Analyses of molecular mechanism of electrophysiological remodeling focusing on SCN5A-Nedd4-2
| Project/Area Number |
17K16019
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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 |
Cardiovascular medicine
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| Research Institution | Yokohama City University |
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Principal Investigator |
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| Research Collaborator |
ISHIGAMI tomoaki
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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 |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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| Keywords | ナトリウムチャンネル / Nedd4-2 / SCN5A / 不整脈 / 高血圧 / ナトリウムチャネル / SCNA5A / 循環器・高血圧 / 心臓イオンチャンネル |
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| Outline of Final Research Achievements |
We demonstrated that Nedd4-2 C2 isoform causes cardiac conduction change in resting condition as well as proarrhythmic change after acute myocardial infarction (MI) and atrial fibrillation (AF). The Nedd4-2 C2 knockout (KO) mice showed prolonged QRS, QT intervals, and suppressed PR interval in resting condition.
Although KO showed higher sympatho-vagal balance, bradycardia was found. In addition, enhancement of T peak/T end interval was found in mice with surgical MI. Burst pacing induced AF was sustained in KO. Morphological analyses based on both ultrasonography of the living heart, as well as histopathological findings revealed that KO mice show no significant structural change.
These results suggested that Nedd4-2 with C2 domain might play an important role through post-transcriptional modification of ion channels.
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| Academic Significance and Societal Importance of the Research Achievements |
心臓突然死を回避するための予防手段は十分には確立されていない。近年、致死的不整脈に対する遺伝的素因の関与が指摘されており、その中でもSCN5A遺伝子は心臓の電気的特性を決定付ける重要な遺伝子である。本研究では、SCN5Aとその制御因子であるNedd4-2に注目し、Nedd4-2 C2ドメインノックアウトマウス(KO)の電気生理学的表現型の評価を行った。KOには心臓の電気生理学的変化をもたらす基盤があり、結果として心血管合併症が重篤化し得ることが示唆された。SCN5A-Nedd4-2系に焦点をあてた研究が新たな治療戦略となる可能性があり、不整脈に対する診断・治療の可能性が拡がることが期待される。
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Report
(3 results)
Research Products
(2 results)
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[Journal Article] An Isoform of Nedd4-2 Plays a Pivotal Role in Electrophysiological Cardiac Abnormalities.2017
Author(s)
Minegishi S, Ishigami T, Kawamura H, Kino T, Chen L, Nakashima-Sasaki R, Doi H, Azushima K, Wakui H, Chiba Y, Tamura K.
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Journal Title
Int J Mol Sci.
Volume: 18
Pages: 1268-1268
Related Report
Peer Reviewed / Open Access
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