研究課題/領域番号 |
21K08119
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研究種目 |
基盤研究(C)
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配分区分 | 基金 |
応募区分 | 一般 |
審査区分 |
小区分53020:循環器内科学関連
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研究機関 | 国立研究開発法人国立循環器病研究センター |
研究代表者 |
ZANKOV DimitarP 国立研究開発法人国立循環器病研究センター, 研究所, 室長 (20631295)
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研究分担者 |
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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研究期間 (年度) |
2021-04-01 – 2024-03-31
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研究課題ステータス |
交付 (2022年度)
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配分額 *注記 |
4,160千円 (直接経費: 3,200千円、間接経費: 960千円)
2023年度: 910千円 (直接経費: 700千円、間接経費: 210千円)
2022年度: 1,430千円 (直接経費: 1,100千円、間接経費: 330千円)
2021年度: 1,820千円 (直接経費: 1,400千円、間接経費: 420千円)
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キーワード | ARVC / Mouse model / Cardiomyopathy / Arrhythmia / Desmosome / Desmoglein 2 |
研究開始時の研究の概要 |
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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研究実績の概要 |
We generated transgenic knock-in mice harbouring desmoglein 2 mutations 297 R>C and 499 D>A, corresponding to the most often found variants in human patients suffering Arrhythmogenic Right Ventricular Cardiomyopathy (Desmoglein 2 292 R>C, 494 D>A) . The phenotype of these mice shows significant similarity to human clinical presentation of the disease. Some of desmoglein 2 297 R>C died suddenly starting from the age of 8 week-old. Morphology of investigated hearts of those mice and the mice that are older shows fibrotic accumulation, in some cases dramatic, with complete replacement of the segments of ventricular wall by collagen. With aging, mice developed gradually cardiac dysfunction as measured by cardiac echography of left ventricle and enlargement and deterioration of right ventricular function. Telemetry experiment exposed electrophysiological abnormalities in homozygous desmoglein 2 297 R>C mice in the form of ventricular premature beats and in more severe cases ventricular tachycardia at the age of 14-16 week-old. Confocal microscopy of heterozygous and homozygous 297 R>C and 499 D>A, stained for collagen detection, confirmed the findings of the above experimental techniques showing cardiomyocytes with abnormal morphology and areas with missing cells. All these findings confirmed successful generation of mice model of Arrhythmogenic Right Ventricular Cardiomyopathy and further investigation will target molecular and cellular mechanisms underlying the observed phenotype.
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現在までの達成度 (区分) |
現在までの達成度 (区分)
2: おおむね順調に進展している
理由
Experiments are planned and conducted according to the project with no major impediments. The work was done with necessary intensity and the results are promising.
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今後の研究の推進方策 |
Our plan for the future research is to investigate in details molecular and cellular responses to desmosomal dysfunction caused by desmoglein 2. This will include transcriptome evaluation (RNA sequencing) comparing mutant and wild type hearts as well various experimental techniques to detect RNA and protein dysfunction.
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