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

Role of mutant calreticulin in pulmonary hypertension associated with myeloproliferative neoplasm

Research Project

Project/Area Number 19K17532
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 53020:Cardiology-related
Research InstitutionFukushima Medical University

Principal Investigator

Yokokawa Tetsuro  福島県立医科大学, 医学部, 助教 (80748773)

Project Period (FY) 2019-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2020: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2019: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywords肺高血圧症 / CALR変異 / 骨髄増殖性疾患 / Calreticulin変異
Outline of Research at the Start

骨髄増殖性疾患は肺高血圧症を高頻度で合併し、かつ肺高血圧症合併例は予後不良であることが知られている。しかしながら骨髄増殖性疾患における肺高血圧症の病態はいまだに不明であり、詳細な機序の解明が待たれている。近年、骨髄増殖性疾患の新たな原因遺伝子変異としてcalreticulin(CALR)変異が同定された。我々は、CALR変異に着目し、CALR変異陽性患者における肺高血圧症を検討するとともに、骨髄増殖性疾患に合併した肺高血圧症の分子メカニズムを解明するため、CALR変異ノックインマウスを用いてCALR変異における肺高血圧症の病態について明らかにする。

Outline of Final Research Achievements

To investigate whether the hematopoietic CALR mutation contributes to pulmonary hypertension, we applied a bone marrow transplantation (BMT) with the donor cells from Calr with a 10-bp deletion knock-in mice or control wild-type (WT) mice. The recipient mice transplanted with bone marrow cells from Calr with a 10-bp deletion knock-in mice (Del-R mice) and WT mice (WT-R mice) were exposed to chronic hypoxia to induce pulmonary hypertension. After chronic hypoxia exposure, the right ventricular pressure in the Del-R mice was significantly increased compared to that in the WT-R mice. Hematopoietic Calr mutation accelerated pulmonary artery muscularization as well as elevation of endothelin-1 expression. Macrophage infiltration was observed under chronic hypoxia. Bone-marrow derived macrophages carrying Calr mutation showed increases in endothelin-1 expression. These results indicated a novel mechanism through endothelin-1 expression in pulmonary hypertension associated with CALR mutation.

Academic Significance and Societal Importance of the Research Achievements

これまで明らかではなかった、CALR変異を有する骨髄増殖性疾患における肺高血圧症発症のメカニズムを、エンドセリン1に着目して解明した。

Report

(3 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • Research Products

    (17 results)

All 2021 2020

All Journal Article (9 results) (of which Peer Reviewed: 9 results,  Open Access: 8 results) Presentation (8 results) (of which Int'l Joint Research: 4 results)

  • [Journal Article] Anti-mitochondrial Antibodies in Patients with Dilated Cardiomyopathy2021

    • Author(s)
      Yokokawa T, Yoshihisa A, Misaka T, Sato T, Kaneshiro T, Oikawa M, Kobayashi A, Yamaki T, Kunii H, Takeishi Y.
    • Journal Title

      Internal Medicine

      Volume: 60 Issue: 2 Pages: 201-208

    • DOI

      10.2169/internalmedicine.5422-20

    • NAID

      130007968962

    • ISSN
      0918-2918, 1349-7235
    • Year and Date
      2021-01-15
    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Clonal hematopoiesis and JAK2V617F mutations in patients with cardiovascular disease.2021

    • Author(s)
      Yokokawa T, Misaka T, Kimishima Y, Wada K, Minakawa K, Kaneshiro T, Yoshihisa A, Ikeda K, Takeishi Y.
    • Journal Title

      JACC: CardioOncology

      Volume: 3 Pages: 134-136

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Myeloproliferative neoplasm-driving Calr frameshift promotes the development of pulmonary hypertension in mice.2021

    • Author(s)
      Minakawa K, Yokokawa T, Ueda K, Nakajima O, Misaka T, Kimishima Y, Wada K, Tomita Y, Miura S, Sato Y, Mimura K, Sugimoto K, Nakazato K, Nollet KE, Ogawa K, Ikezoe T, Hashimoto Y, Takeishi Y, Ikeda K.
    • Journal Title

      J Hematol Oncol.

      Volume: 14 Issue: 1 Pages: 52-52

    • DOI

      10.1186/s13045-021-01064-8

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Crucial role of hematopoietic JAK2V617F in the development of aortic aneurysms.2021

    • Author(s)
      Yokokawa T, Misaka T, Kimishima Y, Wada K, Minakawa K, Sugimito K, Ishida T, Morishita S, Komatsu N, Ikeda K, Takeishi Y.
    • Journal Title

      Haematologica

      Volume: - Issue: 7 Pages: 1910-1922

    • DOI

      10.3324/haematol.2020.264085

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Endothelin-1 upregulates activin receptor-like kinase-1 expression via G i/RhoA/Sp-1/Rho kinase pathways in human pulmonary arterial endothelial cells.2021

    • Author(s)
      Sugimoto K, Yokokawa T, Misaka T, Kaneshiro T, Yamada S, Yoshihisa A, Nakazato K, Takeishi Y.
    • Journal Title

      Front Cardiovasc Med

      Volume: 8 Pages: 648981-648981

    • DOI

      10.3389/fcvm.2021.648981

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Significance of Pulmonary Vascular Resistance and Diastolic Pressure Gradient on the New Definition of Combined Post-Capillary Pulmonary Hypertension2020

    • Author(s)
      Sugimoto K, Yoshihisa A, Nakazato K, Yokokawa T, Misaka T, Oikawa M, Kobayashi A, Yamaki T, Kunii H, Ishida T, Takeishi Y.
    • Journal Title

      International Heart Journal

      Volume: 61 Issue: 2 Pages: 301-307

    • DOI

      10.1536/ihj.19-476

    • NAID

      130007821526

    • ISSN
      1349-2365, 1349-3299
    • Year and Date
      2020-03-28
    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Residual Gensini Score Is Associated With Long-Term Cardiac Mortality in Patients With Heart Failure After Percutaneous Coronary Intervention2020

    • Author(s)
      Yokokawa T, Yoshihisa A, Kiko T, Shimizu T, Misaka T, Yamaki T, Kunii H, Nakazato K, Ishida T, Takeishi Y.
    • Journal Title

      Circulation Reports

      Volume: 2 Issue: 2 Pages: 89-94

    • DOI

      10.1253/circrep.CR-19-0121

    • NAID

      130007796308

    • ISSN
      2434-0790
    • Year and Date
      2020-02-10
    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Pulmonary Hypertension and Hereditary Hemorrhagic Telangiectasia Related to an <i>ACVRL1</i> Mutation2020

    • Author(s)
      Yokokawa T, Sugimoto K, Kimishima Y, Misaka T, Yoshihisa A, Morisaki H, Yamada O, Nakazato K, Ishida T, Takeishi Y.
    • Journal Title

      Internal Medicine

      Volume: 59 Issue: 2 Pages: 221-227

    • DOI

      10.2169/internalmedicine.3625-19

    • NAID

      130007785091

    • ISSN
      0918-2918, 1349-7235
    • Year and Date
      2020-01-15
    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Clinical significance of circulating cardiomyocyte-specific cell-free DNA in patients with heart failure: a proof-of-concept study.2020

    • Author(s)
      Yokokawa T, Misaka T, Kimishima Y, Shimizu T, Kaneshiro T, Takeishi Y.
    • Journal Title

      Can J Cardiol

      Volume: - Issue: 6 Pages: 931-935

    • DOI

      10.1016/j.cjca.2019.10.016

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Presentation] JAK2V617F-positive myeloproliferative neoplasm is associated with aortic aneurysm2021

    • Author(s)
      Yokokawa T, Misaka T, Kimishima Y, Wada K, Sugimoto K, Ishida T, Takeishi Y.
    • Organizer
      第85回 日本循環器学会学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Clinical significance of myeloproliferative neoplasm driver mutation-mediated clonal hematopoiesis in patients with cardiovascular diseases2021

    • Author(s)
      和田健斗, 三阪智史, 横川哲朗, 君島勇輔, 皆川敬冶, 義久精臣, 池田和彦, 竹石恭知
    • Organizer
      第85回 日本循環器学会学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Crucial role of Jak2V617f-positive myeloproliferative neoplasm in the development of aortic aneurysm.2020

    • Author(s)
      Yokokawa T, Misaka T, Kimishima Y, Wada K, Minakawa K, Sugimoto K, Ishida T, Ikeda K, Takeishi Y.
    • Organizer
      American Heart Association Scientific Session 2020
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Clinical significance of clonal hematopoiesis with JAK2V617F in patients with cardiovascular diseases2020

    • Author(s)
      Wada K, Misaka T, Yokokawa T, Kimishima Y, Minakawa K, Kaneshiro T, Yoshihisa A, Ikeda K, Takeishi Y
    • Organizer
      American Heart Association Scientific Session 2020
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Endothelin-1 increases ACVRL-1 expression at the transcriptional and post-transcriptional levels in human pulmonary arterial endothelial cells via Gi, RhoA and Rho kinase pathway with involvement of Sp-12020

    • Author(s)
      Sugimoto K, Yokokawa T, Misaka T, Yokokawa S, Nakazato K, Ishida T, Takeishi Y
    • Organizer
      American Heart Association Scientific Session 2020
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Hematopoietic JAK2V617F mutation exacerbates aortic aneurysm development.2020

    • Author(s)
      Yokokawa T, Misaka T, Kimishima Y, Wada K, Minakawa K, Sugimoto K, Ishida T, Ikeda K, Takeishi Y.
    • Organizer
      The 64th Annual Scientific Meeting of The Korean Society of Cardiology
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Clinical significance of clonal hematopoiesis with JAK2V617F in patients with cardiovascular disease2020

    • Author(s)
      Wada K, Misaka T, Yokokawa T, Kimishima Y, Minakawa K, Kaneshiro T, Yoshihisa A, Ikeda K, Takeishi Y
    • Organizer
      The 4th JCS Council Forum on Basic CardioVascular Research
    • Related Report
      2020 Annual Research Report
  • [Presentation] Crucial role of hematopoietic JAK2V617F mutation in the development of aortic aneurysms2020

    • Author(s)
      Yokokawa T, Misaka T, Kimishima Y, Wada K, Minakawa K, Sugimoto K, Ishida T, Ikeda K, Takeishi Y.
    • Organizer
      The 4th JCS Council Forum on Basic CardioVascular Research
    • Related Report
      2020 Annual Research Report

URL: 

Published: 2019-04-18   Modified: 2022-01-27  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi