2018 Fiscal Year Final Research Report
Elucidation of the molecular pathogenesis of pulmonary hypertension via inflammatory cytokines
| Project/Area Number |
16H05298
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Cardiovascular medicine
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| Research Institution | National Cardiovascular Center Research Institute |
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Principal Investigator |
NAKAOKA YOSHIKAZU 国立研究開発法人国立循環器病研究センター, 研究所, 部長 (90393214)
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| Research Collaborator |
SHIRAI MIKIYASU
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Keywords | 肺高血圧症 / 肺動脈性肺高血圧症（PAH) / 炎症 / 炎症性サイトカイン / インターロイキン６ / インターロイキン２１ / 血管リモデリング |
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| Outline of Final Research Achievements |
Pulmonary arterial hypertension (PAH) is a severe disease which causes stenosis and occlusion in the pulmonary small arteries and arterioles, leading to elevation of pulmonary arterial pressure due to unknown etiology. Since PAH patients might eventually result in right heart failure and death without adequate treatment, PAH is designated as an intractable disease by MHLW.We need to develop a novel therapeutic strategy for PAH which is distinct from the anti-PAH vaso-dilating agents. We identified IL-21 as a downstream target of IL-6 responsible for promoting the pathogenesis of HPH(PNAS.112: E2677, 2015).In this study, we tried to validate the effect of either IL-6 blockade or IL-21 blockade on the pathogenesis of PAH in a more severe animal model, namely the Sugen5416(Su)/Hypoxia/Normoxia (Su/Hx) rat model. We found that both IL-6 knockout and IL-21 receptor knockout rats showed significant resistance to severe PAH compared with conrol wild-type rats.
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| Free Research Field |
循環器内科学、血管病学
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| Academic Significance and Societal Importance of the Research Achievements |
これまでの遺伝子改変動物での肺高血圧症の病態研究は、低酸素誘発性肺高血圧症モデルマウスの系で遺伝子欠損マウスを用いて主に行われてきた。本研究ではCRISPR/Cas9システムを用いて、炎症性サイトカインのIL-6やIL-21受容体をノックアウトして、現在の最も重症な肺高血圧症モデルであるSugen5416/低酸素重症肺高血圧症モデルラットの系で、IL-6欠損、IL-21受容体欠損の効果を検討した。その結果、炎症性サイトカインの阻害によって肺高血圧症の重症化は顕著に抑制されて、炎症性サイトカイン阻害は新しい肺高血圧症に対する治療法の開発に繋がると期待されて、臨床的意義は大きいと考えられる。
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