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Multi-scale platform for untangling physiological complexity

Administrative Group

Project AreaMulti-scale platform for untangling physiological complexity
Project/Area Number 21H05111
Research Category

Grant-in-Aid for Transformative Research Areas (B)

Allocation TypeSingle-year Grants
Review Section Transformative Research Areas, Section (II)
Research InstitutionUniversity of Tsukuba

Principal Investigator

Saitoh Tsuyoshi  筑波大学, 国際統合睡眠医科学研究機構, 准教授 (80609933)

Co-Investigator(Kenkyū-buntansha) 井上 飛鳥  東北大学, 薬学研究科, 教授 (50525813)
寿野 良二  関西医科大学, 医学部, 准教授 (60447521)
櫻井 勝康  筑波大学, 国際統合睡眠医科学研究機構, 准教授 (70507920)
Project Period (FY) 2021-08-23 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2023: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2022: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2021: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywordsオピオイド受容体 / Gタンパク質共役型受容体 / シグナル伝達 / クライオ電子顕微鏡単粒子解析 / 神経回路 / 創薬化学 / GPCR / オピオイド / 構造生物学 / 神経科学 / 作動薬
Outline of Research at the Start

本領域は、生体内の複雑な生理作用および情報処理機構の構成要素を定量的に解明し、分子から細胞、そして個体の各スケールにおける素過程の重ね合わせの形で記述・可視化することで、生理作用をデジタル上で再構築可能とする技術基盤の構築を目指す。そのために、各スケールでの独自性の高い分析技術と、ユニークな作用を持つ独自の化合物群をかけ合わせ、スケール横断的な「生理作用の因数分解」プラットホームの構築に挑戦する。

Outline of Final Research Achievements

This research area aims to establish an integrated platform for next-generation rational drug discovery by collecting and utilizing high-dimensional information across molecular, cellular, and organismal scales. Specifically, it focuses on constructing and applying a novel information collection platform that integrates rapid protein complex structure analysis at the molecular level, comprehensive intracellular signaling pathway analysis at the cellular level, and drug-stimulus-dependent neural cell labeling at the organismal level. To achieve this goal, we established an inter-group communication platform to share research progress by leveraging online environments. Additionally, to disseminate our research activities, we hosted and co-hosted several symposiums. These efforts have established a foundation for interdisciplinary collaboration among researchers from different fields, promoting new fusion research areas.

Academic Significance and Societal Importance of the Research Achievements

本研究を通じて、オピオイド受容体を始めとするGPCRの作用、構造、シグナル、神経回路に関する網羅的かつ高品質な情報を取得するプラットフォームが構築できることが示された。これにより、これまで困難であった動的に機能するタンパク質を標的とした創薬において、作用に紐付く意味のある構造情報を基にした分子設計手法の開発に繋がると考えられ、医療の進展に大きく寄与することが期待される。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Annual Research Report
  • 2021 Annual Research Report
  • Research Products

    (42 results)

All 2024 2023 2022 2021 Other

All Journal Article (13 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 13 results,  Open Access: 8 results) Presentation (22 results) (of which Int'l Joint Research: 8 results,  Invited: 16 results) Remarks (7 results)

  • [Journal Article] Morphinan Evolution: The Impact of Advances in Biochemistry and Molecular Biology2024

    • Author(s)
      Kajino Keita、Tokuda Akihisa、Saitoh Tsuyoshi
    • Journal Title

      The Journal of Biochemistry

      Volume: 175 Issue: 4 Pages: 337-355

    • DOI

      10.1093/jb/mvae021

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Design and synthesis of unique morphinan-type molecules: Their application to the search for the unexplored binding domain between opioid receptors and morphinan ligands2024

    • Author(s)
      Maeda Kenta、Sugai Tomoya、Tokuda Akihisa、Kajino Keita、Saitoh Tsuyoshi、Nagase Hiroshi、Kutsumura Noriki
    • Journal Title

      Bioorganic & Medicinal Chemistry Letters

      Volume: 99 Pages: 129611-129611

    • DOI

      10.1016/j.bmcl.2024.129611

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Chemogenetic activation of G12 signaling enhances adipose tissue browning2023

    • Author(s)
      Ono Y, Ito R, Arai K, Singh G, Saitoh T, Russell RB, Raimondi F, Aoki J, Sakai J, Inoue A.
    • Journal Title

      Signal Transduction and Targeted Therapy

      Volume: 8 Issue: 1 Pages: 307-307

    • DOI

      10.1038/s41392-023-01524-2

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The present and future of synthetic orexin receptor agonists2023

    • Author(s)
      Saitoh Tsuyoshi、Sakurai Takeshi
    • Journal Title

      Peptides

      Volume: 167 Pages: 171051-171051

    • DOI

      10.1016/j.peptides.2023.171051

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Design and Synthesis of Orexin 1 Receptor-Selective Agonists2023

    • Author(s)
      Keita Iio, Kao Hashimoto, Yasuyuki Nagumo, Mao Amezawa, Taisei Hasegawa, Naoshi Yamamoto, Noriki Kutsumura, Katsuhiko Takeuchi, Yukiko Ishikawa, Hikari Yamamoto, Akihisa Tokuda, Tetsu Sato, Yasuo Uchida, Asuka Inoue, Ryuji Tanimura, Masashi Yanagisawa, Hiroshi Nagase, Tsuyoshi Saitoh
    • Journal Title

      Journal of Medicinal Chemistry

      Volume: 66 Issue: 8 Pages: 5453-5464

    • DOI

      10.1021/acs.jmedchem.2c01773

    • Related Report
      2023 Annual Research Report 2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Design and synthesis of novel orexin 2 receptor agonists with a 1,3,5-trioxazatriquinane skeleton2023

    • Author(s)
      Mao Amezawa, Naoshi Yamamoto, Yasuyuki Nagumo, Noriki Kutsumura, Yukiko Ishikawa, Masashi Yanagisawa, Hiroshi Nagase, Tsuyoshi Saitoh
    • Journal Title

      Bioorganic & Medicinal Chemistry Letters

      Volume: 82 Pages: 129151-129151

    • DOI

      10.1016/j.bmcl.2023.129151

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Discovery of novel orexin receptor antagonists using a 1,3,5-trioxazatriquinane bearing multiple effective residues (TriMER) librasy2022

    • Author(s)
      Saitoh T, Amezawa M, Horiuchi J, Nagumo Y, Yamamoto N, Kutsumura N, Ohshita R, Tokuda A, Irukayama-Tomobe Y, Ogawa Y, Ishikawa Y, Hasegawa E, Sakurai T, Uchida Y, Sato T, Gouda H, Tanimura R, Yanagisawa M, Nagase H.
    • Journal Title

      Eur J Med Chem

      Volume: 240 Pages: 114505-27

    • DOI

      10.1016/j.ejmech.2022.114505

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Discovery of orexin 2 receptor selective and dual orexin receptor agonists based on the tetralin structure: Switching of receptor selectivity by chirality on the tetralin ring2022

    • Author(s)
      Keita Iio, Tsuyoshi Saitoh, Ryuichiro Ohshita, Tsubasa Hino, Mao Amezawa, Yoshiaki Takayama, Yasuyuki Nagumo, Naoshi Yamamoto, Noriki Kustumura, Yoko Irukayama-Tomobe, Yukiko Ishikawa, Ryuji Tanimura, Masashi Yanagisawa, Hiroshi Nagase
    • Journal Title

      Bioorganic & Medicinal Chemistry Letters

      Volume: 60 Pages: 128555-128555

    • DOI

      10.1016/j.bmcl.2022.128555

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Design and synthesis of novel orexin 2 receptor agonists based on naphthalene skeleton2022

    • Author(s)
      Tsubasa Hino, Tsuyoshi Saitoh, Yasuyuki Nagumo, Naoshi Yamamoto, Noriki Kutsumura, Yoko Irukayama-Tomobe, Yukiko Ishikawa, Ryuji Tanimura, Masashi Yanagisawa, Hiroshi Nagase
    • Journal Title

      Bioorganic & Medicinal Chemistry Letters

      Volume: 59 Pages: 128530-128530

    • DOI

      10.1016/j.bmcl.2022.128530

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Synthesis of unnatural morphinan compounds to induce itch-like behaviors in mice: Towards the development of MRGPRX2 selective ligands2022

    • Author(s)
      Iio Keita、Kutsumura Noriki、Nagumo Yasuyuki、Saitoh Tsuyoshi、Tokuda Akihisa、Hashimoto Kao、Yamamoto Naoshi、Kise Ryoji、Inoue Asuka、Mizoguchi Hirokazu、Nagase Hiroshi
    • Journal Title

      Bioorganic & Medicinal Chemistry Letters

      Volume: 56 Pages: 128485-128485

    • DOI

      10.1016/j.bmcl.2021.128485

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Heterotrimeric Gq proteins?act as a switch for GRK5/6 selectivity underlying β-arrestin transducer bias2022

    • Author(s)
      Kawakami Kouki、Yanagawa Masataka、Hiratsuka Suzune、Yoshida Misaki、Ono Yuki、Hiroshima Michio、Ueda Masahiro、Aoki Junken、Sako Yasushi、Inoue Asuka
    • Journal Title

      Nature Communications

      Volume: 13 Issue: 1 Pages: 870-870

    • DOI

      10.1038/s41467-022-28056-7

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Vibrational spectroscopy analysis of ligand efficacy in human M2 muscarinic acetylcholine receptor (M2R)2021

    • Author(s)
      Katayama Kota、Suzuki Kohei、Suno Ryoji、Kise Ryoji、Tsujimoto Hirokazu、Iwata So、Inoue Asuka、Kobayashi Takuya、Kandori Hideki
    • Journal Title

      Communications Biology

      Volume: 4 Issue: 1 Pages: 1-10

    • DOI

      10.1038/s42003-021-02836-1

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Structural basis of sphingosine-1-phosphate receptor 1 activation and biased agonism2021

    • Author(s)
      Xu Zhenmei、Ikuta Tatsuya、Kawakami Kouki、Kise Ryoji、Qian Yu、Xia Ruixue、Sun Ming-Xia、Zhang Anqi、Guo Changyou、Cai Xue-Hui、Huang Zhiwei、Inoue Asuka、He Yuanzheng
    • Journal Title

      Nature Chemical Biology

      Volume: 18 Issue: 3 Pages: 281-288

    • DOI

      10.1038/s41589-021-00930-3

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Presentation] 鎮静作用を分離したκオピオイド受容体作動薬の創製2023

    • Author(s)
      斉藤 毅、南雲 康行、梶野 景太、谷田 誠浩、德田 明久、寿野(池田) 千代、 寿野 良二、清水(小林) 拓也、長瀬 博
    • Organizer
      第42回鎮痛薬・オピオイドペプチドシンポジウム
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] Re:ゼロから始めるメドケム研究2023

    • Author(s)
      斉藤毅
    • Organizer
      第56回天然物化学談話会
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] 鎮静作用を分離したκオピオイド受容体作動薬の創製2023

    • Author(s)
      斉藤毅、梶野景太、谷田誠浩、徳田明久、南雲康行、長瀬博
    • Organizer
      日本薬学会第143年会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] プロスタグランジン受容体の構造解析によるシグナル伝達機構の解明2023

    • Author(s)
      寿野良二
    • Organizer
      日本薬学会第143年会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] Non-canonical activation of β-arrestin and G protein2023

    • Author(s)
      Asuka Inoue
    • Organizer
      GPCR Workshop 2023
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] ON-OFFを見る -神経活動の遷移の大規模な可視化-2023

    • Author(s)
      櫻井勝康
    • Organizer
      日本薬学会第143年会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] 意識をハックする分子の創製2022

    • Author(s)
      斉藤毅
    • Organizer
      第9回慶應有機化学若手シンポジウム
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] 生理作用の因数分解:副作用のない薬の創製を目指して2022

    • Author(s)
      斉藤毅、梶野景太、谷田誠浩、徳田明久、南雲康行、長瀬博
    • Organizer
      第95回日本生化学会大会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] 構造生物学的技術によるGPCRの多様なシグナル伝達機構の解明2022

    • Author(s)
      寿野良二
    • Organizer
      第95回日本生化学会大会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] 「創薬に資するGPCRの構生物学」異分野融合による精神神経疾患の新規治療標的に基づいた創薬研究2022

    • Author(s)
      寿野良二
    • Organizer
      Neuro 2022
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] GRK-independent arrestin activation2022

    • Author(s)
      Asuka Inoue
    • Organizer
      FASEB SRC: The G Protein-coupled Receptor Kinases and Arrestins Conference: Key Modulators of Signal Transduction
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] オピオイド受容体のシグナル解読とバイアス型リガンドによる自在制御2022

    • Author(s)
      井上飛鳥
    • Organizer
      第95回日本生化学会大会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] 細分化して見えてくるGPCRシグナル原理第17回 GPCR研究会2022

    • Author(s)
      井上飛鳥
    • Organizer
      第17回 GPCR研究会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] 新規機能的コネクトーム解析法2022

    • Author(s)
      櫻井勝康
    • Organizer
      第95回日本生化学会大会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] 分子の形に注目した創薬研究2022

    • Author(s)
      斉藤毅
    • Organizer
      日本薬学会第142年会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] ヒトプロスタグランジン受容体EP3-Gタンパク質複合体の構造解析2021

    • Author(s)
      寿野良二
    • Organizer
      第59回日本生物物理学会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Design and synthesis of 17-N-fluoroalkyl nalfurafine derivatives to improve pharmacological properties2021

    • Author(s)
      Natsumi Sakamoto; Tsuyoshi Saitoh; Yukiko Ishikawa; Akihisa Tokuda; Tsubasa Hino; Naoshi Yamamoto; Yasuyuki Nagumo; Noriki Kutsumura; Masashi Yanagisawa; Hiroshi Nagase
    • Organizer
      The 2021 International Chemical Congress of Pacific Basin Societies (Pacifichem)
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Design and synthesis of novel morphinan-type κ opioid receptor agonists bearing bicyclo[2.2.2]octane skeleton and these pharmacological activities2021

    • Author(s)
      Keita Kajino; Masahiro Yata; Tsuyoshi Saitoh; Naoshi Yamamoto; Yasuyuki Nagumo; Tsubasa Hino; Akihisa Tokuda; Noriki Kutsumura; Hiroshi Nagase
    • Organizer
      The 2021 International Chemical Congress of Pacific Basin Societies (Pacifichem)
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Discovery of novel orexin receptor antagonists with 1,3,5-trioxazatriquinane skeleton2021

    • Author(s)
      Mao Amezawa; Tsuyoshi Saitoh; Yukiko Ishikawa; Yoko Irukayama; Emi Hasegawa; Hiroaki Gouda; Naoshi Yamamoto; Noriki Kutsumura; Yasuyuki Nagumo; Sakurai Takeshi; Masashi Yanagisawa; Hiroshi Nagase
    • Organizer
      The 2021 International Chemical Congress of Pacific Basin Societies (Pacifichem)
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Synthesis of unnatural morphinan compounds to induce itch like behavior in mice: Towards the development of MRGPRX2 selective ligands2021

    • Author(s)
      Keita Iio; Noriki Kutsumura; Yasuyuki Nagumo; Tsuyoshi Saitoh; Naoshi Yamamoto; Akihisa Tokuda; Kao Hashimoto; Hirokazu Mizoguchi; Hiroshi Nagase
    • Organizer
      The 2021 International Chemical Congress of Pacific Basin Societies (Pacifichem)
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Design and Synthesis of Novel Orexin Receptor Antagonists with 1,3,5-Trioxazatriquinane skeleton2021

    • Author(s)
      Mao Amezawa; Jumpei Horiuchi; Tsuyoshi Saitoh; Ryuichiro Ohshita; Naoshi Yamamoto; Yasuyuki Nagumo; Yukiko Ishikawa; Yoko Irukayama; Emi Hasegawa; Noriki Kutsumura; Ryuji Tanimura; Sakurai Takeshi; Masashi Yanagisawa; Hiroshi Nagase
    • Organizer
      AIMECS2021
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Design and Synthesis of Novel Orexin Receptor Dual Agonists with Tetralin Skeleton2021

    • Author(s)
      Keita Iio, Tsuyoshi Saitoh, Ryuichiro Ohshita, Tsubasa Hino, Mao Amezawa, Sayaka Ohrui, Takahiro Okada, Yasuyuki Nagumo, Naoshi Yamamoto, Yukiko Ishikawa, Yoko Irukayama-Tomobe, Noriki Kutsumura, Masashi Yanagisawa, Hiroshi Nagase
    • Organizer
      AIMECS2021
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Remarks] 領域ホームページ

    • URL

      https://seiri-bunkai.com/report/

    • Related Report
      2023 Annual Research Report 2022 Annual Research Report
  • [Remarks] 第97回日本薬理学会年会ホームページ

    • URL

      https://pharmacology.main.jp/jps97/

    • Related Report
      2023 Annual Research Report
  • [Remarks] Journal of Biochemistry誌Special Issue

    • URL

      https://academic.oup.com/jb/issue/175/4

    • Related Report
      2023 Annual Research Report
  • [Remarks] 化学ポータルサイトChemStationにおける紹介記事

    • URL

      https://www.chem-station.com/blog/2023/03/sympo.html

    • Related Report
      2022 Annual Research Report
  • [Remarks] 日本薬学会第143年会(共同主催シンポジウム)

    • URL

      https://confit.atlas.jp/guide/event/pharm143/session/2B115-19/category

    • Related Report
      2022 Annual Research Report
  • [Remarks] 第17回GPCR研究会(共催シンポジウム)

    • URL

      https://www.gpcr.info/

    • Related Report
      2022 Annual Research Report
  • [Remarks] 第95階日本生化学会大会(主催シンポジウム)

    • URL

      https://www2.aeplan.co.jp/jbs2022/program/#1S15e

    • Related Report
      2022 Annual Research Report

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Published: 2021-10-22   Modified: 2025-01-30  

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