Establishment of analysis method of ryanodine receptor arrhythmogenic mutations and its application to therapeutic drug screening
| Project/Area Number |
15K08243
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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 |
General pharmacology
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| Research Institution | Juntendo University |
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Principal Investigator |
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| Research Collaborator |
MURAYAMA takashi
YAMASHITA fumiyoshi
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| Project Period (FY) |
2015-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | リアノジン受容体 / 不整脈 / 心臓 / カルシウム / 抗不整脈薬 / CPVT / RyR2 |
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| Outline of Final Research Achievements |
In this project, we aimed to understand the mutant RyR2-related arrhythmogenic mechanism and to establish a screening procedure for RyR2 inhibitors as anti-arrhythmic drugs. First, functional evaluation of RyR2 mutations were carried out using HEK cell expression system and a cardiomyocyte cell line. We found gain-of-function type and loss-of-function type of arrhythmogenic mutations. In the former, our functional analysis has proved to be very useful for predicting the severity of diseases caused by the mutations. Next, we developed a screening system for specific RyR2 inhibitors utilizing the ER Ca2+ monitoring, which was found to be an accurate indicator of RyR2 activity.
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| Academic Significance and Societal Importance of the Research Achievements |
我々が確立した機能解析系は疾患の重症度や治療方針の判断に有用である。不整脈治療薬に関してRyR2阻害薬が本当に抗不整脈作用を持つか未だ証明されていないため、新規のRyR2特異的な化合物の発見は不整脈の成り立ちを研究する上で学術的にも有用な発見である。またRyR2変異による不整脈疾患には現存の治療薬が効かない事が多いため、本研究により新分野の良い薬が見つかれば、不整脈を有する患者さんのQOL向上に役立つと考えられる。
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Report
(5 results)
Research Products
(34 results)
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[Journal Article] Genotype-phenotype correlations of malignant hyperthermia and central core disease mutations in the central region of the RYR1 channel.2016
Author(s)
Murayama, T., Kurebayashi, N., Ogawa, H., Yamazawa, T., Oyamada, H., Suzuki, J., Kanemaru, K., Oguchi, K., Iino, M. and Sakurai, T.
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Journal Title
Hum Mutat.
Volume: 37
Issue: 11
Pages: 1231-1241
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Inositol 1,4,5-trisphosphate receptor determines intracellular Ca2+ concentration in Trypanosoma cruzi throughout its life cycle2016
Author(s)
Hashimoto M, Doi M, Kurebayashi N, Furukawa K, Hirawake-Mogi H, Ohmiya Y, Sakurai T, Mita T, Mikoshiba K, Nara T.
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Journal Title
FEBS Open Bio.
Volume: 6(12)
Issue: 12
Pages: 1178-1185
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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