2019 Fiscal Year Final Research Report
Metalloprotease nardilysin controls heart rate through the transcriptional regulation of ion channels critical for sinus automaticity
| Project/Area Number |
17K09575
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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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| Research Field |
Cardiovascular medicine
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| Research Institution | Shiga University of Medical Science |
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Principal Investigator |
Ohno Mikiko 滋賀医科大学, 医学部, 准教授 (10583198)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Keywords | 洞房結節自動能 / メタロプロテアーゼ |
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| Outline of Final Research Achievements |
We have shown that NRDC, a multifunctional protease, controls heart rate by transcriptional regulation of HCN ion-channels responsible for cardiac sinus node automaticity. We specifically demonstrated that NRDC regulates gene expression of these ion channels involved in sinus automaticity by ChIP method using anti-NRDC antibody. Moreover, bradycardia was also shown in atrial (sinoatrial node) specific NRDC-deficient mice (Sln-Nrdc-KO), and expression levels of HCN ion channels were also reduced in Sln-Nrdc knockout hearts. In addition, we generated and analyzed the enzyme-activity-deficient mutant NRDC knock-in mice.
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| Free Research Field |
循環器内科
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| Academic Significance and Societal Importance of the Research Achievements |
NRDCの生体における機能はこれまで全く不明であったが、NRDC-/-における研究成果から、NRDCが心拍数、血圧、体温調節などの恒常性維持に重要な役割を持つことが示唆された。一方、NRDCは全身に広く発現するので、NRDC-/-の表現型が一次的かどうかを判断するには困難を伴う。そこで、最近作製した臓器特異的NRDC欠損マウスや酵素活性欠失型変異NRDCマウスの解析を行い、心拍数調節のメカニズムの解明の足掛かりとした。これらの成果を今後発展させることで、ヒトにおける遺伝性洞不全症候群の原因解明やNRDCの酵素活性中心をターゲットとした創薬開発の基盤に役立てることができると考えられた。
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