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Mechanistic insight into CCR4-NOT deadenylase-mediated heart function control and its potential application for therapeutics

Research Project

Project/Area Number 26293050
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypePartial Multi-year Fund
Section一般
Research Field General pharmacology
Research InstitutionAkita University

Principal Investigator

Kuba Keiji  秋田大学, 医学(系)研究科(研究院), 教授 (10451915)

Project Period (FY) 2014-04-01 – 2017-03-31
Project Status Completed (Fiscal Year 2016)
Budget Amount *help
¥15,990,000 (Direct Cost: ¥12,300,000、Indirect Cost: ¥3,690,000)
Fiscal Year 2016: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2015: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2014: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000)
KeywordsCCR4-NOT / heart failure / deadenylase / CNOT3 / 心不全 / デアデニレース / オートファジー / ネクローシス / RNA代謝 / 脱アデニル化 / 循環器 / RNA創薬 / 遺伝子改変マウス / CCR4-NOT / poly(A) / 心臓
Outline of Final Research Achievements

In this study, we analyzed the mechanisms how CCR4-NOT deadenylase regulates mRNA decay and nucleotide metabolism in controlling heart functions. mRNA decay by CCR4-NOT complex was revealed to alter adenine nucleotide levels in the heart. In addition, bulk mRNA poly(A) shortening and alteration of nucleotide levels were sensed by an autophagy molecule, which is crucial for cardiomyocyte survival. Furthermore, CCR4-NOT-mediated adenine nucleotide regulation was also shown to affect energy-sensing signaling pathway. Both pathways are likely important for CCR4-NOT-mediated heart function control. Finally, we conducted chemical compound screening for CCR4-NOT deadenylase inhibitors.

Report

(4 results)
  • 2016 Annual Research Report   Final Research Report ( PDF )
  • 2015 Annual Research Report
  • 2014 Annual Research Report
  • Research Products

    (32 results)

All 2017 2016 2015 2014 Other

All Int'l Joint Research (3 results) Journal Article (8 results) (of which Int'l Joint Research: 5 results,  Peer Reviewed: 8 results,  Open Access: 6 results,  Acknowledgement Compliant: 5 results) Presentation (21 results) (of which Int'l Joint Research: 1 results,  Invited: 9 results)

  • [Int'l Joint Research] Max Planck Institute(ドイツ)

    • Related Report
      2016 Annual Research Report
  • [Int'l Joint Research] Institute of Medical Biology, A*STAR(シンガポール)

    • Related Report
      2016 Annual Research Report
  • [Int'l Joint Research] IMBA(オーストリア)

    • Related Report
      2016 Annual Research Report
  • [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
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Vps34 regulates myofibril proteostasis to prevent hypertrophic cardiomyopathy.2017

    • Author(s)
      Kimura H, Eguchi S, Sasaki J, Kuba K, Nakanishi H, Takasuga S, Yamazaki M, Goto A, Watanabe H, Itoh H, Imai Y, Suzuki A, Mizushima N, Sasaki T
    • Journal Title

      JCI Insight

      Volume: 2 Issue: 1 Pages: 89462-89478

    • DOI

      10.1172/jci.insight.89462

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Evaluation of Lecithinized Superoxide Dismutase for the Prevention of Acute Respiratory Distress Syndrome in Animal Models.2017

    • Author(s)
      Tanaka KI, Tamura F, Sugizaki T, Kawahara M, Kuba K, Imai Y, Mizushima T
    • Journal Title

      Am J Respir Cell Mol Biol

      Volume: 56 Pages: 179-190

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Interaction of CCR4-NOT with EBF1 regulates gene-specific transcription and mRNA stability in B lymphopoiesis.2016

    • Author(s)
      Yang CY, Ramamoorthy S, Boller S, Rosenbaum M, Rodriguez Gil A, Mittler G, Imai Y, Kuba K, Grosschedl R
    • Journal Title

      Genes & Development

      Volume: 30 Pages: 2310-2324

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Structure-activity relationship of cyclic pentapeptide malformins as fibrinolysis enhancers.2016

    • Author(s)
      Koizumi Y, Nagai K, Hasumi K, Kuba K, Sugiyama T
    • Journal Title

      Bioorg Med Chem Lett

      Volume: 26 Issue: 21 Pages: 5267-5271

    • DOI

      10.1016/j.bmcl.2016.09.045

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Cationic nanoparticles directly bind angiotensin-converting enzyme 2 and induce acute lung injury in mice.2015

    • Author(s)
      Sun Y, Kuba K, et al.
    • Journal Title

      Part Fibre Toxicol.

      Volume: 12 Pages: 4-4

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Cationic nanoparticles directly bind angiotensin-converting enzyme 2 and induce acute lung injury in mice.2015

    • Author(s)
      Sun Y, Kuba K, Jiang C, et al.(23著者、13番目)
    • Journal Title

      Part Fibre Toxicol

      Volume: 12 Issue: 1

    • DOI

      10.1186/s12989-015-0080-x

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The arachidonic acid metabolome as conserved regulator of cholesterol metabolism.2014

    • Author(s)
      Demetz E, Schroll A, Auer K, Heim C, Patsch JR, Eller P, Theurl M, Lener D, Stanzl U, Seifert M, Haschka D, Asshoff M, Dichtl S, Nairz M, Huber E, Stadlinger M, Li X, Pallweber P, Scharnagl H, Stojakovic T, Marz W, Kleber ME, Garlaschelli K, Uboldi P, Catapano AL, Kuba K, Imai Y, Arita M, Tancevski I.
    • Journal Title

      Cell Metab.

      Volume: 20 Issue: 5 Pages: 787-798

    • DOI

      10.1016/j.cmet.2014.09.004

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [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90回日本薬理学会 シンポジウム3
    • Place of Presentation
      長崎
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] Dissecting the functional role of A Novel APJ ligand, ELABELA, in heart failure2016

    • Author(s)
      佐藤輝紀、久場敬司
    • Organizer
      日本薬理学会
    • Place of Presentation
      横浜
    • Year and Date
      2016-03-09
    • Related Report
      2015 Annual Research Report
  • [Presentation] RNA分解による心臓エネルギー代謝の恒常性維持2016

    • Author(s)
      久場敬司
    • Organizer
      第4回 CCR4-NOT研究会
    • Place of Presentation
      秋田
    • Year and Date
      2016-02-12
    • Related Report
      2015 Annual Research Report
  • [Presentation] 心臓のmRNA poly(A)分解とエネルギー感知シグナルの相互作用機構の解明2016

    • Author(s)
      山口智和、鈴木享、佐藤輝紀、夏井美幸、門脇歩美、佐藤チトセ、小泉幸央、高橋明格、山本雅、今井由美子、久場敬司
    • Organizer
      第26回 日本循環薬理学会
    • Place of Presentation
      松本
    • Related Report
      2016 Annual Research Report
  • [Presentation] 心不全病態における新規APJリガンドELABELAの機能的意義の解明2016

    • Author(s)
      佐藤輝紀, 山口智和, 渡邊博之, 門脇歩美, 佐藤チトセ, 伊藤宏, 今井由美子, 久場敬司
    • Organizer
      第26回 日本循環薬理学会
    • Place of Presentation
      松本
    • Related Report
      2016 Annual Research Report
  • [Presentation] CCR4-NOT complex controls adenine nucleotide metabolism and energy sensing in cardiac homeostasis2016

    • Author(s)
      久場敬司
    • Organizer
      The 89th JBS meeting symposium 3S17
    • Place of Presentation
      東北大学
    • Related Report
      2016 Annual Research Report
  • [Presentation] RNA代謝制御による心機能の恒常性維持2016

    • Author(s)
      久場敬司
    • Organizer
      第10回 京阪神心不全研究会
    • Place of Presentation
      大阪
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] RNA分解制御による心臓エネルギー恒常性維持の分子機構2015

    • Author(s)
      久場敬司
    • Organizer
      BMB2015
    • Place of Presentation
      神戸
    • Year and Date
      2015-12-04
    • Related Report
      2015 Annual Research Report
  • [Presentation] 心臓における新規Apelin受容体リガンドApelaの機能的意義の解析2015

    • Author(s)
      久場敬司
    • Organizer
      生理学研究所 研究会 2015 「心臓・血管系の包括的な機能統合研究」
    • Place of Presentation
      岡崎
    • Year and Date
      2015-10-29
    • Related Report
      2015 Annual Research Report
  • [Presentation] CNOT3を介した心臓のアデニン核酸制御機構の解析2015

    • Author(s)
      山口智和、久場敬司
    • Organizer
      第66回 日本薬理学会北部会
    • Place of Presentation
      富山
    • Year and Date
      2015-09-18
    • Related Report
      2015 Annual Research Report
  • [Presentation] Signaling network to maintain cardiac homeostasis in failing hearts2015

    • Author(s)
      久場敬司
    • Organizer
      The 4th Hsien Wu and Ray Wu Symposia “Proteins, Genes and Diseases”
    • Place of Presentation
      北京
    • Year and Date
      2015-08-10
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] CCR4-NOT複合体によるアデニン核酸制御機構の解析2015

    • Author(s)
      山口智和、久場敬司
    • Organizer
      RNA学会
    • Place of Presentation
      札幌
    • Year and Date
      2015-07-13
    • Related Report
      2015 Annual Research Report
  • [Presentation] mRNA分解制御を介した心臓の恒常性維持2015

    • Author(s)
      久場敬司
    • Organizer
      第一回 J-ISCP学術集会
    • Place of Presentation
      京都
    • Year and Date
      2015-06-20
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] 心臓のmRNA分解とエネルギー代謝の恒常性維持2015

    • Author(s)
      久場敬司
    • Organizer
      第2回 仙台先進循環器研究会
    • Place of Presentation
      仙台
    • Year and Date
      2015-06-20
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] アンジオテンシン変換酵素2(ACE2)の多彩な生理機能と制御機構の解明2015

    • Author(s)
      久場敬司
    • Organizer
      第160回日本循環器学会東北地方会
    • Place of Presentation
      盛岡
    • Year and Date
      2015-04-10
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] Angiotensin converting enzyme 2 (ACE2) links Apelin and angiotensin systems in controlling heart function.2015

    • Author(s)
      久場敬司
    • Organizer
      日本解剖学会・日本生理学会合同大会
    • Place of Presentation
      神戸
    • Year and Date
      2015-03-23
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] Dissecting the role of CCR4-NOT-associated ubiquitin converting enzyme in controlling heart functions.2015

    • Author(s)
      山口智和、門脇歩美、小泉幸央、夏井美幸、佐藤チトセ、今井由美子、久場敬司
    • Organizer
      第88回 日本薬理学会
    • Place of Presentation
      名古屋
    • Year and Date
      2015-03-18 – 2015-03-20
    • Related Report
      2014 Annual Research Report
  • [Presentation] A crucial role of CNOT3 in stem cell proliferation and early embryonic development2015

    • Author(s)
      小泉幸央、山口智和、門脇歩美、夏井美幸、佐藤チトセ、今井由美子、久場敬司
    • Organizer
      第88回 日本薬理学会
    • Place of Presentation
      名古屋
    • Year and Date
      2015-03-18 – 2015-03-20
    • Related Report
      2014 Annual Research Report
  • [Presentation] 酵母からヒトまで保存されたCCR4-NOT複合体による心機能制御メカニズム2014

    • Author(s)
      久場敬司
    • Organizer
      第24回 日本循環薬理学会
    • Place of Presentation
      山形
    • Year and Date
      2014-12-05
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] CCR4-NOT deadenylase complex links mRNA metabolism to energy sensing in cardiac homeostasis2014

    • Author(s)
      久場敬司
    • Organizer
      第 31 回 国際心臓研究学会(ISHR)日本部会
    • Place of Presentation
      名古屋
    • Year and Date
      2014-11-29
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] Dissecting the mechanisms for regulation of cardiac energy metabolism by CCR4-NOT complex2014

    • Author(s)
      久場敬司
    • Organizer
      第 16 回 日本RNA学会年会
    • Place of Presentation
      名古屋
    • Year and Date
      2014-07-23
    • Related Report
      2014 Annual Research Report

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Published: 2014-04-04   Modified: 2018-03-22  

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