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Mechanistic insights into spatio-temporal regulation of RNA in cardio-metabolic disease

Research Project

Project/Area Number 20H03426
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 48030:Pharmacology-related
Research InstitutionAkita University

Principal Investigator

Kuba Keiji  秋田大学, 医学系研究科, 非常勤講師 (10451915)

Co-Investigator(Kenkyū-buntansha) 今井 由美子  国立研究開発法人医薬基盤・健康・栄養研究所, 医薬基盤研究所 ワクチン・アジュバント研究センター, プロジェクトリーダー (50231163)
Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000)
Fiscal Year 2022: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2021: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2020: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
KeywordsRNA分解 / 翻訳 / ユビキチン修飾 / CCR-NOT / 心不全 / 肥満 / 脂肪細胞 / CCR4-NOT / エピトランスクリプトーム / ユビキチン化
Outline of Research at the Start

循環代謝病は超高齢化社会を迎える先進国ではその予防・治療法の開発は重要な課題である。循環代謝病の病態についてRNAの局在、翻訳、分解などといったRNA制御 の果たす役割、意義については不明な点が多い。本研究では、循環・代謝臓器における細胞内でのオルガネラレベルでのRNA分解やmRNA翻訳の分子機構に着目して、循環代謝病態での小胞体や細胞骨格など時空間的なRNA制御を介した病態メカニズムを解明する。さらに、エピトランスクリプトームと翻訳・mRNA分解を結びつける分子メカニズムの解明を通じて、RNAの時空間制御による循環代謝病の新しい予防・治療法の開発を目指す。

Outline of Final Research Achievements

Spatiotemporal regulation of RNA in obesity, fatty liver and heart failure was studied focusing on the molecular mechanisms of regulation of translation and mRNA degradation in intracellular organelles. The regulatory mechanism by CNOT4 in adipose and liver was found to be important for nuclear RNA/epigenome regulation, and CNOT4 was found to be involved in the pathogenesis of obesity and fatty liver by inducing adipocyte differentiation and enhancing inflammatory responses through binding to RNA binding proteins. In heart failure, mRNA degradation of fibrosis-inducing factors by RNA poly(A)-degrading factor CNOT6L was found to be important in suppressing cardiac remodeling. We also found that mitochondria are key organelles for the new role of the CCR4-NOT complex in energy metabolism. Furthermore, we identified new candidate therapeutic target factors by time-series analysis of the translation dynamics of heart failure.

Academic Significance and Societal Importance of the Research Achievements

本研究により心不全や肥満・脂肪肝における時空間的なRNA分解や翻訳制御の分子メカニズムが明らかになり合わせて新たな治療標的の候補因子を見出したことから、新しい治療法の開発に資することが考えられる。また、CCR4-NOT複合体やその関連因子を介したミトコンドリア機能や核内恒常性維持の制御機構が新たに見出され、RNAとオルガネラ制御という観点で学術的意義が高いと思われる。

Report

(4 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Annual Research Report
  • 2020 Annual Research Report
  • Research Products

    (48 results)

All 2023 2022 2021 2020 Other

All Int'l Joint Research (6 results) Journal Article (21 results) (of which Int'l Joint Research: 9 results,  Peer Reviewed: 14 results,  Open Access: 15 results) Presentation (20 results) (of which Int'l Joint Research: 1 results,  Invited: 7 results) Patent(Industrial Property Rights) (1 results)

  • [Int'l Joint Research] University of British Columbia(カナダ)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] The University of Hong Kong(中国)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] Ludwig Maximilians University of Munich(ドイツ)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] The University of Hong Kong(中国)

    • Related Report
      2020 Annual Research Report
  • [Int'l Joint Research] University of British Columbia/Hospital for Sick Children(カナダ)

    • Related Report
      2020 Annual Research Report
  • [Int'l Joint Research] University of Florida(米国)

    • Related Report
      2020 Annual Research Report
  • [Journal Article] Apelin expression is downregulated in T cells in a murine model of chronic colitis2023

    • Author(s)
      Yamada D、Kojima Yi、Hosoya A、Suzuki、Watabe T、Inoue T、Tsugawa N、Asakawa T、Yonemoto Y、Onizawa M、Nemoto Y、Oshima S、Shimonaka M、Kuba Ki、Ishida J、Fukamizu A、Penninger JM、Watanabe M、Okamoto R、Nagaishi T
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 647 Pages: 72-79

    • DOI

      10.1016/j.bbrc.2023.01.068

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Identification of Galectin-7 as a crucial metastatic enhancer of squamous cell carcinoma associated with immunosuppression2022

    • Author(s)
      An Jianbo、Nagaki Yushi、Motoyama Satoru、Kuze Yuta、Hoshizaki Midori、Kemuriyama Kohei、Yamaguchi Tomokazu、Ebihara Takashi、Minamiya Yoshihiro、Suzuki Yutaka、Imai Yumiko、Kuba Keiji
    • Journal Title

      Oncogene

      Volume: 41 Issue: 50 Pages: 5319-5330

    • DOI

      10.1038/s41388-022-02525-1

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] ACE2-like enzyme B38-CAP suppresses abdominal sepsis and severe acute lung injury2022

    • Author(s)
      Minato Takafumi、Yamaguchi Tomokazu、Hoshizaki Midori、Nirasawa Satoru、An Jianbo、Takahashi Saori、Penninger Josef M.、Imai Yumiko、Kuba Keiji
    • Journal Title

      PLOS ONE

      Volume: 17 Issue: 7 Pages: 0270920-0270920

    • DOI

      10.1371/journal.pone.0270920

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Peritumoral CD16b positive-neutrophil accumulation strongly correlates with regional lymph node metastasis in thoracic esophageal squamous cell cancer2022

    • Author(s)
      Fujita Hiromu、Motoyama Satoru、An Jianbo、Nagakai Yushi、Yamaguchi Tomokazu、Koyota Souichi、Sato Yusuke、Wakita Akiyuki、Imai Kazuhiro、Kuba Keiji、Minamiya Yoshihiro
    • Journal Title

      Surgery

      Volume: S0039-6060 Issue: 6 Pages: 1170-1170

    • DOI

      10.1016/j.surg.2021.11.022

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] ACE2の循環器疾患および感染症における意義2022

    • Author(s)
      久場敬司
    • Journal Title

      CARDIAC PRACTICE

      Volume: 2 Pages: 36-41

    • Related Report
      2021 Annual Research Report
  • [Journal Article] Angiotensin-Converting Enzyme 2 (ACE2) in the Pathogenesis of ARDS in COVID-192021

    • Author(s)
      Kuba Keiji、Yamaguchi Tomokazu、Penninger Josef M.
    • Journal Title

      Frontiers in Immunology

      Volume: 12 Pages: 732690-732690

    • DOI

      10.3389/fimmu.2021.732690

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] ACE2-like carboxypeptidase B38-CAP protects from SARS-CoV-2-induced lung injury2021

    • Author(s)
      Yamaguchi T, Hoshizaki M, Minato T, Nirasawa S, Asaka MN, Niiyama M, Imai M, Uda A, Chan JF, Takahashi S, An J, Saku A, Nukiwa R, Utsumi D, Kiso M, Yasuhara A, Poon VK, Chan CC, Fujino Y, Motoyama S, Nagata S, Penninger JM, Kamada H, Yuen KY, Kamitani W, Maeda K, Kawaoka Y, Yasutomi Y, Imai Y, Kuba Keiji
    • Journal Title

      Nature Communications

      Volume: 12 Issue: 1 Pages: 6791-6791

    • DOI

      10.1038/s41467-021-27097-8

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Highly susceptible SARS-CoV-2 model in CAG promoter?driven hACE2-transgenic mice2021

    • Author(s)
      Asaka Masamitsu N.、Utsumi Daichi、Kamada Haruhiko、Nagata Satoshi、Nakachi Yutaka、Yamaguchi Tomokazu、Kawaoka Yoshihiro、Kuba Keiji、Yasutomi Yasuhiro
    • Journal Title

      JCI Insight

      Volume: 6 Issue: 19 Pages: 1-2

    • DOI

      10.1172/jci.insight.152529

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Incomplete antiviral treatment may induce longer durations of viral shedding during SARS-CoV-2 infection2021

    • Author(s)
      Kim Kwang Su、Iwanami Shoya、Oda Takafumi、Fujita Yasuhisa、Kuba Keiji、Miyazaki Taiga、Ejima Keisuke、Iwami Shingo
    • Journal Title

      Life Science Alliance

      Volume: 4 Issue: 10 Pages: e202101049-e202101049

    • DOI

      10.26508/lsa.202101049

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Suv4-20h2 protects against influenza virus infection by suppression of chromatin loop formation2021

    • Author(s)
      Shiimori Masami、Ichida Yu、Nukiwa Ryota、Sakuma Toshie、Abe Haruka、Kajitani Rei、Fujino Yuji、Kikuchi Akira、Kawamura Takeshi、Kodama Tatsuhiko、Toyooka Shinichi、Shirahige Katsuhiko、Schotta Gunnar、Kuba Keiji、Itoh Takehiko、Imai Yumiko
    • Journal Title

      iScience

      Volume: 24 Issue: 6 Pages: 102660-102660

    • DOI

      10.1016/j.isci.2021.102660

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] SARS-CoV-2とRAS/ACE22021

    • Author(s)
      久場敬司
    • Journal Title

      Thrombosis Medicine

      Volume: 11 Pages: 32-36

    • Related Report
      2021 Annual Research Report
  • [Journal Article] COVID-19の発症機序2021

    • Author(s)
      久場敬司
    • Journal Title

      月刊 心臓

      Volume: 53 Pages: 1-1

    • Related Report
      2021 Annual Research Report
  • [Journal Article] Clonal hematopoiesis in adult pure red cell aplasia2021

    • Author(s)
      Fujishima N、Kohmaru J、Koyota S、Kuba K、Saga T、Omokawa A、Moritoki Y、Ueki S、Ishida F、Nakao S、Matsuda A、Ohta A、Tohyama K、Yamasaki H、Usuki K、Nakashima Y、Sato S、Miyazaki Y、Nannya Y、Ogawa S、Sawada K、Mitani K、Hirokawa M
    • Journal Title

      Scientific Reports

      Volume: 11 Issue: 1 Pages: 2253-2253

    • DOI

      10.1038/s41598-021-81890-5

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] 種を超えて保存されたACE2様酵素B38-CAPの循環器疾患への治療応用2021

    • Author(s)
      久場敬司
    • Journal Title

      BIO Clinica

      Volume: 36 Pages: 228-230

    • Related Report
      2020 Annual Research Report
  • [Journal Article] Virus database annotations assist in tracing information on patients infected with emerging pathogens2020

    • Author(s)
      Akiko Nakashima, Mitsue Takeya, Keiji Kuba, Makoto Takano, Noriyuki Nakashima
    • Journal Title

      Informatics in Medicine Unlocked

      Volume: 100442 Pages: 100442-100442

    • DOI

      10.1016/j.imu.2020.100442

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Eosinophils promote corneal wound healing via the 12/15‐lipoxygenase pathway2020

    • Author(s)
      Ogawa Mamoru、Ishihara Tomoaki、Isobe Yosuke、Kato Taiga、Kuba Keiji、Imai Yumiko、Uchino Yuichi、Tsubota Kazuo、Arita Makoto
    • Journal Title

      The FASEB Journal

      Volume: 34 Issue: 9 Pages: 12492-12501

    • DOI

      10.1096/fj.202000483r

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The CCR4-NOT complex maintains liver homeostasis through mRNA deadenylation2020

    • Author(s)
      Takahashi Akinori、Suzuki Toru、Soeda Shou、Takaoka Shohei、Kobori Shungo、Yamaguchi Tomokazu、Mohamed Haytham Mohamed Aly、Yanagiya Akiko、Abe Takaya、Shigeta Mayo、Furuta Yasuhide、Kuba Keiji、Yamamoto Tadashi
    • Journal Title

      Life Science Alliance

      Volume: 3 Issue: 5 Pages: 1-19

    • DOI

      10.26508/lsa.201900494

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] m6A demethylase ALKBH5 promotes proliferation of esophageal squamous cell carcinoma associated with poor prognosis2020

    • Author(s)
      Nagaki Yushi、Motoyama Satoru、Yamaguchi Tomokazu、Hoshizaki Midori、Sato Yusuke、Sato Teruki、Koizumi Yukio、Wakita Akiyuki、Kawakita Yuta、Imai Kazuhiro、Nanjo Hiroshi、Watanabe Hiroyuki、Imai Yumiko、Minamiya Yoshihiro、Kuba Keiji
    • Journal Title

      Genes to Cells

      Volume: 25 Issue: 8 Pages: 547-561

    • DOI

      10.1111/gtc.12792

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] ACE2-like carboxypeptidase B38-CAP protects from SARS-CoV-2-induced lung injury2020

    • Author(s)
      Minato T, Hoshizaki M, Yamaguchi T, Nirasawa S, Asaka MN, Kamada H, Yuen KM, Kawaoka Y, Yasutomi Y, Imai Y, Kuba K, et al.
    • Journal Title

      researchsquare.com/article/rs-124634/v1

      Volume: -

    • DOI

      10.21203/rs.3.rs-124634/v1

    • Related Report
      2020 Annual Research Report
    • Open Access / Int'l Joint Research
  • [Journal Article] 新規微生物由来酵素B38-CAPはACE2活性により高血圧と心不全を改善する2020

    • Author(s)
      湊隆文,久場敬司
    • Journal Title

      実験医学

      Volume: 38 Pages: 2371-2374

    • Related Report
      2020 Annual Research Report
  • [Journal Article] 微生物由来の新規ACE2様酵素による循環器疾患症状の改善2020

    • Author(s)
      久場敬司,韮澤悟
    • Journal Title

      BIOSCIENCE & INDUSTRY

      Volume: 78 Pages: 512-513

    • Related Report
      2020 Annual Research Report
  • [Presentation] RNA 制御を介したストレス応答と生体恒常性維持機構2023

    • Author(s)
      久場敬司
    • Organizer
      レドックスR&D戦略委員会・春のシンポジウム
    • Related Report
      2022 Annual Research Report
  • [Presentation] Dissecting the roles of CCR4-NOT complex and CNOT4 in maintaining tissue homeostasis2022

    • Author(s)
      Tomokazu Yamaguchi, Midori Hoshizaki, Jianbo An, Yukio Kawahara, Yutaka Suzuki, Yumiko Imai, Toshifumi Inada, Tadashi Yamamoto, Keiji Kuba
    • Organizer
      第23回 日本RNA学会
    • Related Report
      2022 Annual Research Report
  • [Presentation] ACE2-like carboxypeptidase B38-CAP suppresses severe acute lung injury induced by aspiration pneumonia and abdominal sepsis as well as SARS-CoV-2 infection2022

    • Author(s)
      Tomokazu Yamaguchi, Takafumi Minato, Midori Hoshizaki, Satoru Nirasawa, Jianbo An, Saori Takahashi, Josef M. Penninger, Yumiko Imai, Keiji Kuba
    • Organizer
      第96回 日本薬理学会年会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Physiological roles of CCR4-NOT complex and CNOT4 in neuronal homeostasis2022

    • Author(s)
      Tomokazu Yamaguchi, Keiji Kuba
    • Organizer
      The 9th CCR4-NOT Meeting
    • Related Report
      2022 Annual Research Report
  • [Presentation] 心不全におけるRNA制御メカニズム2022

    • Author(s)
      久場敬司
    • Organizer
      第174回日本循環器学会東北地方会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] 循環器疾患におけるCCR4-NOT複合体によるRNA制御ネットワークの解析2021

    • Author(s)
      久場敬司
    • Organizer
      第44回日本分子生物学会年会 ワークショップ3AW-07
    • Related Report
      2021 Annual Research Report
  • [Presentation] COVID-19のARDS/急性肺傷害に対するACE2酵素活性の治療効果2021

    • Author(s)
      久場敬司
    • Organizer
      第17回霊長類医科学フォーラム
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] ACE2酵素活性による COVID-19 急性肺傷害の治療2021

    • Author(s)
      久場敬司
    • Organizer
      第94回日本生化学会大会シンポジウム1S10e
    • Related Report
      2021 Annual Research Report
  • [Presentation] 心不全におけるmRNA代謝の制御機構2021

    • Author(s)
      久場敬司
    • Organizer
      第25回 日本心不全学会学術集会 シンポジウム
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Dissecting CCR4-NOT complex-mediated mRNA control in cardiac pathology/physiology and beyond2021

    • Author(s)
      久場敬司
    • Organizer
      RIKEN IMS seminar
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] ACE2酵素B38-CAPの循環呼吸器疾患への治療応用2021

    • Author(s)
      久場敬司
    • Organizer
      創薬薬理フォーラム 第69回談話会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] CCR4-NOT Deadenylase Complex Controls the Expression of Autophagy Genes and Prevents Atg7-Dependent Cell Death in the Heart2021

    • Author(s)
      山口 智和, 鈴木 享, 佐藤 輝紀, 高橋 明格, 山本 雅, 今井 由美子, 久場 敬司
    • Organizer
      第85回 日本循環器学会学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Suppression of SARS-CoV-2-induced lung injury by ACE2-like carboxypeptidase B38-CAP in COVID-19 mouse model2021

    • Author(s)
      Tomokazu Yamaguchi, Takafumi Minato, Midori Hoshizaki, Masamitsu N Asaka, Satoru Nirasawa, Mayumi Niiyama, Masaki Imai, Saori Takahashi, Daichi Utsumi, Jianbo An, Satoshi Nagata, Haruhiko Kamada, Yoshihiro Kawaoka, Yasuhiro Yasutomi, Yumiko Imai, Keiji Kuba
    • Organizer
      第94回 日本薬理学会
    • Related Report
      2020 Annual Research Report
  • [Presentation] ACE2酵素活性によるCOVID-19急性肺傷害の治療2021

    • Author(s)
      久場敬司
    • Organizer
      第5回 理論免疫学ワークショップ
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] 呼吸循環器疾患とRNA制御因子2020

    • Author(s)
      久場敬司
    • Organizer
      Cardiology Research & Clinical seminar
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] m6A demethylase ALKBH5 promotes proliferation of esophageal squamous cell carcinoma associated with poor prognosis.2020

    • Author(s)
      Yushi Nagaki, Keiji Kuba
    • Organizer
      第79回 日本癌学会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 微生物由来のACE2様酵素B38-CAPはマウスにおける 心臓のリモデリングと機能不全を改善する2020

    • Author(s)
      湊 隆文, 山口 智和, 佐藤 輝紀, 韮澤 悟, 今井 由美子, 高橋 砂織, 渡邊 博之, 久場 敬司
    • Organizer
      第71回 日本薬理学会北部会
    • Related Report
      2020 Annual Research Report
  • [Presentation] B38-CAP is a bacteria-derived carboxypeptidase which resembles SARS-CoV-2 receptor ACE2 enzyme activity and suppresses hypertension and cardiac dysfunction in mice2020

    • Author(s)
      Teruki Sato, Takafumi Minato, Satoru Nirasawa, Tomokazu Yamaguchi, Hiroyuki Watanabe, Yumiko Imai, Saori Takahashi, Keiji Kuba
    • Organizer
      NIPS International meeting, HOLISTIC UNDERSTANDING OF CARDIOVASCULAR SYSTEM BY MECHANISTIC ANALYSIS OF PHYSIOLOGICAL AND PATHOLOGICAL CONDITIONS
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] MRTF-Aはマクロファージ機能を制御して動脈硬化形成に関わる2020

    • Author(s)
      安 健博,成瀬 妙子,日野原 邦彦,副島 友莉恵,沢辺 元司,中川 靖章,桑原 宏一郎,久場 敬 司,木村 彰方
    • Organizer
      第71回 日本薬理学会北部会
    • Related Report
      2020 Annual Research Report
  • [Presentation] MRTF-Aはマクロファージ機能を制御して動脈硬化形成に関わる2020

    • Author(s)
      安健博、成瀬妙子、日野原邦彦、副島友莉恵、沢辺元司、中川靖章、桑原宏一郎、久場敬司、木村彰方
    • Organizer
      日本生化学会東北支部第86回例会
    • Related Report
      2020 Annual Research Report
  • [Patent(Industrial Property Rights)] 原核微生物由来ポリペプチドを含有する肺損傷および障害を処置または予防するための医薬組成物2020

    • Inventor(s)
      久場敬司、今井由美子
    • Industrial Property Rights Holder
      秋田大学
    • Industrial Property Rights Type
      特許
    • Filing Date
      2020
    • Related Report
      2020 Annual Research Report

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Published: 2020-04-28   Modified: 2024-01-30  

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