• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to previous page

RNA metabolism-based regulation of heart function and its application for treatment of heart failure

Research Project

Project/Area Number 17H04028
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field General pharmacology
Research InstitutionAkita University

Principal Investigator

Kuba Keiji  秋田大学, 医学系研究科, 教授 (10451915)

Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000)
Fiscal Year 2019: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2018: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2017: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000)
KeywordsRNA / heart failure / deadenylation / ubiquitination / ace2 / translation / ATP / fibroblasts / CCR4-NOT / transcription / nucleotide / 心不全 / CNOT3 / Atg7 / cardiomyocyte / cell death
Outline of Final Research Achievements

We conducted this research project to dissect the mechanisms how RNA regulation contributes to cardiac homeostasis in physiological maintenance of heart functions and pathological conditions in heart failure. In physiological conditions, executor of RNA poly(A) degradation CCR4-NOT deadenylase complex was revealed to regulate stability of Atg7 mRNA and thereby maintain healthy cardiomyocytes. In the pathology of heart failure, a deadenylase factor was elucidated to induce cardiac remodeling and fibrosis through RNA regulation in cardiac fibroblasts, suggesting that RNA regulation is a potential target for treating heart failure. Furthermore, defined molecular mechanisms for RNA regulation in cardiac homeostasis were investigated with PAR-CLIP and other comprehensive RNA analyses with deep sequencing, and potential new targets for therapeutics were identified in this study.

Academic Significance and Societal Importance of the Research Achievements

本研究により心不全病態におけるCCR4-NOTを介したRNA制御の分子機構や分子実体が明らかになったことから、CCR4-NOT標的因子が心臓の機能改善、再生を含めた新しい治療法の開発につながると考えられる。また、poly(A)制御によるエネルギー代謝が解糖やミトコンドリア呼吸鎖を制御することが分かったので、これらの研究成果は心臓の恒常性や心不全病態のみならず肥満や脂肪肝など代謝性疾患の予防や治療の開発に資することが考えられる。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Annual Research Report
  • 2017 Annual Research Report
  • Research Products

    (40 results)

All 2020 2019 2018 2017

All Journal Article (15 results) (of which Int'l Joint Research: 11 results,  Peer Reviewed: 14 results,  Open Access: 13 results,  Acknowledgement Compliant: 1 results) Presentation (24 results) (of which Int'l Joint Research: 2 results,  Invited: 7 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] B38-CAP is a bacteria-derived ACE2-like enzyme that suppresses hypertension and cardiac dysfunction2020

    • Author(s)
      Minato T, Nirasawa S, Sato T, Yamaguchi T, Hoshizaki M, Inagaki T, Nakahara K, Yoshihashi T, Ozawa R, Yokota S, Natsui M, Koyota S, Yoshiya T, Yoshizawa-Kumagaye K, Motoyama S, Gotoh T, Nakaoka Y, Penninger JM, Watanabe H, Imai Y, Takahashi S, Kuba K
    • Journal Title

      Nature Communications

      Volume: 11(1) Issue: 1 Pages: 1058-1058

    • DOI

      10.1038/s41467-020-14867-z

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Essential functions of the CNOT7/8 catalytic subunits of the CCR4-NOT complex in mRNA regulation and cell viability2020

    • Author(s)
      Mostafa Dina、Takahashi Akinori、Yanagiya Akiko、Yamaguchi Tomokazu、Abe Takaya、Kureha Taku、Kuba Keiji、Kanegae Yumi、Furuta Yasuhide、Yamamoto Tadashi、Suzuki Toru
    • Journal Title

      RNA Biology

      Volume: 17 Issue: 3 Pages: 403-416

    • DOI

      10.1080/15476286.2019.1709747

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The CCR4-NOT deadenylase complex maintains adipocyte identity2019

    • Author(s)
      Takahashi A., Takaoka S., Kobori S., Yamaguchi T., Ferwati S., Kuba K., Yamamoto T., and Suzuki T.
    • Journal Title

      Int. J. Mol. Sci.

      Volume: 20 Issue: 21 Pages: 5274-5274

    • DOI

      10.3390/ijms20215274

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Apelin inhibition prevents resistance and metastasis associated with anti‐angiogenic therapy2019

    • Author(s)
      Uribesalgo I, Hoffmann D, Zhang Y, Kavirayani A, Lazovic J, Berta J, Novatchkova M, Pai TP, Wimmer RA, Laszlo V, Schramek D, Karim R, Tortola L, Deswal S, Haas L, Zuber J, Szucs M, Kuba K, Dome B, Cao Y, Haubner B, Penninger JM
    • Journal Title

      EMBO Molecular Medicine

      Volume: 11 Issue: 8

    • DOI

      10.15252/emmm.201809266

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The functional role of endogenous APJ agonists; Apelin and Elabela/Toddler in cardiovascular diseases2019

    • Author(s)
      Sato Teruki、Kuba Keiji
    • Journal Title

      Folia Pharmacologica Japonica

      Volume: 153 Issue: 4 Pages: 172-178

    • DOI

      10.1254/fpj.153.172

    • NAID

      130007630616

    • ISSN
      0015-5691, 1347-8397
    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Genome‐Scale CRISPR/Cas9 Screening Reveals Squalene Epoxidase as a Susceptibility Factor for Cytotoxicity of Malformin A12019

    • Author(s)
      Koizumi Yukio、Fukushima Jun、Kobayashi Yayoi、Kadowaki Ayumi、Natsui Miyuki、Yamaguchi Tomokazu、Imai Yumiko、Sugiyama Toshihiro、Kuba Keiji
    • Journal Title

      ChemBioChem

      Volume: 20 Issue: 12 Pages: 1-7

    • DOI

      10.1002/cbic.201800769

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Loss of Apelin Augments Angiotensin II-Induced Cardiac Dysfunction and Pathological Remodeling2019

    • Author(s)
      Sato Teruki、Kadowaki Ayumi、Suzuki Takashi、Ito Hiroshi、Watanabe Hiroyuki、Imai Yumiko、Kuba Keiji
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 20 Issue: 2 Pages: 239-239

    • DOI

      10.3390/ijms20020239

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Pulmonary phagocyte-derived NPY controls the pathology of severe influenza virus infection.2018

    • Author(s)
      Fujiwara S., Hoshizaki M., Ichida Y., Lex D., Kuroda E., Ishii KJ., Magi S., Okada M., Takao H., Gando M., Imai H., Hara R., Herzog H., Yoshimura A., Okamura H., Penninger JM., Slutsky AS., Uhlig S., Kuba K., and Imai Y.
    • Journal Title

      Nature Microbiology

      Volume: 4(2) Issue: 2 Pages: 258-268

    • DOI

      10.1038/s41564-018-0289-1

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Apelin and Elabela/Toddler; double ligands for APJ/Apelin receptor in heart development, physiology, and pathology.2018

    • Author(s)
      Kuba K, Sato T, Imai Y, Yamaguchi T
    • Journal Title

      Peptides.

      Volume: in press Pages: 62-70

    • DOI

      10.1016/j.peptides.2018.04.011

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Involvement of RSK1 activation in malformin-enhanced cellular fibrinolytic activity2018

    • Author(s)
      Koizumi Y, Nagai K, Gao L, Koyota S, Yamaguchi T, Natsui M, Imai Y, Hasumi K, Sugiyama T, Kuba K
    • Journal Title

      Sci Rep

      Volume: 8(1) Issue: 1 Pages: 5472-5472

    • DOI

      10.1038/s41598-018-23745-0

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] New aspects of poly(A) tail shortening of mRNA in controlling heart functions2018

    • Author(s)
      Kuba K.
    • Journal Title

      Folia Pharmacologica Japonica

      Volume: 151 Issue: 3 Pages: 94-99

    • DOI

      10.1254/fpj.151.94

    • NAID

      130006470906

    • ISSN
      0015-5691, 1347-8397
    • Related Report
      2017 Annual Research Report
  • [Journal Article] The CCR4-NOT deadenylase complex controls Atg7-dependent cell death and heart function2018

    • Author(s)
      Yamaguchi Tomokazu et al
    • Journal Title

      Science Signaling

      Volume: 11 Issue: 516 Pages: 3638-3638

    • DOI

      10.1126/scisignal.aan3638

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Loss of Apela Peptide in Mice Causes Low Penetrance Embryonic Lethality and Defects in Early Mesodermal Derivatives2017

    • Author(s)
      Freyer Laina、Hsu Chih-Wei、Nowotschin Sonja、Pauli Andrea、Ishida Junji、Kuba Keiji、Fukamizu Akiyoshi、Schier Alexander F.、Hoodless Pamela A.、Dickinson Mary E.、Hadjantonakis Anna-Katerina
    • Journal Title

      Cell Rep.

      Volume: 20 Issue: 9 Pages: 2116-2130

    • DOI

      10.1016/j.celrep.2017.08.014

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] The CCR4-NOT complex contributes to repression of Major Histocompatibility Complex class II transcription2017

    • Author(s)
      Rodriguez-Gil Alfonso、Ritter Olesja、Saul Vera V.、Wilhelm Jochen、Yang Chen-Yuan、Grosschedl Rudolf、Imai Yumiko、Kuba Keiji、Kracht Michael、Schmitz M. Lienhard
    • Journal Title

      Scientific Reports

      Volume: 7(1) Issue: 1 Pages: 3547-3547

    • DOI

      10.1038/s41598-017-03708-7

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] ELABELA-APJ axis protects from pressure overload heart failure and angiotensin II-induced cardiac damage2017

    • Author(s)
      Sato T, Sato C, Kadowaki A, Watanabe H, Ho L, Ishida J, Yamaguchi T, Kimura A, Fukamizu A, Penninger JM, Reversade B, Ito H, Imai Y, Kuba K
    • Journal Title

      Cardiovasc Res

      Volume: 113(7) Issue: 7 Pages: 760-769

    • DOI

      10.1093/cvr/cvx061

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Presentation] Identification of B38-CAP as an ACE2-like enzyme to suppress hypertension and cardiac dysfunction in mice2020

    • Author(s)
      Keiji Kuba, Takafumi Minato, Satoru Nirasawa, Teruki Sato, Tomokazu Yamaguchi, Hiroyuki Watanabe, Yumiko Imai, Saori Takahashi
    • Organizer
      第93回 日本薬理学会年会(紙上開催)
    • Related Report
      2019 Annual Research Report
  • [Presentation] Dissecting the role of CNOT6L deadenylase in pressure overload-induced cardiac fibrosis2020

    • Author(s)
      山口智和、佐藤輝紀、湊隆文、安健博、星崎みどり、渡邊博之、今井由美子、山本雅、久場敬司
    • Organizer
      第93回 日本薬理学会年会(紙上開催)
    • Related Report
      2019 Annual Research Report
  • [Presentation] MRTF-A regulates proliferation and survival properties of pro-atherogenic macrophages2020

    • Author(s)
      Jianbo An,Taeko Naruse,Kunihiko Hinohara,Yurie Soejima,Motoji Sawabe,Yasuaki Nakagawa,Koichiro Kuwahara,Keiji Kuba,Akinori Kimura
    • Organizer
      第93回 日本薬理学会年会(紙上開催)
    • Related Report
      2019 Annual Research Report
  • [Presentation] mRNA deadenylation-mediated control of cardiac homeostasis2019

    • Author(s)
      Keiji Kuba
    • Organizer
      The 50th NIPS International Symposium ‘MIRACLES’ in Cardiovascular Physiology
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] mRNA poly(A)制御の破綻による循環器疾患の病態発現機構の解明2019

    • Author(s)
      久場 敬司
    • Organizer
      第42回 日本分子生物学会年会 ワークショップ3AW-08「RNA制御と疾患」
    • Related Report
      2019 Annual Research Report
  • [Presentation] RNA制御の破綻による循環器疾患の病態発現機構2019

    • Author(s)
      久場 敬司
    • Organizer
      第29回 日本循環薬理学会・第55回高血圧関連疾患モデル学会合同学会 シンポジウム
    • Related Report
      2019 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2019

    • 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29回 日本循環薬理学会・第55回高血圧関連疾患モデル学会合同学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] CCR4-NOT脱アデニル化因子による 心臓リモデリング抑制作用の解析2019

    • Author(s)
      山口 智和、佐藤輝紀、湊隆文、安健博、星崎みどり、渡邊博之、今井由美子、山本雅、久場 敬司
    • Organizer
      第29回 日本循環薬理学会・第55回高血圧関連疾患モデル学会合同学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 心臓リモデリングにおける CCR4-NOT deadenylaseの機能解析2019

    • Author(s)
      安健博、佐藤 輝紀、湊 隆文、山口 智和、星崎 みどり、夏井 美幸、 渡邊 博之、今井 由美子、山本 雅、久場 敬司
    • Organizer
      第92回 日本生化学会大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 肥満組織におけるCNOT4ユビキチン リガーゼの生理機能解析2019

    • Author(s)
      山口 智和、佐藤 輝紀、星崎 みどり、山本 雅、今井 由美子、久場 敬司
    • Organizer
      第92回 日本生化学会大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 単球/マクロファージ活性化制御における CNOT3の役割・機能の解析2019

    • Author(s)
      安健博、久場 敬司
    • Organizer
      第7回 CCR4-NOT研究会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 細胞増殖制御におけるユビキチン転移酵素CNOT4の機能解析2019

    • Author(s)
      山口 智和、久場 敬司
    • Organizer
      第7回 CCR4-NOT研究会
    • Related Report
      2019 Annual Research Report
  • [Presentation] RNA 制御を介した心機能の恒常性維持機構の解明2019

    • Author(s)
      久場 敬司
    • Organizer
      Research PlaNet 2019
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] RNA制御による循環機能調節の分子機構2019

    • Author(s)
      久場 敬司
    • Organizer
      第22回京都心血管代謝セミナー
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] CCR4-NOT複合体を介したRNA制御による生体恒常性維持機構2019

    • Author(s)
      久場敬司
    • Organizer
      第3回 理論免疫学ワークショップ
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] CCR4-NOT脱アデニル化酵素複合体による心機能制御機構の解明2018

    • 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20回日本RNA学会年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] A bacteria-derived ACE2-like enzyme suppresses cardiac remodeling and dysfunction in mice.2018

    • Author(s)
      湊隆文, 韮澤悟, 佐藤輝紀, 小澤諒, 高橋砂織, 渡邊博之, 久場敬司
    • Organizer
      第2回日本循環器学会基礎研究フォーラム
    • Related Report
      2018 Annual Research Report
  • [Presentation] CCR4-NOT脱アデニル化酵素複合体によるAtg7依存性細胞死の阻害と心機能改善作用2018

    • Author(s)
      山口智和, 鈴木享, 佐藤輝紀, 高橋明格, 門脇歩美, 夏井美幸, 小泉幸央, 山本雅, 今井由美子, 久場敬司
    • Organizer
      第91回日本生化学会大会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 微生物由来のアンジオテンシン変換酵素2(ACE2)様酵素による心臓リモデリング・機能不全の改善2018

    • Author(s)
      久場敬司, 佐藤輝紀, 湊隆文, 韮澤悟, 小澤諒, 山口智和, 中原和彦, 渡邊博之, 今井由美子,高橋砂織
    • Organizer
      生理学研究所研究会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 心臓の恒常性維持における分子ネットワークとシステム連関2018

    • Author(s)
      久場敬司
    • Organizer
      第83回 秋田県医学会総会・秋田県医師会設立71周年記念医学大会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] 心不全病態におけるRNA分解制御の新しい生理的意義2017

    • Author(s)
      久場 敬司
    • Organizer
      第21回 日本心不全学会学術集会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] mRNA deadenylation-guided regulation of cardiac homeostasis2017

    • Author(s)
      久場 敬司
    • Organizer
      理化学研究所IMS疾患生物学セミナー
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] New aspects of RNA decay in controlling heart function2017

    • Author(s)
      久場 敬司
    • Organizer
      富山大学 大学院特別セミナー
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] RNA deadenylation-guided control of cardiac homeostasis.2017

    • Author(s)
      Kuba K
    • Organizer
      Cutting Edge Developments in RNA Biology for the Control of Gene Expression.
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Patent(Industrial Property Rights)] アンジオテンシン変換酵素2活性を有する原核微生物由来ポリペプチドの医薬用途2020

    • Inventor(s)
      久場敬司
    • Industrial Property Rights Holder
      久場敬司
    • Industrial Property Rights Type
      特許
    • Filing Date
      2020
    • Related Report
      2019 Annual Research Report

URL: 

Published: 2017-04-28   Modified: 2021-02-19  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi