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Study for the mechanism underlying neuropathic pain by manipulating the membrane phospholipid

Research Project

Project/Area Number 19K16938
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 51030:Pathophysiologic neuroscience-related
Research InstitutionNational Center for Global Health and Medicine

Principal Investigator

Shota Yamamoto  国立研究開発法人国立国際医療研究センター, その他部局等, 特任研究員 (50825693)

Project Period (FY) 2019-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2019: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
Keywords神経障害性疼痛 / 生体膜リン脂質 / リゾリン脂質アシル転移酵素 / 脂質メディエーター / 疼痛 / 後根神経節 / 感覚情報伝達
Outline of Research at the Start

神経障害性疼痛は,神経系の損傷や機能異常により発症し,触刺激でさえ激烈な痛みとして感じる疼痛症状を呈するが,現在,十分な疼痛管理ができていない。一方,細胞構成に必須であるリン脂質は多様で1000分子種を超え,各細胞機能に応じて組成は異なる。その多様性を生む生体分子としてリゾリン脂質アシル転移酵素(LPLATs) が近年複数同定されている。
本研究では,知覚情報伝達を担う神経系において神経損傷時に発現変動するLPLATsを探索し,生体膜リン脂質組成への影響を検討する。また,特定のリン脂質量を変動できるLPLAT遺伝子欠損動物を用い,神経障害性疼痛病態時における生体膜リン脂質の役割を明らかにする。

Outline of Final Research Achievements

Neuropathic pain is a pathological chronic pain condition that occurs after nerve injury, and the underlying mechanisms remain unclear. Glycerophospholipids (PLs) play essential roles in our body, such as main structural components of biological membranes and precursors of bioactive lipid mediators. Over the last ten years, lysophospholipid acyltransferases (LPLATs) have been identified as the responsible genes to generate PLs diversity. In this study, we revealed that peripheral nerve injury (PNI) induced dynamic changes of PLs composition and increase of lipid mediators in the dorsal root ganglia and spinal cord. Using several mice lines lacking LPLAT gene, we found that PNI-induced chronic pain was attenuated in these mice. These findings suggest that LPLATs may be the novel target molecules to treat chronic pain.

Academic Significance and Societal Importance of the Research Achievements

生体膜リン脂質の多様性の生理・病態学的な意義についてはほとんどブラックボックスである。本研究では,神経障害性疼痛病態時における膜リン脂質組成の変化や,リン脂質を前駆体とする脂質メディエーターの産生増加が疼痛症状の発症維持に寄与することを明らかにした。膜リン脂質組成の変化が疼痛に繋がる詳細なメカニズムについてはさらなる検討が必要だが,リン脂質多様性を制御するLPLAT欠損マウスにて疼痛軽減の表現型が得られたことは,今後のリン脂質多様性の生物学において学術的意義が認められる。

Report

(3 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • Research Products

    (9 results)

All 2021 2020 2019

All Journal Article (4 results) (of which Peer Reviewed: 4 results,  Open Access: 2 results) Presentation (5 results)

  • [Journal Article] Drug Repositioning for the Prevention and Treatment of Chemotherapy-Induced Peripheral Neuropathy: A Mechanism- and Screening-Based Strategy2021

    • Author(s)
      Yamamoto Shota、Egashira Nobuaki
    • Journal Title

      Frontiers in Pharmacology

      Volume: 11 Pages: 607780-607780

    • DOI

      10.3389/fphar.2020.607780

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Pathological Mechanisms of Bortezomib-Induced Peripheral Neuropathy2021

    • Author(s)
      Yamamoto Shota、Egashira Nobuaki
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 22 Issue: 2 Pages: 888-888

    • DOI

      10.3390/ijms22020888

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Biosynthetic Enzymes of Membrane Glycerophospholipid Diversity as Therapeutic Targets for Drug Development2020

    • Author(s)
      Valentine William J.、Hashidate-Yoshida Tomomi、Yamamoto Shota、Shindou Hideo
    • Journal Title

      Advances in Experimental Medicine and Biology

      Volume: 1274 Pages: 5-27

    • DOI

      10.1007/978-3-030-50621-6_2

    • ISBN
      9783030506209, 9783030506216
    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Lysophosphatidylethanolamine acyltransferase 2 (LPEAT2) incorporates DHA into phospholipids and has possible functions for fatty acid-induced cell death2020

    • Author(s)
      Eto Miki、Shindou Hideo、Yamamoto Shota、Tamura-Nakano Miwa、Shimizu Takao
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 526 Issue: 1 Pages: 246-252

    • DOI

      10.1016/j.bbrc.2020.03.074

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Presentation] “Quality of Lipid” in the dorsal root ganglion2021

    • Author(s)
      山本将大,清水孝雄,進藤英雄
    • Organizer
      第94回日本薬理学会年会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Platelet-activating factor (PAF) is increased in neuropathic pain mice: different regulation of PAF levels between the spinal cord and the dorsal root ganglia.2020

    • Author(s)
      山本将大,吉田(橋立)智美,進藤英雄,清水孝雄
    • Organizer
      第93回日本薬理学会年会
    • Related Report
      2019 Research-status Report
  • [Presentation] 抗がん薬オキサリプラチン誘発末梢神経障害に対する新規予防薬の探索2019

    • Author(s)
      山本将大
    • Organizer
      第29回日本医療薬学会年会
    • Related Report
      2019 Research-status Report
  • [Presentation] 神経障害性疼痛マウスモデルの後根神経節および脊髄における包括的脂質解析2019

    • Author(s)
      山本将大,吉田(橋立)智美,進藤英雄,清水孝雄
    • Organizer
      第92回日本生化学会大会
    • Related Report
      2019 Research-status Report
  • [Presentation] 神経障害性疼痛マウスモデルの後根神経節におけるリン脂質組成および脂質メディエーターの網羅的解析2019

    • Author(s)
      山本将大,吉田(橋立)智美,進藤英雄,清水孝雄
    • Organizer
      第13回日本緩和医療薬学会年会
    • Related Report
      2019 Research-status Report

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Published: 2019-04-18   Modified: 2022-01-27  

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