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

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K15900
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Nagoya 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
• Keywords: チロシンキナーゼ / 先天性心疾患 / CRISPR-Cas9

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.

Free Research Field

先天性心疾患

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。