsuki N, Suzuki H, Shibasaki M, Arai H.
  • Journal Title: Biol. Reprod. 77 Pages: 954-959
  • Peer Reviewed
• [Journal Article] Phospholipase A (1) assays using a radiolabeled substrate and mass spectrometry. (2007)
  • Author(s): Morikawa R, Tsujimoto M, Arai H, Aoki J.
  • Journal Title: Methods Enzymol. 434 Pages: 1-13
  • Peer Reviewed
• [Journal Article] Serum lysophospholipase D/autotaxin may be a new nutritional assessment marker: study on prostate cancer patients. (2007)
  • Author(s): Nakamura K, Takeuchi T, Ohkawa R, Okubo S, Yokota H, Tozuka M, Aoki J, Arai H, Ikeda H, Ohshima N, Kitamura T, Yatomi Y.
  • Journal Title: Ann. Clin. Biochem. 44 Pages: 549-556
  • Peer Reviewed
• [Journal Article] Type I platelet-activating factor acetylhydrolase calalytic subunits over-expression induces pleiomorphic nuclei and centrosome amplification. (2007)
  • Author(s): Yamaguclu N, Koizumi H, Aoki J, Natori Y, Nishikawa K, Natori Y, Takanezawa Y, Arai H.
  • Journal Title: Genes Cells 12 Pages: 1153-1161
  • Peer Reviewed
• [Journal Article] Plasma lySophosphatidic acid level and serum autotaxin activity are increased in liver injury in rats in relation to its severity. (2007)
  • Author(s): Watanabe N, Ikeda H, Nakamura K, Ohkawa R, Kume Y, Tomiya T, Tejima K, Nishikawa T, Arai M, Yanase M, Aoki J, Arai H, Omata M, Fujiwara K, Yatomi Y.
  • Journal Title: Life Sci. 81 Pages: 1009-1015
  • Peer Reviewed
• [Journal Article] Submucosal connective tissue-type mast cells contribute to the production of lysophosphatidic acid (LPA) in the gastrointestinal tract through the secretion of autotaxin (ATX)/lysophospholipase D (lysoPLD). (2007)
  • Author(s): Mori K, Kitayama J, Aoki J, Kishi Y, Shida D, Yamashita H, Arai H, Nagawa H.
  • Journal Title: Virchows Arch. 451 Pages: 47-56
  • Peer Reviewed
• [Journal Article] Lysophosphatidic acid protection against apoptosis in the human pre-B-cell line Nalm-6. (2007)
  • Author(s): Satoh Y, Ohkawa R, Nakamura K, Higashi K, Kaneko M, Yokota H, Aoki J, Arai H, Yuasa Y, Yatomi Y.
  • Journal Title: Eur. J. Haematol. 78 Pages: 510-517
  • Peer Reviewed
• [Journal Article] Diversified expression patterns of autotaxin, a gene for phospholipid-generating enzyme during mouse and chicken development (2007)
  • Author(s): Ohuchi H, Hayashibaza Y, Matsuda H, Onoi M, Mitsumori M, Tanaka M, Aoki J, Arai H, Noji S.
  • Journal Title: Dev. Dyn. 236 Pages: 1134-1143
  • Peer Reviewed
• [Journal Article] Peritoneal fluids from patients with certain gynecologic tumor contain elevated levels of bioactive lysophospholipase D activity. (2007)
  • Author(s): Tokumura A, Kume T, Fukuzawa K, Tahara M, Tasaka K, Aoki J, Arai H
  • Journal Title: Life Sci. 80 Pages: 1641-1649
  • Peer Reviewed
• [Journal Article] Neuroprotective Role of Transgenic PAF-Acetylhydrolase II in Mouse Models of Focal Cerebral Ischemia. (2007)
  • Author(s): Umemura K, Kato I, Hirashima Y, Ishii Y, Inoue T, Aoki J, Kono N, Oya T, Hayashi N, Hamada H, Endo S, Oda M, Arai H, Kinouchi H, Hiraga K.
  • Journal Title: Stroke 38 Pages: 1036-1068
  • Peer Reviewed
• [Journal Article] Plasma lysophosphatidic acid is increased in liver fibrosis in rats and human with enhanced serum autotaxin level. (2007)
  • Author(s): Watanabe N, Ikeda H, Nakamura K, Ohkawa R, Kume Y, Aoki J, Hama K, Okudaira S, Tanaka M, Yanase M, Nagashima K, Tomiya T, Arai M, Inoue Y, Tejima K, Nishikawa T, Arai H, Omata M, Fujiwara K, Yatomi Y
  • Journal Title: J. Clin. Gastroenterol 41 Pages: 616-623
  • Peer Reviewed
• [Journal Article] Structure and function of extracellular phospholipase Al belonging to the pancreatic lipase gene family (review). (2007)
  • Author(s): Aoki J, Inoue A, Makide K, Saiki N, Arai H.
  • Journal Title: Biochimie 89 Pages: 197-204
  • Peer Reviewed
• [Journal Article] Measurement of lysophospholipase D/autotaxin activity in human serum samples (2007)
  • Author(s): Nakamura K, Ohkawa R, Okubo S, Tozuka M, Okada M, Aoki S, Aoki J, Arai H, Ikeda H, Yatomi Y
  • Journal Title: Clin. Biochem. 40 Pages: 274-277
  • Peer Reviewed
• [Journal Article] Autotaxin (NPP-2) in the brain: Cell type-specific expression and regulation during development and after neurotrauma (2007)
  • Author(s): Savaskan NE, Rocha L, Kotter MR, Lubec G, Baer A, van Meeteren LA, Kishi Y, Aoki J, Moolenaar WH, Nitsch R, Brauer AU.
  • Journal Title: Cell. Mol. Life Sci. 64 Pages: 230-243
  • Peer Reviewed
• [Presentation] オーファンGPCR, P2Y10のリガンド探索と機能解析 (2008)
  • Author(s): 北村一、巻出久美子、秋山るみ、佐藤侑介、青木淳賢
  • Organizer: ファーマ・バイオフオーラム2008
  • Place of Presentation: 東京、渋谷、日本薬学会長井記念ホール
• [Presentation] リゾボスファチジルセリン受容体GPR34の解析 (2008)
  • Author(s): 巻出久美子、佐藤侑介、北村一、秋山るみ、青木淳賢
  • Organizer: BMB2008
  • Place of Presentation: 兵庫県、神戸、国際会議場
• [Presentation] P2Y10受容体のリガンド探索と機能解析 (2008)
  • Author(s): 北村一、巻出久美子、秋山るみ、佐藤侑介、青木淳賢
  • Organizer: BMB2008
  • Place of Presentation: 兵庫県、神戸、国際会議場