| Project/Area Number |
18K05993
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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 42020:Veterinary medical science-related
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| Research Institution | Tottori University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
山野 好章 鳥取大学, 農学部, 教授 (00182593)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2018: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
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| Keywords | 肺高血圧症 / 肺血管リモデリング / チロシンキナーゼ阻害薬 / 分裂促進因子活性化タンパク質キナーゼ経路 / イマチニブ / マシチニブ / ソラフェニブ / トセラニブ / ホスホジエステラーゼ5阻害薬 / シルデナフィル / タダラフィル / 右心肥大 / スニチニブ / 血管リモデリング / 血小板由来成長因子 / 分子標的薬 / MAPKシグナル伝達 |
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| Outline of Final Research Achievements |
Using pulmonary hypertension rat model, this study was conducted to examine the inhibitory effects of tyrosine kinase inhibitors imatinib, sunitinib, sorafenib, toceranib and masitinib on PH, cardiac and pulmonary vascular remodeling, and remodeling-related factors. As a result, imatinib, sorafenib and masitinib treatments improved pulmonary vascular remodeling, right ventricular hypertrophy and pulmonary hypertension by suppressing the mitogen-activated protein kinase pathway through inhibition of tyrosine kinase receptor and C-X-C chemokine receptor 4. This effect exhibited at the dose lower than the anticancer drug dose, suggesting its application to veterinary medicine. In addition, the improvement effects of long-term administrations of low-dose imatinib and combined with sildenafil for canine pulmonary hypertension were clarified. These tyrosine kinase inhibitors may provide a novel reversal agent to target the cardiopulmonary remodeling in the pulmonary hypertension.
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| Academic Significance and Societal Importance of the Research Achievements |
肺高血圧症は肺血管リモデリングと血管収縮により肺動脈圧が著しく上昇する致死的な病態です。本研究はラットを用いて肺高血圧症の本質的原因である肺血管リモデリングへの様々なシグナリング異常に着目し、5種類のチロシンキナーゼ阻害薬の肺高血圧症治療の有効性とその機序の一部を明らかにするとともに、イヌ肺高血圧症に対する有効性も明らかにしました。本研究の新知見は、獣医学および医学双方の肺高血圧症における新規分子標的治療法の開発に有用であり、肺高血圧症の分子病態メカニズムの解明にも貢献するものです。
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