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Elucidation of epigenome-mediated mechanisms involved in experimental pulmonary hypertension induced by perinatal insult

Research Project

Project/Area Number 21K07817
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 52050:Embryonic medicine and pediatrics-related
Research InstitutionMie University

Principal Investigator

Mitani Yoshihide  三重大学, 医学部附属病院, 准教授 (60273380)

Co-Investigator(Kenkyū-buntansha) 丸山 一男  鈴鹿医療科学大学, 医学系研究科, 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)
Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2023: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2022: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords肺高血圧 / エピゲノム / 周産期侵襲 / DOHaD仮説 / 炎症 / 動物モデル / ゲノム編集 / DNAメチル化 / 肺動脈性肺高血圧 / 周産期刺激 / MCP1 / 肺動脈平滑筋 / 周産期 / バーカー仮説
Outline of Research at the Start

肺動脈性肺高血圧 (PAH)は、原因不明の予後不良な肺血管閉塞性病変を伴う肺高血圧であり、新規の治療法と予防法の開発には病態解明が重要である。周産期侵襲が思春期・成人期のPAHの発症に関わるかは、今後の課題である。これは、①新生児医療の進歩による成人移行例の増加、②周産期の介入の個別化予防の可能性、③エビゲノム変化の受攻期としての周産期の3点から重要である以上から、本研究は、肺循環のBarker仮説の検証研究であり、思春期・成人期のPAHの予防、治療に資する事が、本研究の全体目標である。

Outline of Final Research Achievements

Pulmonary arterial hypertension (PAH) is an intractable disease of unknown etiology that occurs in a hereditable manner (BMPR2), or in response to any stimuli (inflammation, etc.). We therefore evaluated the exacerbating effects of perinatal hypoxia on rat PAH and the cellular effects and DNA methylation status in pulmonary vascular smooth muscle (PASMC). In addition, we investigated the exacerbating and ameliorating effects of BMPR2-disruption or MCP1 receptor (CCR2)-disruption on PAH in rats. Perinatal hypoxia exacerbated rat PAH, and pulmonary arterial smooth muscles in such rats showed hyperproliferative and inflammatory responses associated with DNA methylation. BMPR2 disruption and CCR2-disruption exacerbate or ameliorated PAH in rats and provoked or suppressed proliferation and inflammation in cultured PASMCs. This findings demonstrates the involvement of inflammation in the pathogenesis of experimental pulmonary hypertension in rats, which may have therapeutic implications.

Academic Significance and Societal Importance of the Research Achievements

PAHは、特発性、遺伝性ないし種々の刺激に対して2次的に発症する小肺動脈の閉塞性病変を伴う原因不明の難治性疾患で、予後の改善、予防には病態解明が重要である。本研究により、周産期侵襲(周産期酸素)ないしCCR2を解する炎症が肺高血圧の病態に関与することが明らかとなった。本研究は、新生児医療の進歩による成人移行例の増加、周産期の介入の個別化予防の可能性、ヒトの生涯の中でエピゲノム変化の受攻期としての周産期の3点から重要であり、さらに炎症の関与を示した。肺循環に於けるDOHaD(Developmental Origin of Health and Disease)(Barker)仮説の検証となる。

Report

(2 results)
  • 2023 Final Research Report ( PDF )
  • 2022 Research-status Report
  • Research Products

    (11 results)

All 2023 2022

All Journal Article (4 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 4 results,  Open Access: 4 results) Presentation (4 results) (of which Int'l Joint Research: 2 results,  Invited: 3 results) Book (3 results)

  • [Journal Article] A registry study of Kawasaki disease patients with coronary artery aneurysms (KIDCAR): a report on a multicenter prospective registry study three years after commencement.2023

    • Author(s)
      Koyama Y, Miura M, Kobayashi T, Hokosaki T, Suganuma E, Numano F, Furuno K, Shiono J, Ebata R, Fuse S, Fukazawa R, Mitani Y
    • Journal Title

      Eur J Pediatr

      Volume: 182(2) Issue: 2 Pages: 633-640

    • DOI

      10.1007/s00431-022-04719-x

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Analysis of Coronary Arterial Aneurysm Regression in Patients With Kawasaki Disease by Aneurysm Severity: Factors Associated With Regression2023

    • Author(s)
      Kato Taichi、Hirono Keiichi、et al
    • Journal Title

      Journal of the American Heart Association

      Volume: 12 Issue: 3

    • DOI

      10.1161/jaha.121.022417

    • Related Report
      2022 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 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 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Perinatal hypoxia aggravates occlusive pulmonary vasculopathy in rats later in life: association with epigenetic changes.2022

    • Author(s)
      Hironori Oshita, Yoshihide Mitani, Hirofumi Sawada, Naoki Tsuboya, Junko Maruyama, Noriko Yodoya, Hiroyuki Ohashi, Kazunobu Oya, Yuhei Nishimura, Shinji Saitoh, Kazuo Maruyama, Masahiro Hirayama
    • Organizer
      Association for European Pediatric and Congenital Cardiology
    • Related Report
      2022 Research-status Report
    • Int'l Joint Research
  • [Presentation] APSC Guideline for the management of adults with a history of Kawasaki disease. Transition of KD patients with coronary sdequelae2022

    • Author(s)
      Yoshihide Mitani
    • Organizer
      Asian Pacific Society of Cardiology Congress
    • Related Report
      2022 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] 小児肺循環領域におけるAI応用:胸部X線によるQp/Qsと学校心電図検診によるPHの早期診断へ2022

    • Author(s)
      三谷義英
    • Organizer
      第7回日本肺高血圧肺循環学会
    • Related Report
      2022 Research-status Report
    • Invited
  • [Presentation] 小児循環器領域における人工知能の応用:12誘導心電図2022

    • Author(s)
      三谷義英
    • Organizer
      第58回日本小児循環器学会学術集会
    • Related Report
      2022 Research-status Report
    • Invited
  • [Book] 心疾患をもつ児童・生徒の学校管理下での取り扱い方、今日の治療指針2022年度版2022

    • Author(s)
      三谷義英
    • Total Pages
      2151
    • Publisher
      医学書院
    • Related Report
      2022 Research-status Report
  • [Book] 川崎病、循環器疾患、最新の治療2022-20232022

    • Author(s)
      三谷義英
    • Total Pages
      502
    • Publisher
      南江堂
    • Related Report
      2022 Research-status Report
  • [Book] 内科学第12版(心室中隔欠損、心房中隔欠損、房室中隔欠損、動脈管開存、Eisenmenger症候群)2022

    • Author(s)
      三谷義英
    • Total Pages
      2485
    • Publisher
      朝倉書店
    • Related Report
      2022 Research-status Report

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Published: 2021-04-28   Modified: 2025-01-30  

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