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2022 年度 実施状況報告書

Elucidation of the pathology in ARVC caused by Japanese-specific DSG2 mutations using knock-in mice models: searching for the therapeutic targets

研究課題

研究課題/領域番号 21K08119
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)

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)
研究期間 (年度) 2021-04-01 – 2024-03-31
キーワードARVC / Mouse model
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.

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.

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.

次年度使用額が生じた理由

To buy experimental goods and publish article.

  • 研究成果

    (1件)

すべて 2022

すべて 雑誌論文 (1件) (うち国際共著 1件、 査読あり 1件、 オープンアクセス 1件)

  • [雑誌論文] Identification of transmembrane protein 168 mutation in familial Brugada syndrome2022

    • 著者名/発表者名
      Shimizu A, Zankov DP, Sato A, Komeno M, Toyoda F, Yamazaki S, Makita T, Noda T, Ikawa M, Asano Y, Miyashita Y, Takashima S, Morita H, Ishikawa T, Makita N, Hitosugi M, Matsuura H, Ohno S, Horie M, Ogita H.
    • 雑誌名

      FASEB journal

      巻: 34(5) ページ: 6399-6417

    • DOI

      10.1096/fj.201902991R

    • 査読あり / オープンアクセス / 国際共著

URL: 

公開日: 2023-12-25  

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