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Mechanism analysis of a syndrome with congenital heart disease due to tyrosine kinase gene abnormality

Research Project

Project/Area Number 21K15900
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 52050:Embryonic medicine and pediatrics-related
Research InstitutionNagoya University

Principal Investigator

Yamamoto Hidenori  名古屋大学, 医学部附属病院, 医員 (80801662)

Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
Fiscal Year 2023: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2022: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Keywordsチロシンキナーゼ / 先天性心疾患 / CRISPR-Cas9 / プロテオーム解析 / 骨格異常 / 成長障害
Outline of Research at the Start

先天性心疾患の多くは多因子遺伝と考えられているが、一部に単一遺伝子異常によるものが存在する。近年、チロシンキナーゼ発現遺伝子であるABL1の生殖細胞における機能獲得型変異が、先天性心疾患、骨格異常、皮膚異常などの原因になることが2017年に初めて報告されたが、そのメカニズムは殆ど未解明である。研究代表者は近年、家族性先天性心疾患の家系においてABL1の新規変異を発見し、培養細胞実験でUFD1、AXIN1、ATRXのリン酸化が本症候群の発症メカニズムに関与する可能性を報告した。本研究の目的は、モデル動物を用いて、ABL1の機能獲得型変異による各表現型の発症メカニズムを検討することである。

Outline of Final Research Achievements

Germline ABL1 gain-of-function mutations are known to cause a syndrome associated with congenital heart disease, but the mechanism of pathogenesis is unknown.
We knocked in gain-of-function mutations in Abl1 by CRISPR-Cas9 in laboratory mice (C57BL/6). Total proteins were extracted from fetal hearts of model mice, and proteomic analysis revealed that the expression of protein A, which is also known to be involved in cardiac development, was markedly increased in the model mice. Immunostaining of downstream proteins of s showed that the activation of proteins related to the regulation of apoptosis was suppressed, suggesting their involvement in the pathogenesis of cardiac disease.

Academic Significance and Societal Importance of the Research Achievements

ABL1機能獲得型変異による心疾患発症のメカニズムは未解明である。本研究は近年確立した実験手法であるCRISPR-Cas9・プロテオーム解析などを用いて世界で初めてその解明を試みた。骨髄細胞におけるABL1の機能獲得が白血病の原因になることが知られているが、今回の研究により生殖細胞においては骨髄とはまったく異なる分子メカニズムが関与する可能性が示唆された。今後、培養細胞実験で検証を行ったうえで学術発表を計画している。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • Research Products

    (7 results)

All 2024 2023 2022

All Journal Article (5 results) (of which Peer Reviewed: 4 results,  Open Access: 2 results) Presentation (2 results) (of which Int'l Joint Research: 1 results)

  • [Journal Article] Dysbiosis of gut microbiota in patients with protein-losing enteropathy after the Fontan procedure2024

    • Author(s)
      Go Kiyotaka、Horiba Kazuhiro、Yamamoto Hidenori、Morimoto Yoshihito、Fukasawa Yoshie、Ohashi Naoki、Yasuda Kazushi、Ishikawa Yuichi、Kuraishi Kenji、Suzuki Kazutaka、Ito Yoshinori、Takahashi Yoshiyuki、Kato Taichi
    • Journal Title

      International Journal of Cardiology

      Volume: 396 Pages: 131554-131554

    • DOI

      10.1016/j.ijcard.2023.131554

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Case report: High-dose epoprostenol therapy in pediatric patients with pulmonary hypertension and developmental lung disease2023

    • Author(s)
      Fukasawa Yoshie、Yamamoto Hidenori、Ito Miharu、Saito Akiko、Go Kiyotaka、Morimoto Yoshihito、Yasuda Kazushi、Sato Yoshiaki、Hayakawa Masahiro、Kato Taichi
    • Journal Title

      Frontiers in Pediatrics

      Volume: 11 Pages: 1-7

    • DOI

      10.3389/fped.2023.1116434

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Tension hemothorax 1 week after pericardiocentesis associated with thrombocytopenia2022

    • Author(s)
      Yamamoto Hidenori、Go Kiyotaka、Morimoto Yoshihito、Fukasawa Yoshie、Kato Taichi
    • Journal Title

      Pediatrics International

      Volume: 64 Issue: 1 Pages: 1-2

    • DOI

      10.1111/ped.15395

    • Related Report
      2022 Research-status Report
  • [Journal Article] Familial cardiac septal defect due to a novel nine‐base deletion in TBX202022

    • Author(s)
      Yamamoto Hidenori、Inagaki Hidehito、Hayano Satoshi、Kurahashi Hiroki、Kato Taichi
    • Journal Title

      Pediatrics International

      Volume: 64 Issue: 1

    • DOI

      10.1111/ped.14995

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Conception by assisted reproductive technology in infants with critical congenital heart disease in Japan2022

    • Author(s)
      Morimoto Yoshihito、Go Kiyotaka、Yamamoto Hidenori、Fukasawa Yoshie、Nakai Michikazu、Morihana Eiji、Yasuda Kazushi、Nishikawa Hiroshi、Ohashi Naoki、Takahashi Yoshiyuki、Kato Taichi
    • Journal Title

      Reproductive BioMedicine Online

      Volume: 44 Issue: 1 Pages: 163-170

    • DOI

      10.1016/j.rbmo.2021.10.005

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Comprehensive genetic analysis of 9 families with hereditary WPW syndrome2023

    • Author(s)
      Hidenori Yamamoto, Hidehito Inagaki, Kiyotaka Go, Yoshihito Morimoto, Yoshie Fukasawa, Hiroko Goto, Sayaka Mii, Hiroki Kurahashi, and Taichi Kato
    • Organizer
      Human Genetics Asia 2023
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] ZC4H2機能喪失は遺伝子Xの発現調節を介して徐脈性不整脈を呈する~プロテオーム解析を用いた遺伝性不整脈の機能解析~2022

    • Author(s)
      山本 英範, 郷 清貴, 森本 美仁, 深澤 佳絵, 加藤 太一
    • Organizer
      第55回日本小児循環器学会
    • Related Report
      2022 Research-status Report

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Published: 2021-04-28   Modified: 2025-01-30  

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