| Project/Area Number |
18K08111
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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 53020:Cardiology-related
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| Research Institution | Kyoto Prefectural University of Medicine |
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Principal Investigator |
Nakanishi Naohiko 京都府立医科大学, 医学(系)研究科(研究院), 助教 (10637911)
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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 |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | 肺高血圧症 / カベオラ / Caveolin / Cavin / BMPR2 / カベオリン / キャビン |
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| Outline of Final Research Achievements |
Caveolin-1 (Cav1) and Cavin-1 are components of caveolae, and Cav1 is identified as a related gene of pulmonary arterial hypertension (PAH). BMPRII, which is the common gene mutation in PAH, is localized in caveolae. However, the role of the Caveolin-Cavin system in PAH has not been well-known.
Cav1 knockdown in human pulmonary artery endothelial cells (hPAECs) reduced BMPRII at the plasma membrane and Smad 1/5/9 phosphorylation, and increased hypoxia-induced apoptosis. Cavin-1 inhibited the interaction of BMPRII with Cav1 and reduced BMPRII localization on the membrane of hPAECs. Both Cavin-1 and BMPRII were associated with the Cav1 scaffolding domain. Cavin-1 knockdown reversed BMPRII localization at the plasma membrane and Smad 1/5/9 phosphorylation induced by Cav1 knockdown. These results suggest that Cavin-1 interacts with Cav1 and inhibits the association of Cav1 with BMPRII, resulting in modulating Smad signaling pathway and involving in the development of PAH.
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| Academic Significance and Societal Importance of the Research Achievements |
今回の我々の研究結果からは、CaveolinおよびCavinがカベオラでのBMPRIIの局在に関与し、下流のSmadシグナルを調節していることが判明した。CaveolinとCavinの結合がBMPRIIの細胞膜上への局在に重要であり、肺高血圧症の発症に関与している可能性が示唆された。肺動脈性肺高血圧症は発症・進展のメカニズムが未だ不明であり根治的治療が確立していない難病である。今回の結果はCaveolin-Cavinシステムの肺高血圧症における役割を明らかにし、肺動脈のリバースリモデリングを可能とする治療法の開発に寄与することが出来たと考えられる。
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