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2020 Fiscal Year Final Research Report

Novel pathophysiology underlying cardiac conduction defect due to mutations of gap junction genes

Research Project

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Project/Area Number 18K19550
Research Category

Grant-in-Aid for Challenging Research (Exploratory)

Allocation TypeMulti-year Fund
Review Section Medium-sized Section 53:Organ-based internal medicine and related fields
Research InstitutionNational Cardiovascular Center Research Institute (2019-2020)
Nagasaki University (2018)

Principal Investigator

Makita Naomasa  国立研究開発法人国立循環器病研究センター, 研究所, 副所長 (00312356)

Co-Investigator(Kenkyū-buntansha) 西井 明子 (関明子)  東京女子医科大学, 医学部, 准教授 (80408608)
柴田 恭明  長崎大学, 医歯薬学総合研究科(医学系), 准教授 (80253673)
本荘 晴朗  名古屋大学, 環境医学研究所, 准教授 (70262912)
Project Period (FY) 2018-06-29 – 2021-03-31
Keywordsギャップ結合 / コネキシン40 / コネキシン45 / 心臓伝導障害 / ノックインマウス / CRISPR/Cas9 / ゲノム編集 / 胎生致死
Outline of Final Research Achievements

In contrast to patients with connexin mutations,Cx40-Q58L heterozygous knock-in mice showed no conduction disturbance. We also established another Cx40-Q58L mice with Cx30.2 knock-out, but we failed to restore the frozen embryos probably due to some technical problems. For Cx45-Q58L, we tried several methods including CRISPR/Cas9 and iGONAD, but we failed to establish the Cx45-R57H knock-in mice, probably because perturbations of the Cx45 protein during the embryonic stage may not be compatible with life .

Free Research Field

循環器内科

Academic Significance and Societal Importance of the Research Achievements

Cx40変異, C45変異はともに伝導障害患者で同定された変異だが、Cx40変異のヘテロノックインマウスは心臓伝導障害を示さず、Cx45変異のヘテロヘテロノックインマウスは逆に、おそらく胎生致死のために樹立されなかった。これは心臓コネキシンサブユニットの分布や機能に明らかな種差があることを示唆する。将来的に心臓コネキシン病の動物モデルを作成する際には、マウス以外の動物を考慮する必要がある。

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Published: 2022-01-27  

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