2023 Fiscal Year Final Research Report
Elucidation of epigenome-mediated mechanisms involved in experimental pulmonary hypertension induced by perinatal insult
| Project/Area Number |
21K07817
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 52050:Embryonic medicine and pediatrics-related
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| Research Institution | Mie University |
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Principal Investigator |
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| 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)
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| Project Period (FY) |
2021-04-01 – 2024-03-31
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| 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 |
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| 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.
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| Free Research Field |
小児循環器学
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| 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。
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