| Project/Area Number |
21K08119
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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 | National Cardiovascular Center Research Institute |
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Principal Investigator |
Zankov Dimitar P 国立研究開発法人国立循環器病研究センター, オープンイノベーションセンター, 室長 (20631295)
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| Co-Investigator(Kenkyū-buntansha) |
大野 聖子 国立研究開発法人国立循環器病研究センター, 研究所, 部長 (20610025)
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| Project Period (FY) |
2021-04-01 – 2024-03-31
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| Project Status |
Completed (Fiscal Year 2023)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2023: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2021: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | ARVC / dsg2 / knock-in mouse / DSG2 / Mouse model / Cardiomyopathy / Arrhythmia / Desmosome / Desmoglein 2 |
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| Outline of Research at the Start |
Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is an inherited disease, which
progresses to terminal heart failure and may cause sudden cardiac death. Causative mutations affect mainly desmosomal proteins in the intercalated disks. So far, there is no curative therapy for ARVC. We generated knock-in mice carrying the most common mutations among Japanese ARVC patients: DSG2 p.R292C and p.D494A. We perform in vivo and in vitro experiments to characterize the phenotype and detect specific signaling underlying pathology in ARVC. Our purpose is to identify a possible therapeutic target(s).
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| Outline of Final Research Achievements |
There are two DSG2 founder variants in Japanese ARVC, p.R292C and p.D494A. In human, most patients carry the variants in homozygous or compound heterozygous manner. We constructed knock-in (KI) mice model with these variants, dsg2 R297C and D499A. The survival of homozygous R297C mice was worse than others. In the echo cardiography and cardiac MRI, we could confirm the enlargement of both ventricles and decreased contraction function. Exercise stress training except for homozygous R297C exacerbated cardiac function and enlarged the cavities in mice models. In the histological analysis, we found severe fibrosis, especially in the right ventricular wall.
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| Academic Significance and Societal Importance of the Research Achievements |
Phenotype of ARVC caused by variants in DSG2 are different from those in PKP2. Our knock-in mice showed similar phenotype with human ARVC, therefore, we can use our mice to develop effective treatment for Japanese ARVC.
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