2021 Fiscal Year Final Research Report

Genetic-environmental interaction for congenital cardiovascular disease

Research Project

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Project/Area Number	19H03622
Research Category	Grant-in-Aid for Scientific Research (B)
Allocation Type	Single-year Grants
Section	一般
Review Section	Basic Section 52050:Embryonic medicine and pediatrics-related
Research Institution	Keio University
Principal Investigator	YAMAGISHI Hiroyuki 慶應義塾大学, 医学部(信濃町), 教授 (40255500)
Co-Investigator(Kenkyū-buntansha)	土橋隆俊慶應義塾大学, 医学部(信濃町), 客員講師 (10286528) 古道一樹慶應義塾大学, 医学部(信濃町), 講師 (10338105) 内田敬子慶應義塾大学, 保健管理センター(日吉), 准教授 (50286522) 湯浅慎介慶應義塾大学, 医学部(信濃町), 講師 (90398628)
Project Period (FY)	2019-04-01 – 2022-03-31
Keywords	多因子遺伝 / 総動脈幹症 / TBX1
Outline of Final Research Achievements	In a mouse model in which the expression of TBX1, the gene responsible for congenital heart disease associated with 22q11.2 deletion syndrome, was downregulated by genetic engineering technology, folic acid administration to pregnant mother mice successfully reduced the congenital heart disease phenotype in the fetuses, and a mechanism in which folic acid activates NOTCH signaling and rescues defects of development/differentiation in a cardiac progenitor cell lineage, namely cardiac neural crest, was suggested. In addition, crossbreeding experiments with transgenic mice revealed that TBX20, a member of the same gene family as TBX1, functions in cardiac development with genetic interaction and may be involved in cardiac looping and ventricular septum formation by regulating the expression of the downstream transcription factor PITX2.
Free Research Field	小児循環器学
Academic Significance and Societal Importance of the Research Achievements	本研究課題におけるTBX1とTBX20の遺伝的相補性が示された成果は、多因子遺伝と考えられる複雑先天性心疾患の発症分子機序解明のための一つの基礎的知見として重要である。また、ヒト染色体・遺伝子異常そのものを治療・修復する医療は困難だが、葉酸によるTbx1発現低下マウスの心疾患表現型の軽症化および心臓神経堤細胞の機能回復とその分子経路を示唆した本研究成果の学術的意義は高く、将来的にヒト22q11.2欠失症候群の心疾患を軽症化する治療・予防法につながる可能性を示すことから、数多くの心疾患への応用を含めて社会的意義は大きい。