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Metalloprotease nardilysin controls heart rate through the transcriptional regulation of ion channels critical for sinus automaticity

Research Project

Project/Area Number 17K09575
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Cardiovascular medicine
Research InstitutionShiga University of Medical Science

Principal Investigator

Ohno Mikiko  滋賀医科大学, 医学部, 准教授 (10583198)

Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywords洞房結節自動能 / メタロプロテアーゼ / 洞不全症候群 / イオンチャネル / 酵素活性 / プロテアーゼ / 転写制御 / 循環器 / 洞房結節
Outline of Final Research Achievements

We have shown that NRDC, a multifunctional protease, controls heart rate by transcriptional regulation of HCN ion-channels responsible for cardiac sinus node automaticity. We specifically demonstrated that NRDC regulates gene expression of these ion channels involved in sinus automaticity by ChIP method using anti-NRDC antibody. Moreover, bradycardia was also shown in atrial (sinoatrial node) specific NRDC-deficient mice (Sln-Nrdc-KO), and expression levels of HCN ion channels were also reduced in Sln-Nrdc knockout hearts. In addition, we generated and analyzed the enzyme-activity-deficient mutant NRDC knock-in mice.

Academic Significance and Societal Importance of the Research Achievements

NRDCの生体における機能はこれまで全く不明であったが、NRDC-/-における研究成果から、NRDCが心拍数、血圧、体温調節などの恒常性維持に重要な役割を持つことが示唆された。一方、NRDCは全身に広く発現するので、NRDC-/-の表現型が一次的かどうかを判断するには困難を伴う。そこで、最近作製した臓器特異的NRDC欠損マウスや酵素活性欠失型変異NRDCマウスの解析を行い、心拍数調節のメカニズムの解明の足掛かりとした。これらの成果を今後発展させることで、ヒトにおける遺伝性洞不全症候群の原因解明やNRDCの酵素活性中心をターゲットとした創薬開発の基盤に役立てることができると考えられた。

Report

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

Research Products

(19 results)

All 2019 2018 2017 Other

All Journal Article (9 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 9 results,  Open Access: 5 results,  Acknowledgement Compliant: 1 results) Presentation (8 results) (of which Int'l Joint Research: 2 results,  Invited: 1 results) Remarks (2 results)

  • [Journal Article] Response to Letter of Stephenson et al.: Nardilysin: A potential biomarker for the early diagnosis of acute coronary syndrome2019

    • Author(s)
      Ohno M, Chen PM, Kimura T, Nishi E.
    • Journal Title

      International Journal of Cardiology

      Volume: 277 Pages: 249-249

    • DOI

      10.1016/j.ijcard.2018.10.022

    • Related Report
      2019 Annual Research Report 2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Serum nardilysin, a surrogate marker for epithelial-mesenchymal transition, predicts prognosis of intrahepatic cholangiocarcinoma after surgical resection2019

    • Author(s)
      Yoh T, Hatano E, Kasai Y, Fujii H, Nishi K, Toriguchi K, Sueoka H, Ohno M, Seo S, Iwaisako K, Taura K, Yamaguchi R, Kurokawa M, Fujimoto J, Kimura T, Uemoto S, and Nishi E.
    • Journal Title

      Clinical Cancer Research

      Volume: 25(2) Pages: 619-628

    • DOI

      10.1158/1078-0432.ccr-18-0124

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Reply: Nardilysin is a promising biomarker for the early diagnosis of acute coronary syndrome.2018

    • Author(s)
      Chen PM, Ohno M, Kimura T, Nishi E.
    • Journal Title

      International Journal of Cardiology

      Volume: 265 Pages: 236-236

    • DOI

      10.1016/j.ijcard.2018.04.056

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Turbulence Activates Platelet Biogenesis to Enable Clinical Scale Ex Vivo Production.2018

    • Author(s)
      Ito Y, Nakamura S, Sugimoto N, Shigemori T, Kato Y, Ohno M, Sakuma S, Ito K, Kumon H, Hirose H, Okamoto H, Nogawa M, Iwasaki M, Kihara S, Fujio K, Matsumoto T, Higashi N, Hashimoto K, Sawaguchi A, Harimoto KI, Nakagawa M, Yamamoto T, Handa M, Watanabe N.
    • Journal Title

      Cell

      Volume: 174(3) Issue: 3 Pages: 636-648

    • DOI

      10.1016/j.cell.2018.06.011

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Nardilysin controls intestinal tumorigenesis through HDAC1/p53-dependent transcriptional regulation.2018

    • Author(s)
      Kanda K, Sakamoto J, Matsumoto Y, Ikuta K, Goto N, Morita Y, Ohno M, Nishi K, Eto K, Kimura Y, Nakanishi Y, Ikegami K, Yoshikawa T, Fukuda A, Kawada K, Sakai Y, Ito A, Yoshida M, Kimura T, Chiba T, Nishi E, Seno H.
    • Journal Title

      JCI insight

      Volume: 3 Issue: 8 Pages: 1-15

    • DOI

      10.1172/jci.insight.91316

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Association of serum levels of antibodies against MMP1, CBX1, and CBX5 with transient ischemic attack and cerebral infarction2017

    • Author(s)
      Wang H,Zhang X-M,Tomiyoshi G,Nakamura R,Shinmen N,Kuroda H,Kimura R,Mine S,Kamitsukasa I,Wada T,Aotsuka A,Yoshida Y,Kobayashi E,Matsutani T,Iwadate Y,Sugimoto K,Mori M,Uzawa A,Muto M,Kuwabara S,Takemoto M,Kobayashi K,Kawamura H,Ishibashi R,Yokote K,Ohno M,
    • Journal Title

      Oncotarget

      Volume: 9 Pages: 5600-5613

    • DOI

      10.18632/oncotarget.23789

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Nardilysin is involved in autoimmune arthritis via the regulation of tumour necrosis factor alpha secretion2017

    • Author(s)
      Fujii Takayuki、Nishi Eiichiro、Ito Hiromu、Yoshitomi Hiroyuki、Furu Moritoshi、Okabe Namiko、Ohno Mikiko、Nishi Kiyoto、Morita Yusuke、Morita Yugo、Azukizawa Masayuki、Okahata Akinori、Tomizawa Takuya、Kimura Takeshi、Matsuda Shuichi
    • Journal Title

      RMD Open.

      Volume: 3

    • DOI

      10.1136/rmdopen-2017-000436

    • NAID

      120006325113

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Nardilysin promotes hepatocellular carcinoma through activation of signal transducer and activator of transcription 32017

    • Author(s)
      Kasai Y, Toriguchi K, *Hatano E, Nishi K, Ohno M, Yoh T, Fukuyaman K, Nishio T, Okuno M, Iwaisako K, Seo S, Taura K, Kurokawa M, Kunichika M, Uemoto S, *Nishi E
    • Journal Title

      Cancer Sci

      Volume: 108 Pages: 910-17

    • DOI

      10.1111/cas.13204

    • NAID

      120006333898

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Nardilysin is a promising biomarker for the early diagnosis of acute coronary syndrome2017

    • Author(s)
      Chen Po-Min、Ohno Mikiko、Hiwasa Takaki、Nishi Kiyoto、Saijo Sayaka、Sakamoto Jiro、Morita Yusuke、Matsuda Shintaro、Watanabe Shin、Kuwabara Yasuhide、Ono Koh、Imai Masao、Inoue Katsumi、Murai Tatsuya、Inada Tsukasa、Tanaka Masaru、Kita Toru、Kimura Takeshi、Nishi Eiichiro
    • Journal Title

      Int J Cardiol.

      Volume: 243 Pages: 1-8

    • DOI

      10.1016/j.ijcard.2017.04.047

    • NAID

      130007900462

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Presentation] Metalloprotease nardilysin controls heart rate through the transcriptional regulation of ion channels critical for sinus automaticity2019

    • Author(s)
      Ohno M, Matsuura H., Makiyama T., Nishi K., Iwasaki H., Matsuda S., Kita T., Kimura T., and Nishi E.
    • Organizer
      ESC congress
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Metalloprotease nardilysin controls heart rate through the transcriptional regulation of ion channels critical for sinus automaticity2019

    • Author(s)
      Ohno M, Matsuura H., Makiyama T., Nishi K., Iwasaki H., Matsuda S., Kita T., Kimura T., and Nishi E.
    • Organizer
      第92回日本薬理学会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Metalloprotease nardilysin controls heart rate through the transcriptional regulation of ion channels critical for sinus automaticity2019

    • Author(s)
      Mikiko Ohno, Hiroshi Matsuura, Takeru Makiyama, Hirotaka Iwasaki, Shintaro Matsuda, Eiichiro Nishi
    • Organizer
      第83回日本循環器学会総会
    • Related Report
      2018 Research-status Report
  • [Presentation] Nardilysin regulates cardiac dynamics and cardiac sympathetic innervation through modulating p75NTR shedding2018

    • Author(s)
      大野美紀子, 西 清人, 平岡 義範, 新妻 晋一郎, 西城 さやか, 坂本 二郎, 陳 博俊, 森田 雄介, 松田 真太郎, 椋本 淑子, 清成 寛, 松浦 博, 北 徹, 木村 剛, 西 英一郎.
    • Organizer
      神経科学大会
    • Related Report
      2018 Research-status Report
  • [Presentation] Nardilysin is a Promising Biomarker for the Early Diagnosis of Acute Coronary Syndrome.2018

    • Author(s)
      Ohno M, Chen P-M, Hiwasa T, Nishi K, Saijo S, Sakamoto J, Morita Y, Watanabe S, Kuwabara Y, Ono K, Imai M, Inoue K, Murai T, Kita T, Kimura T, and Nishi E.
    • Organizer
      18th World Congress of Basic and Clinical Pharmacology
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] 急性冠症候群における新規バイオマーカー「ナルディライジン」の有用性についての検討2017

    • Author(s)
      大野美紀子、陳博俊、日和佐隆樹、西清人、西城さやか、森田雄介、松田真太郎、木村剛、西英一郎.
    • Organizer
      第22回日本病態プロテアーゼ学会
    • Related Report
      2017 Research-status Report
  • [Presentation] 多機能タンパク質NardilysinのACSバイオマーカーとしての意義2017

    • Author(s)
      大野美紀子
    • Organizer
      第3回Cardiac Biomarker研究会
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] ナルディライジンは神経栄養因子受容体(p75NTR)のシェディングを介して心臓交感神経の分布を制御する2017

    • Author(s)
      大野美紀子, 西 清人, 平岡 義範, 新妻 晋一郎, 西城 さやか, 坂本 二郎, 陳 博俊, 森田 雄介, 松田 真太郎, 椋本 淑子, 清成 寛, 松浦 博, 北 徹, 木村 剛, 西 英一郎
    • Organizer
      生命科学系学会合同年次大会(第40回日本分子生物学会年会)
    • Related Report
      2017 Research-status Report
  • [Remarks] 滋賀医科大学薬理学講座ホームページ

    • URL

      http://www.shiga-med.ac.jp/pharm/

    • Related Report
      2019 Annual Research Report
  • [Remarks] 滋賀医科大学薬理学講座

    • URL

      http://www.shiga-med.ac.jp/pharm/

    • Related Report
      2017 Research-status Report

URL: 

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

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