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Mechanisms of neointima formation in pulmonary hypertension: an approach using pulmonary transcriptome analysis.

Research Project

Project/Area Number 20K08565
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 53030:Respiratory medicine-related
Research InstitutionMie University

Principal Investigator

Yodoya Noriko  三重大学, 医学部附属病院, 助教 (40525367)

Co-Investigator(Kenkyū-buntansha) 丸山 一男  鈴鹿医療科学大学, 保健衛生学部, 教授 (20181828)
西村 有平  三重大学, 医学系研究科, 教授 (30303720)
澤田 博文  三重大学, 医学系研究科, 講師 (30362354)
三谷 義英  三重大学, 医学部附属病院, 准教授 (60273380)
Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords肺高血圧 / トランスクリプトーム / 創薬 / 動物モデル / 炎症 / トランスクリプトーム解析 / 新生内膜形成
Outline of Research at the Start

肺動脈性肺高血圧(PAH)は、予後不良の難治性の疾患であり、近年の治療薬の開発により予後の改善が認められる。しかしこれらの治療で疾患の治癒は得られないため、新たな治療標的が必要である。PAHの閉塞性血管病変では、新生内膜病変で異常増殖する細胞の由来や内膜病変形成に至る分子機序は不明である。本研究では、血管病変の新生内膜病変の有無という点で、特徴の異なる動物モデルを用い、遺伝子発現パターンの違いに着目し、新生内膜をターゲットとした新規治療の開発を目的とする。研究の知見は、PAH患者さんに治癒をもたらす新たな治療法の開発に繋がると考えられる。

Outline of Final Research Achievements

In this study, we attempted to identify target genes by comparative analysis of transcriptomes in the lungs of rat PAH models with different vascular lesions. From the analysis, differentially expressed genes (DEGs) were selected, and a weighted gene network analysis of co-expressed genes in commonly altered DEGs was performed to identify candidate target genes related to neointima formation in pulmonary hypertension. As a result, cell adhesion molecule A and inflammation-related molecule B were identified. Inflammation-related molecule B-deficient rats were generated and phenotypically analyzed. Molecule B knockout rats showed reduced survival and severe pulmonary vascular lesions in monocrotaline-induced rats. Molecule B was shown to be important in maintaining the proliferative and differentiation state of vascular smooth muscle.

Academic Significance and Societal Importance of the Research Achievements

肺動脈性肺高血圧(PAH)は、予後不良の難治性の病態であり、近年のプロスタサイクリン系、エンドセリンレセプター拮抗薬、ホスホジエステラーゼ5型阻害薬などの治療薬の開発により予後の改善が認められるが、これら薬剤の血管病変退縮効果は示されておらず、生涯にわたり治療を継続する必要があり、医療経済的な負担も大きな課題である。PAHの閉塞性血管病変の退縮に至る新たな機序に基づく治療の開発へ繋がる成果であり、将来的に、本疾患を罹患する患者さんへの大きな利益となると考えられる。

Report

(4 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (7 results)

All 2022 2021

All Journal Article (5 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 5 results,  Open Access: 5 results) Presentation (2 results) (of which Invited: 2 results)

  • [Journal Article] Lung damage created by high tidal volume ventilation in rats with monocrotaline-induced pulmonary hypertension2022

    • Author(s)
      Masako Kawai 1 2 , Erquan Zhang 1 3 , Jane Chanda Kabwe , Amphone Okada , Junko Maruyama , Hirofumi Sawada , Kazuo Maruyama
    • Journal Title

      BMC Pulmonary Medicine

      Volume: 78 Issue: 1 Pages: 1-13

    • DOI

      10.1186/s12890-022-01867-6

    • Related Report
      2022 Annual Research Report 2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] CRISPR-mediated Bmpr2 point mutation exacerbates late pulmonary vasculopathy and reduces survival in rats with experimental pulmonary hypertension2022

    • Author(s)
      Kabwe JC, Sawada H, Mitani Y, Oshita H, Tsuboya N, Zhang E, Maruyama J, Miyasaka Y, Ko H, Oya K, Ito H, Yodoya N, Otsuki S, Ohashi H, Okamoto R, Dohi K, Nishimura Y, Mashimo T, Hirayama M, Maruyama K.
    • Journal Title

      Respir Res.

      Volume: ;23 Issue: 1 Pages: 1-22

    • DOI

      10.1186/s12931-022-02005-w

    • Related Report
      2022 Annual Research Report 2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Perinatal hypoxia aggravates occlusive pulmonary vasculopathy in SU5416/hypoxia-treated rats later in life2022

    • Author(s)
      Oshita H, Sawada H, Mitani Y, Tsuboya N, Kabwe JC, Maruyama J, Yusuf A, Ito H, Okamoto R, Otsuki S, Yodoya N, Ohashi H, Oya K, Kobayashi Y, Kobayashi I, Dohi K, Nishimura Y, Saitoh S, Maruyama K, Hirayama M
    • Journal Title

      Am J Physiol Lung Cell Mol Physiol. 2022 Aug 1;323(2):L178-L192.

      Volume: 323 Issue: 2 Pages: 178-192

    • DOI

      10.1152/ajplung.00422.2021

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Erythema and Induration of Bacillus Calmette-Guerin Scar Associated With Multisystem Inflammatory Syndrome in Children in Japan: A Case Report2022

    • Author(s)
      Tsuboya Naoki、Makino Hirotoshi、Mitani Yoshihide、Ito Michiko、Ohya Kazunobu、Morimoto Mari、Hanaki Ryo、Yodoya Noriko、Ohashi Hiroyuki、Sawada Hirofumi、Sugiyama Kenji、Hirayama Masahiro
    • Journal Title

      Frontiers in Pediatrics

      Volume: 10 Pages: 849473-849473

    • DOI

      10.3389/fped.2022.849473

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Model difference in the effect of cilostazol on the development of experimental pulmonary hypertension in rats2021

    • Author(s)
      Ito T、Zhang E、Omori A、Kabwe J、Kawai M、Maruyama J、Okada A、Yokochi A、Sawada H、Mitani Y、Maruyama K
    • Journal Title

      BMC Pulmonary Medicine

      Volume: 21 Issue: 1 Pages: 377-377

    • DOI

      10.1186/s12890-021-01710-4

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Effects of Genetic Modifications of Bmpr2 and a Chemokine Receptor on Progressive Pulmonary Hypertension in Rats: What Does CRISPR/Cas9 Bring to Pulmonary Hypertension Research?2022

    • Author(s)
      Hirofumi Sawada
    • Organizer
      第86回日本循環器学会学術集会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] 教育セッション 「一般病院で診る肺高血圧」 小児期PAH - 初期診断のポイント -2022

    • Author(s)
      澤田博文
    • Organizer
      第87回日本循環器学会学術集会
    • Related Report
      2022 Annual Research Report
    • Invited

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Published: 2020-04-28   Modified: 2024-01-30  

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