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The role of hematopoietic lineage cells marked by smooth muscle-targeted Cre mice in cardiovascular diseases

Research Project

Project/Area Number 19K17622
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 53020:Cardiology-related
Research InstitutionNational Cardiovascular Center Research Institute

Principal Investigator

Ishibashi Tomohiko  国立研究開発法人国立循環器病研究センター, 研究所, 上級研究員 (30722285)

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: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Keywords肺動脈性肺高血圧症 / 平滑筋細胞 / gp130 / IL-6 / リンパ球 / サイトカイン / 血管平滑筋 / 造血幹細胞
Outline of Research at the Start

心筋梗塞などの動脈硬化性疾患は我が国の死亡原因の大きな部分を占めており、その病態解明は疾患の予防や治療成績の向上に不可欠である。循環器疾患の病態には、血管内皮細胞、平滑筋細胞、血液細胞など様々な系列の細胞が関与している。我々は、平滑筋細胞特異的に遺伝子を欠損させる目的でよく使われるマウスで、実際には血液細胞の多くでも遺伝子欠損が起きることを見出した。本研究はこれを発展させ、このような血液細胞の特徴や循環器疾患の病態形成に果たす役割を明らかにし、循環器疾患の新たな病態解明を目指すものである。

Outline of Final Research Achievements

Smooth muscle protein 22 alpha (SM22α)-Cre mouse are widely used as smooth muscle cell (SMC)-specific Cre recombination mice for the study of vascular biology. We found that SM22α-Cre mice showed unexpected Cre recombination in hematopoietic lineage cells. Deletion of gp130, which constitutes the interleukin-6 (IL-6) receptor, using SM22α-Cre mice improved the phenotype of hypoxia-induced pulmonary hypertension (HPH). It was suggested that this improvement was the result of nonspecific deletion of gp130 in CD4-positive T cells. In fact, CD4-positive cell-specific gp130 deletion by crossing gp130 flox mice with CD4-Cre mice ameliorated right ventricular systolic pressure in HPH mouse. These findings suggest that gp130-mediated signaling in CD4-positive cells plays an important role in the pathogenesis of PAH. Besides, careful attention should be paid when using SMC-targeted Cre recombination mice for the purpose of SMC-specific gene knockout and lineage tracing studies.

Academic Significance and Societal Importance of the Research Achievements

平滑筋細胞特異的Creマウスとして広く研究に使用されているSM22α-Creマウスで、実際には血液細胞のすべての系統でCreリコンビネーションが生じることを明らかにした。SM22α-Creを用いた実験結果は慎重に解釈する必要があることを示すものであり、学術的に意義がある。また、指定難病である肺動脈性肺高血圧症の病態形成にIL-6が重要であることはこれまでも報告されてきたが、本研究の成果は、その標的としてCD4陽性T細胞が重要であることを示すものであり、新規治療法の開発などの臨床応用へ向けた基盤となると考えられる。

Report

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

    (17 results)

All 2021 2020 2019

All Journal Article (5 results) (of which Peer Reviewed: 5 results,  Open Access: 5 results) Presentation (12 results) (of which Int'l Joint Research: 3 results)

  • [Journal Article] Aryl hydrocarbon receptor is essential for the pathogenesis of pulmonary arterial hypertension2021

    • Author(s)
      Masaki T, Okazawa M, Asano R, Inagaki T, Ishibashi T, Yamagishi A, Umeki-Mizushima S, Nishimura M, Manabe Y, Ishibashi-Ueda H, Shirai M, Tsuchimochi H, Pearson JT, Kumanogoh A, Sakata Y, Ogo T, Kishimoto T, Nakaoka Y
    • Journal Title

      Proc Natl Acad Sci U S A

      Volume: 118 Issue: 11

    • DOI

      10.1073/pnas.2023899118

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Autonomous TGFβ signaling induces phenotypic variation in human acute myeloid leukemia2021

    • Author(s)
      Yasuhiro Shingai , Takafumi Yokota,et al
    • Journal Title

      Stem cells

      Volume: - Issue: 6 Pages: 723-736

    • DOI

      10.1002/stem.3348

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Pristane/Hypoxia (PriHx) Mouse as a Novel Model of Pulmonary Hypertension Reflecting Inflammation and Fibrosis2020

    • Author(s)
      Mori Hiroyoshi、Ishibashi Tomohiko、Inagaki Tadakatsu、Okazawa Makoto、Masaki Takeshi、Asano Ryotaro、Manabe Yusuke、Ohta-Ogo Keiko、Narazaki Masashi、Ishibashi-Ueda Hatsue、Kumanogoh Atsushi、Nakaoka Yoshikazu
    • Journal Title

      Circulation Journal

      Volume: 84 Issue: 7 Pages: 1163-1172

    • DOI

      10.1253/circj.CJ-19-1102

    • NAID

      130007864283

    • ISSN
      1346-9843, 1347-4820
    • Year and Date
      2020-06-25
    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Ectonucleotidase CD39 is highly expressed on ATLL cells and is responsible for their immunosuppressive function.2020

    • Author(s)
      Yasuhiro Nagate, Sachiko Ezoe, Jiro Fujita, Daisuke Okuzakis, Daisuke Motooka, Tomohiko Ishibashi, Michiko Ichii, Akira Tanimura, Masako Kurashige, Eiichi Morii, Takuya Fukushima, Youko Suehiro, Takafumi Yokota, Hirohiko Shibayama, Kenji Oritani, Yuzuru Kanakura
    • Journal Title

      Leukemia

      Volume: - Issue: 1 Pages: 107-118

    • DOI

      10.1038/s41375-020-0788-y

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Endothelial Cell-Selective Adhesion Molecule Contributes to the Development of Definitive Hematopoiesis in the Fetal Liver2019

    • Author(s)
      Ueda Tomoaki、Yokota Takafumi、Okuzaki Daisuke、Uno Yoshihiro、Mashimo Tomoji、Kubota Yoshiaki、Sudo Takao、Ishibashi Tomohiko、Shingai Yasuhiro、Doi Yukiko、Ozawa Takayuki、Nakai Ritsuko、Tanimura Akira、Ichii Michiko、Ezoe Sachiko、Shibayama Hirohiko、Oritani Kenji、Kanakura Yuzuru
    • Journal Title

      Stem Cell Reports

      Volume: 13 Issue: 6 Pages: 992-1005

    • DOI

      10.1016/j.stemcr.2019.11.002

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] gp130 signaling in CD4 cells is important for the pathogenesis of pulmonary arterial hypertension2020

    • Author(s)
      Ishibashi T, Masaki T, Inagaki T, Okazawa M, Nakaoka Y
    • Organizer
      IVBM 2020
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] IL-6 signaling in the CD4-positive T cells is important for the pathogenesis of PAH2020

    • Author(s)
      Ishibashi T, Masaki T, Inagaki T, Asano R, Okazawa M, Nakaoka Y
    • Organizer
      第4回 日本循環器学会基礎研究フォーラム (BCVR)
    • Related Report
      2020 Annual Research Report
  • [Presentation] Interleukin-21阻害による肺動脈性肺高血圧症の新規治療法開発2020

    • Author(s)
      稲垣 薫克, 浅野 遼太郎, 石橋 知彦, 岡澤 慎, 正木 豪, 三井 麻利江, 青木 一晃, 大郷 剛, 中岡 良和
    • Organizer
      第5回 日本肺高血圧・肺循環学会学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 肺高血圧症における炎症性サイトカインの意義2020

    • Author(s)
      石橋 知彦
    • Organizer
      第6回 血管生物医学会 若手研究会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Critical Roles of Interleukin-21 Signaling in the Pathogenesis of Pulmonary Arterial Hypertension2020

    • Author(s)
      Inagaki T, Ishibashi T, Okazawa M, Masaki T, Mitsui M, Aoki K, Asano R, Ogo T, Nakaoka Y
    • Organizer
      IVBM 2020
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] CD4陽性細胞のIL-6シグナルは肺高血圧症の病態形成に重要である2019

    • Author(s)
      石橋知彦, 正木豪, 稲垣薫克, 森啓悦, 浅野遼太郎, 岡澤慎, 中岡良和
    • Organizer
      第4回 日本肺高血圧・肺循環学会
    • Related Report
      2019 Research-status Report
  • [Presentation] gp130-mediated signaling in CD4-positive cells is important for the pathogenesis of pulmonary arterial hypertension2019

    • Author(s)
      Tomohiko I, Masaki T, Inagaki T, Mori H, Asano R, Okazawa M, Nakaoka Y
    • Organizer
      第3回 日本循環器学会基礎研究フォーラム
    • Related Report
      2019 Research-status Report
  • [Presentation] gp130-mediated signaling in CD4-positive cells has a critical role for the pathogenesis of pulmonary arterial hypertension2019

    • Author(s)
      Tomohiko I, Masaki T, Inagaki T, Okazawa M, Nakaoka Y
    • Organizer
      第3回 Asia Australia Vascular Biology Meeting (AAVBM)
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] CD4陽性細胞におけるgp130シグナルの肺高血圧症病態形成における役割2019

    • Author(s)
      石橋知彦, 正木豪, 稲垣薫克, 森啓悦, 浅野遼太郎, 岡澤慎, 中岡良和
    • Organizer
      第27回 日本血管生物医学会学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] TrkB has a protective role for right ventricular dysfunction under chronic hypoxia-induced PH2019

    • Author(s)
      Okazawa M, Inagaki T, Ishibashi T, Masaki T, Mori H, Asano R, Takei K, Nakaoka Y
    • Organizer
      第3回 日本循環器学会基礎研究フォーラム
    • Related Report
      2019 Research-status Report
  • [Presentation] Critical roles of interleukin-21 signaling in the pathogenesis of pulmonary arterial hypertension2019

    • Author(s)
      Inagaki T, Mitsui M, Asano R, Ogo T, Aoki K, Masaki T, Ishibashi T, Okazawa M, Nakaoka Y
    • Organizer
      第3回 日本循環器学会基礎研究フォーラム
    • Related Report
      2019 Research-status Report
  • [Presentation] 肺動脈性肺高血圧症の病態形成におけるInterleukin-21の役割の解明と治療法開発2019

    • Author(s)
      稲垣薫克, 浅野遼太郎, 三井麻利江, 青木一晃, 石橋知彦, 岡澤慎, 大郷剛, 中岡良和
    • Organizer
      第27回 日本血管生物医学会学術集会
    • Related Report
      2019 Research-status Report

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

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