| Project/Area Number |
17K15583
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Multi-year Fund |
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| Research Field |
General pharmacology
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| Research Institution | Osaka Medical College |
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Principal Investigator |
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| Research Collaborator |
TOMODA kiichiro
II masaaki
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| Project Period (FY) |
2017-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | ユビキチンリガーゼ / 心不全 / ホスホランバン / 心血管 / 血液 / ユビキチンリガーぜ |
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| Outline of Final Research Achievements |
The E3 ubiquitin ligase, von Hippel-Lindau (VHL), regulates protein expression by polyubiquitination. Although the protein VHL (pVHL) was reported to be involved in the heart function, the underlying mechanism is unclear. Here, we show that pVHL was upregulated in
hearts from two types of genetically dilated cardiomyopathy (DCM) mice models. In comparison with the wild-type mouse, both DCM mice models showed a significant reduction in the expression of phospholamban (PLN), a potent inhibitor of sarco(endo)plasmic reticulum Ca2+-ATPase, and enhanced interaction between pVHL and PLN.
Furthermore, the co-transfection of VHL and PLN in HEK293 cells decreased PLN expression under oxidative stress, whereas knockdown of VHL increased PLN expression both under normal and oxidative stress conditions. Together, we propose that oxidative stress upregulates pVHL expression to induce PLN degradation in failing hearts.
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| Academic Significance and Societal Importance of the Research Achievements |
超高齢化の時代となり、心不全を始めとした心疾患への対策がますます求められている。今回、心臓の律動的な拍動に重要な働きを行なっている心筋収縮調節因子であるPLNに着目し、その分解に関与しているユビキチンリガーゼの探索を試みたところ、VHLがPLNのユビキチン化ならびに分解の一旦を担っていることを明らかにできた。そのため、将来的にVHLを標的とした心不全治療戦略を立てることが可能となり、心不全症状の改善や治療法の向上を目指す上でとても意義があると考えられる。
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