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Study of drug discovery and biomarker for depression based on glial antidepressant receptor (LPA1)

Research Project

Project/Area Number 18H02756
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 52030:Psychiatry-related
Research InstitutionKumamoto University (2020-2022)
Department of Clinical Research, National Hospital Organization Kure Medical Center (2018-2019)

Principal Investigator

竹林 実  熊本大学, 大学院生命科学研究部(医), 教授 (60304440)

Co-Investigator(Kenkyū-buntansha) 功刀 浩  帝京大学, 医学部, 教授 (40234471)
井上 飛鳥  東北大学, 薬学研究科, 准教授 (50525813)
Project Period (FY) 2018-04-01 – 2023-03-31
Project Status Granted (Fiscal Year 2022)
Budget Amount *help
¥17,030,000 (Direct Cost: ¥13,100,000、Indirect Cost: ¥3,930,000)
Fiscal Year 2022: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
Fiscal Year 2021: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
Fiscal Year 2020: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
Fiscal Year 2019: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
Fiscal Year 2018: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Keywordsうつ病 / リゾフォスファチジン酸受容体1 / 抗うつ薬受容体 / 創薬 / バイオマーカー / LPA受容体 / 抗うつ薬創薬 / DHA-LPA / うつ病バイオマーカー / リゾホスファチジン酸1受容体 / 抗うつ薬 / グリア / LPA1受容体 / 脂質メディエーター / リゾリン脂質 / オートタキシン / リン脂質
Outline of Annual Research Achievements

本研究の目的は、リゾフォスファチジン酸(LPA)受容体に関する抗うつ薬の創薬およびうつ病のバイオマーカーの開発である。
本年度は、ある特定カテゴリーの既存の抗うつ薬群が、リゾフォスファチジン酸(LPA)受容体のアゴニスト活性を有することを受容体サブタイプ別に明らかにした。また、そのアゴニスト活性の特異的な作用様式も明らかにした。今回得られた知見は、新しいLPA受容体関連の抗うつ薬の候補を探索する際には貴重な情報となる。現在、市販のLPA受容体リガンドおよびLPA受容体の内因性リガンドであるLPAに関して、今回確立したin vitroアッセイ系を用いて、LPA受容体の作用プロファイリングを行っているところである。ある特定カテゴリーの既存の抗うつ薬群と一致するプリファイリングを有するLPA受容体リガンドが見つかれば、それが新規抗うつ薬の有力な候補になると考えている。
一方で、診断バイオマーカー探索研究としては、うつ病患者の脳脊髄液を用いて、LPA関連分子の検討を行った。多くのLPA関連分子の中で、唯一、オメガ3系脂肪酸「ドコサヘキサエン酸」(DHA)を含むLPA(DHA-LPA)が健常者と比較して低下していることを見出した。この知見は、うつ病のリゾリン脂質異常を示す世界で最初の報告であり、診断バイオマーカーの候補になると考えられる。また、この知見は、最近注目されているオメガ3系脂肪酸に関するうつ病の栄養学的な分子基盤の理解の一助になると考えられ、多くの研究分野への発展が期待できる。

Current Status of Research Progress
Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

実績の概要に示したような、LPA受容体関連の創薬およびうつ病のバイオマーカーの候補探索の研究は順調に進展している。

Strategy for Future Research Activity

市販のLPA受容体リガンドおよびLPA受容体の内因性リガンドであるLPAを用いて、抗うつ行動・不安行動に対する影響の比較検討を行い、新規の抗うつ薬候補の絞り込みを行う。さらに、新規候補が見つかれば、その作用メカニズムの解明のために、網羅的な遺伝子解析を行い、抗うつ効果の分子病態を明らかにする予定である。また、最終年度であるために、成果を英語論文化する予定である。

Report

(4 results)
  • 2021 Annual Research Report
  • 2020 Annual Research Report
  • 2019 Annual Research Report
  • 2018 Annual Research Report

Research Products

(21 results)

All 2021 2020 2019 2018 Other

All Journal Article (14 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 11 results,  Open Access: 6 results) Presentation (6 results) (of which Int'l Joint Research: 5 results,  Invited: 1 results) Remarks (1 results)

  • [Journal Article] Reduced Cerebrospinal Fluid Levels of Lysophosphatidic Acid Docosahexaenoic Acid in Patients With Major Depressive Disorder and Schizophrenia2021

    • Author(s)
      Omori Wataru、Kano Kuniyuki、Hattori Kotaro、Kajitani Naoto、Okada-Tsuchioka Mami、Boku Shuken、Kunugi Hiroshi、Aoki Junken、Takebayashi Minoru
    • Journal Title

      International Journal of Neuropsychopharmacology

      Volume: 24 Pages: 948-955

    • DOI

      10.1093/ijnp/pyab044

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Dysfunction of the proteoglycan Tsukushi causes hydrocephalus through altered neurogenesis in the subventricular zone in mice.2021

    • Author(s)
      Ito, N., Riyadh, M., Ahmad, S., Hattori, S., Miyakawa, T. and Ohta, K., et al.
    • Journal Title

      Science Translational Medicine

      Volume: 13 Issue: 587 Pages: 7896-7896

    • DOI

      10.1126/scitranslmed.aay7896

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Identification and functional characterization of the extremely long allele of the serotonin transporter-linked polymorphic region.2021

    • Author(s)
      1.Ikegame T, Hidaka Y, Nakachi Y, Murata Y, Watanabe R, Sugawara H, Asai T, Kiyota E, Saito T, Ikeda M, Sasaki T, Hashimoto M, Ishikawa T, Takebayashi M, Iwata N, Kakiuchi C, Kato T, Kasai K, Bundo M, Iwamoto K
    • Journal Title

      Translational Psychiatry

      Volume: 11;11(1) Pages: 119-119

    • DOI

      10.1038/s41398-021-01242-9

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] 気分障害におけるグリア研究と創薬に向けた試み2021

    • Author(s)
      竹林 実
    • Journal Title

      日本生物学的精神医学雑誌

      Volume: 32(1) Pages: 44-50

    • NAID

      130008003202

    • Related Report
      2021 Annual Research Report
  • [Journal Article] 脳内変化を反映する脳由来エクソソームに着目したうつ病の診断および治療反応性バイオマーカーの探索研究2021

    • Author(s)
      岡田 麻美,大盛 航,梶谷 直人,竹林 実
    • Journal Title

      医療の広場

      Volume: 61(8) Pages: 11-14

    • Related Report
      2021 Annual Research Report
  • [Journal Article] 単極性気分障害(うつ病)を治療するための標準的知識と技術2021

    • Author(s)
      竹林 実
    • Journal Title

      精神科治療学

      Volume: 36(3) Pages: 251-255

    • Related Report
      2021 Annual Research Report
  • [Journal Article] Differential anatomical and cellular expression of lysophosphatidic acid receptor 1 in adult mouse brain2020

    • Author(s)
      Kajitani Naoto、Okada-Tsuchioka Mami、Kano Kuniyuki、Omori Wataru、Boku Shuken、Aoki Junken、Takebayashi Minoru
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 531 Pages: 89-95

    • DOI

      10.1016/j.bbrc.2020.05.068

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Lysophosphatidic acid induces thrombospondin‐1 production in primary cultured rat cortical astrocytes2020

    • Author(s)
      Hisaoka‐Nakashima Kazue、Yokoe Toshiki、Watanabe Shintaro、Nakamura Yoki、Kajitani Naoto、Okada‐Tsuchioka Mami、Takebayashi Minoru、Nakata Yoshihiro、Morioka Norimitsu
    • Journal Title

      Journal of Neurochemistry

      Volume: in press

    • DOI

      10.1111/jnc.15227

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Increased Matrix Metalloproteinases in Cerebrospinal Fluids of Patients With Major Depressive Disorder and Schizophrenia2020

    • Author(s)
      Omori Wataru、Hattori Kotaro、Kajitani Naoto、Okada-Tsuchioka Mami、Boku Shuken、Kunugi Hiroshi、Okamoto Yasumasa、Takebayashi Minoru
    • Journal Title

      International Journal of Neuropsychopharmacology

      Volume: 23 Pages: 713-720

    • DOI

      10.1093/ijnp/pyaa049

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Decreased serum levels of thrombospondin-1 in female depressed patients.2020

    • Author(s)
      Okada-Tsuchioka M,Omori W,Kajitani N,Shibasaki C,Itagaki K,Takebayashi M.
    • Journal Title

      Neuropsychopharmacology Reports

      Volume: 40 Pages: 39-45

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Differential anatomical and cellular expression of lysophosphatidic acid receptor 1 in adult mouse brain.2020

    • Author(s)
      Kajitani N,Okada-Tsuchioka M,Kano K,Omori W,Boku S,Aoki J,Takebayashi M
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: in press

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Reduced serum and cerebrospinal fluid levels of autotaxin in major depressive disorder.2019

    • Author(s)
      Itagaki K,Takebayashi M,Abe H,Shibasaki C,Kajitani N,Okada-Tsuchioka M,Hattori K,Yoshida S,Kunugi H,Yamawaki S.
    • Journal Title

      International Journal of Neuropsychopharmacology

      Volume: 22 Pages: 261-269

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Reduced Serum and Cerebrospinal Fluid Levels of Autotaxin in Major Depressive Disorder.2019

    • Author(s)
      Itagaki Kei、Takebayashi Minoru、Abe Hiromi、Shibasaki Chiyo、Kajitani Naoto、Okada-Tsuchioka Mami、Hattori Kotaro、Yoshida Sumiko、Kunugi Hiroshi、Yamawaki Shigeto
    • Journal Title

      International Journal of Neuropsychopharmacology

      Volume: 22 Pages: 261-269

    • DOI

      10.1093/ijnp/pyz005

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Antidepressant amitriptyline‐induced matrix metalloproteinase‐9 activation is mediated by Src family tyrosine kinase, which leads to glial cell line‐derived neurotrophic factor mRNA expression in rat astroglial cells.2019

    • Author(s)
      Abe Hiromi、Kajitani Naoto、Okada‐Tsuchioka Mami、Omori Wataru、Yatsumoto Masahide、Takebayashi Minoru
    • Journal Title

      Neuropsychopharmacol Rep.

      Volume: 印刷中

    • DOI

      10.1002/npr2.12055

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] 気分障害におけるグリア病態研究と創薬に向けた試み2020

    • Author(s)
      竹林 実
    • Organizer
      第50回日本神経精神薬理学会年会 第42回日本生物学的精神医学会年会 第4回日本精神薬学会総会・学術集会合同年会ON LINE
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] Distribution of multiple lysophosphatidic acid receptors in adult mouse brain.2019

    • Author(s)
      Kajitani N,Okada-Tsuchioka M,Abe H,Omori W,Itagaki K,Machino A,Takebayashi M.
    • Organizer
      Neuroscience 2019
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Abnormality in metabolism of docosahexaenoic acid-lysophosphatidic acid(DHA-LPA) in major depressive disorder and schizophrenia2019

    • Author(s)
      Omori W,Kano K,Hattori K,Kajitani N,Itagaki K,Okada-Tsuchioka M,Abe H,Machino A,Inoue A,Kunugi H,Aoki J,Takebayashi M.
    • Organizer
      Neuroscience 2019
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Antidepressant induces glial cell line-derived neurotrophic factor production through Gαi/o-coupled lysophosphatidic acid receptor 1/Src tyrosine kinase/matrix metalloproteinase-9 cascade in rat astroglial cells.2019

    • Author(s)
      Abe H,Kajitani N,Okada-Tsuchioka M,Omori W,Yatsumoto M,Takebayashi M.
    • Organizer
      AsCNP2019
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Altered cerebrospinal fluid levels of matrix metalloproteinases in mood disorders and schizophrenia.2018

    • Author(s)
      Omori W,Hattori K,Okada-Tsuchioka M,Itagaki K,Kajitani N,Abe H,Kunugi H,Takebayashi M
    • Organizer
      Neuroscience 2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Cellular localization of lysophosphatidic acid receptor 1 in the mouse brain2018

    • Author(s)
      Kajitani N,Okada-Tsuchioka M,Abe H,Omori W,Itagaki K,Takebayashi M.
    • Organizer
      Neuroscience 2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Remarks] 熊本大学大学院 生命科学研究部神経精神医学講座

    • URL

      https://www.kumamoto-neuropsy.jp/

    • Related Report
      2020 Annual Research Report

URL: 

Published: 2018-04-23   Modified: 2022-12-28  

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