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Analysis of downstream effectors of PDGF signaling to identify novel therapeutic targets in pulmonary hypertension

Research Project

Project/Area Number 18K08128
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 53020:Cardiology-related
Research Institution独立行政法人国立病院機構岡山医療センター(臨床研究部)

Principal Investigator

Matsubara Hiromi  独立行政法人国立病院機構岡山医療センター(臨床研究部), 独立行政法人国立病院機構 岡山医療センター(臨床研究部), 副院長 (70252955)

Co-Investigator(Kenkyū-buntansha) 小川 愛子  独立行政法人国立病院機構岡山医療センター(臨床研究部), 独立行政法人国立病院機構 岡山医療センター(臨床研究部), 分子病態研究室長 (40572748)
狩野 光伸  岡山大学, ヘルスシステム統合科学研究科, 教授 (80447383)
Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywords肺高血圧 / シグナル伝達 / 転写因子 / 肺動脈平滑筋細胞 / 微小血管モデル
Outline of Final Research Achievements

We studied the role of the transcription factor distal-less homeobox 1 (DLX1) in the proliferation of pulmonary arterial smooth muscle cells (PASMCs) isolated from patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension. Knockdown of DLX1 expression resulted in a marked reduction of PASMC proliferation at baseline as well as in the presence of platelet-derived growth factor (PDGF) ligands. Microarray analyses implicated reduced expression of integrin subunits as a mechanism underlying reduced PASMC proliferation upon DLX1 knockdown. Indeed, knockdown of the integrin subunit resulted in a reduced PASMC proliferation at baseline and in the presence of PDGF ligands. Furthermore, the respective ligand of the integrin subunit was elevated in the sera of PH patients compared to healthy controls. Altogether, our results suggest that DLX1, downstream of PDGF signaling, modulates integrin expression to promote PASMC proliferation in the pathogenesis of PH.

Academic Significance and Societal Importance of the Research Achievements

難病である肺高血圧症に対する治療薬が近年複数開発されてきたが,治療成績の改善はまだ不十分である.肺高血圧症の悪化に重要な役割を果たすPDGF経路を効果的に抑制する標的分子の候補を明らかにすることができたため,この分子を特異的に抑制する治療薬を開発することで,肺高血圧症の治療成績が改善できる可能性が示された.

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (48 results)

All 2021 2020 2019 2018

All Journal Article (14 results) (of which Int'l Joint Research: 7 results,  Peer Reviewed: 13 results,  Open Access: 11 results) Presentation (34 results) (of which Int'l Joint Research: 29 results,  Invited: 34 results)

  • [Journal Article] Increased levels of platelet-derived microparticles in pulmonary hypertension2020

    • Author(s)
      Ogawa Aiko、Matsubara Hiromi
    • Journal Title

      Thrombosis Research

      Volume: 195 Pages: 120-124

    • DOI

      10.1016/j.thromres.2020.07.030

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] 3D in vitro Model of Vascular Medial Thickening in Pulmonary Arterial Hypertension2020

    • Author(s)
      Morii Chiharu、Tanaka Hiroyoshi Y.、Izushi Yasuhisa、Nakao Natsumi、Yamamoto Masaya、Matsubara Hiromi、Kano Mitsunobu R.、Ogawa Aiko
    • Journal Title

      Frontiers in Bioengineering and Biotechnology

      Volume: 8 Pages: 482-482

    • DOI

      10.3389/fbioe.2020.00482

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Balloon Pulmonary Angioplasty as a Treatment in Chronic Thromboembolic Pulmonary Hypertension: Past, Present, and Future.2020

    • Author(s)
      Karyofyllis P, Demerouti E, Papadopoulou V, Voudris V, Matsubara H.
    • Journal Title

      Curr Treat Options Cardiovasc Med

      Volume: 22 Issue: 3 Pages: 7-7

    • DOI

      10.1007/s11936-020-0807-3

    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Journal Article] Multicentre randomised controlled trial of balloon pulmonary angioplasty and riociguat in patients with chronic thromboembolic pulmonary hypertension: protocol for the MR BPA study.2020

    • Author(s)
      Kawakami T, Matsubara H, Abe K, Kataoka M, Kohsaka S, Sato Y, Shinke T, Fukuda K.
    • Journal Title

      BMJ Open

      Volume: 10 Issue: 2 Pages: e028831-e028831

    • DOI

      10.1136/bmjopen-2018-028831

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Should oral combination therapy be the standard of care for pulmonary arterial hypertension?2020

    • Author(s)
      Ogawa A, Matsubara H.
    • Journal Title

      Expert Rev Respir Med

      Volume: 28 Issue: 4 Pages: 1-3

    • DOI

      10.1080/17476348.2020.1722641

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] The importance of right ventricular evaluation in risk assessment and therapeutic strategies: Raising the bar in pulmonary arterial hypertension.2020

    • Author(s)
      Badagliacca R, Papa S, Matsubara H, Lang IM, Poscia R, Manzi G, Vizza CD.
    • Journal Title

      Int J Cardiol

      Volume: 15 Pages: 183-189

    • DOI

      10.1016/j.ijcard.2019.10.043

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Sex-specific differences in chronic thromboembolic pulmonary hypertension. Results from the European CTEPH registry.2020

    • Author(s)
      Barco S, Klok FA, Konstantinides SV, Dartevelle P, Fadel E, Jenkins D, Kim NH, Madani M, Matsubara H, Mayer E, Pepke-Zaba J, Simonneau G, Delcroix M, Lang IM.
    • Journal Title

      J Thromb Haemost

      Volume: 18 Issue: 1 Pages: 151-161

    • DOI

      10.1111/jth.14629

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Guidelines for the Treatment of Pulmonary Hypertension (JCS 2017/JPCPHS 2017)2019

    • Author(s)
      Fukuda Keiichi、Kasai Takatoshi、et al、on behalf of the Japanese Circulation Society and the Japanese Pulmonary Circulation and Pulmonary Hypertension Society Joint Working Group
    • Journal Title

      Circulation Journal

      Volume: 83 Issue: 4 Pages: 842-945

    • DOI

      10.1253/circj.CJ-66-0158

    • NAID

      130007620555

    • ISSN
      1346-9843, 1347-4820
    • Year and Date
      2019-03-25
    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Balloon pulmonary angioplasty for the treatment of chronic thromboembolic pulmonary hypertension: is Europe behind?2019

    • Author(s)
      Lang IM, Matsubara H.
    • Journal Title

      Eur Respir J

      Volume: 53 Issue: 5 Pages: 1900843-1900843

    • DOI

      10.1183/13993003.00843-2019

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Chronic thromboembolic pulmonary hypertension in Austria and Japan2019

    • Author(s)
      Chausheva Stella、Naito Akira、Ogawa Aiko、Seidl Veronika、Winter Max-Paul、Sharma Smriti、Sadushi-Kolici Roela、Campean Ioana-Alexandra、Taghavi Shahroukh、Moser Bernhard、Klepetko Walter、Ishida Keiichi、Matsubara Hiromi、Sakao Seiichiro、Lang Irene M.
    • Journal Title

      The Journal of Thoracic and Cardiovascular Surgery

      Volume: 印刷中 Issue: 2 Pages: 604-614

    • DOI

      10.1016/j.jtcvs.2019.01.019

    • Related Report
      2019 Research-status Report 2018 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Chronic thromboembolic pulmonary hypertension2019

    • Author(s)
      Kim Nick H.、Delcroix Marion、Jais Xavier、Madani Michael M.、Matsubara Hiromi、Mayer Eckhard、Ogo Takeshi、Tapson Victor F.、Ghofrani Hossein-Ardeschir、Jenkins David P.
    • Journal Title

      European Respiratory Journal

      Volume: 53 Issue: 1 Pages: 1801915-1801915

    • DOI

      10.1183/13993003.01915-2018

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Vascular Injury Is a Major Cause of Lung Injury After Balloon Pulmonary Angioplasty in Patients With Chronic Thromboembolic Pulmonary Hypertension2018

    • Author(s)
      Ejiri Kentaro、Ogawa Aiko、Fujii Shinya、Ito Hiroshi、Matsubara Hiromi
    • Journal Title

      Circulation: Cardiovascular Interventions

      Volume: 11 Issue: 12

    • DOI

      10.1161/circinterventions.117.005884

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Vessel Stretching Is a Cause of Lumen Enlargement Immediately After Balloon Pulmonary Angioplasty: Intravascular Ultrasound Analysis in Patients With Chronic Thromboembolic Pulmonary Hypertension2018

    • Author(s)
      Shimokawahara H, Ogawa A, Mizoguchi H, Yagi H, Ikemiyagi S, Matsubara H.
    • Journal Title

      Circ Cardiovasc Interv.

      Volume: 11 Issue: 4

    • DOI

      10.1161/circinterventions.117.006010

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Change in R wave in lead V1 predicts survival of patients with pulmonary arterial hypertension2018

    • Author(s)
      Sato Shinji、Ogawa Aiko、Matsubara Hiromi
    • Journal Title

      Pulmonary Circulation

      Volume: 8 Issue: 2 Pages: 1-7

    • DOI

      10.1177/2045894018776496

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] VTE, Unmet Needs2021

    • Author(s)
      Hiromi Matsubara
    • Organizer
      11th Congress of the Asian-Pacific Society on Thrombosis and Hemostasis
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 肺高血圧症診療の変遷2020

    • Author(s)
      松原 広己
    • Organizer
      第84回日本循環器学会学術集会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] Keynote Lecture Progress in CTEPH Treatment2020

    • Author(s)
      Hiromi Matsubara
    • Organizer
      第84回日本循環器学会学術集会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] BPA: Where does it come from, where are we and where are we going?2020

    • Author(s)
      Hiromi Matsubara
    • Organizer
      7th Drug Discovery & Development Symposium for Pulmonary Hypertension
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] New Mechanism of Pulmonary Hypertension2020

    • Author(s)
      Aiko Ogawa
    • Organizer
      American Heart Association Scientific Sessions 2020
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 立体培養法による組織微小環境モデルの開発および疾患研究への応用2020

    • Author(s)
      田中啓祥、狩野光伸
    • Organizer
      日本化学会
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] BPA2019

    • Author(s)
      松原 広己
    • Organizer
      第4回日本肺高血圧・肺循環学会学術集会
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] Current management of CTEPH in JAPAN2019

    • Author(s)
      Hiromi Matsubara
    • Organizer
      1st East Asia Society of Pulmonary Hypertension
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Emerging experience with pulmonary balloon angioplasty for chronic thromboembolic pulmonary hypertension2019

    • Author(s)
      Hiromi Matsubara
    • Organizer
      European Society of Cardiology Congress 2019
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Interventional Treatment for Chronic Thromboembolic Pulmonary Hypertension in Japan2019

    • Author(s)
      Hiromi Matsubara
    • Organizer
      The 28th Annual Meeting of the Japanese Association of Cardiovascular Intervention and Therapeutics
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Balloon Pulmonary Angioplasty ― Japanese Experience2019

    • Author(s)
      Hiromi Matsubara
    • Organizer
      The 31st Annual Scientific Sympoosium of Transcatheter Cardiovascular Therapeutics
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Balloon pulmonary angioplasty: complex cases & technical updates2019

    • Author(s)
      Hiromi Matsubara
    • Organizer
      Endovascular & Coronary Revascularization in Seoul 2019
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] The Last Frontier? Balloon Pulmonary Angioplasty for Chronic Thromboembolic Pulmonary Hypertension2019

    • Author(s)
      Hiromi Matsubara
    • Organizer
      American Heart Association 2019
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Early Prostanoid Thearpy in PAH2019

    • Author(s)
      Hiromi Matsubara
    • Organizer
      ASAN CTEPH Symposium 2019
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Balloon Pulmonary Angioplasty: Defining Essential Differences in Procedure Technique and Uniform Definitions of Complications2019

    • Author(s)
      Ogawa Aiko
    • Organizer
      International Society for Heart and Lung Transplantation 2019
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] 肺静脈閉塞症/肺毛細血管腫症(PVOD/PCH)を見極める2019

    • Author(s)
      小川 愛子
    • Organizer
      第4回日本肺高血圧・肺循環学会学術集会
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] Long term outcome of balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension2019

    • Author(s)
      Matsubara H
    • Organizer
      The 15th Annual Scientific Conference by Korean Society of Interventional Cardiology 2019
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Technical approach to BPA2019

    • Author(s)
      Matsubara H
    • Organizer
      Singapore Live 2019
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Treatment of complications and long-term results2019

    • Author(s)
      Matsubara H
    • Organizer
      Singapore Live 2019
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Lowering mean PA pressure as treatment goal of PAH?2019

    • Author(s)
      Matsubara H
    • Organizer
      14th John Vane memorial symposium
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Balloon pulmonary angioplasty - pros and cons2018

    • Author(s)
      Matsubara H
    • Organizer
      Conference of the Polish Cardiac Society (Interventions in Pulmonary Circulation - IPC II)
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Should Balloon Pulmonary Angioplasty be combined with pulmonary thrombo-endarterectomy?2018

    • Author(s)
      Matsubara H
    • Organizer
      The International Society for Heart & Lung Transplantation 38th Annual Meeting and Scientific Sessions
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Treatment practice of pulmonary arterial hypertension -Current status & future perspective in Okayama-2018

    • Author(s)
      Matsubara H
    • Organizer
      23th International Society of Cardiovascular Pharmacotherapy
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Invited Master Lecture, Balloon pulmonary angioplasty - State of the art2018

    • Author(s)
      Matsubara H
    • Organizer
      12th Pulmonary Hypertension Academy
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] CTEPH Treatment in Japan2018

    • Author(s)
      Matsubara H
    • Organizer
      8th International Critical Care Congress
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Balloon pulmonary angioplasty: emerging gold standard for chronic thromboembolic disease2018

    • Author(s)
      Matsubara H
    • Organizer
      European Society of Cardiology Congress Munich 2018
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Endovascular treatment of CTEPH: Basic concept and clinical outcomes2018

    • Author(s)
      Matsubara H
    • Organizer
      ENdovascular & COronary REvascularization in SEOUL 2018
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Case4: A Case of Balloon Pulmonary Angioplasty for CTEPH Demonstrating the Utility of Intravascular Imaging2018

    • Author(s)
      Matsubara H
    • Organizer
      Transcatheter Cardiovascular Therapeutics 2018
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Balloon Pulmonary Angioplasty for CTEPH: The Japanese Experience2018

    • Author(s)
      Matsubara H
    • Organizer
      Transcatheter Cardiovascular Therapeutics 2018
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Interventional treatment for chronic thromboembolic pulmonary hypertension2018

    • Author(s)
      Matsubara H
    • Organizer
      The 10th Asian Pacific Congress of Heart Failure
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Early and Aggressive Targeted Therapy could improve Long Term Survival of the Patients with Pulmonary Arterial Hypertension2018

    • Author(s)
      Matsubara H
    • Organizer
      Gachon Cardiovascular Research Institute 2018
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Session: 1. Live demonstration; BPA, Title: Recent technical advances in BPA2018

    • Author(s)
      Matsubara H
    • Organizer
      ASAN CTEPH Symposium 2018
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Current Management of CTEPH, Japan Perspective2018

    • Author(s)
      Matsubara H
    • Organizer
      2018 Taiwan Society of Cardiology Winter Scientific Meeting
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] CTEPH treatment in Japan, Session: 4. Technical aspects of BPA, Title: How to select segmental arteries2018

    • Author(s)
      Matsubara H
    • Organizer
      Pulmonary vessel interventional forum
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research / Invited

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Published: 2018-04-23   Modified: 2022-01-27  

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