Analysis for vasculogenesis using genetic engineering mice

使用基因工程小鼠进行血管生成分析

• 批准号: 15390335
• 负责人: NAKAZAWA Makoto
• 金额: $ 9.47万
• 依托单位: Tokyo Women's Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-15390335/
• 关键词: Notch; heart; angiogenesis; morphogenesis; epithelial-mesenchymal transformation; development; valve; 血管形成; 機能; hesr遺伝子; Pitx2遺伝子; マウス; pitx2遺伝子

Notch signaling pathway regulates cell-fate decisions in metazoans through local cell-cell interactions. Notch signaling influences cell proliferation, differentiation, and is an evolutionarily conserved regulation system ranging from flies to humans. Its dysfunction has resulted in a tremendous variety of developmental defects and adult pathologies. We examined the hairy and enhancer of split-related (hesr) genes, encoding basic helix-loop-helix transcription suppressor factors, which are downstream targets of Notch signaling. Although zebrafish mutants of gridlock, a homolog of mouse hesr2, leads to arterial maturation defects, hesr2 knockout mice lost arterial maturation defects. Instead of that, we showed that the mice had anomalies of cardiac morphology, dysplasia of the atrioventricular valve, a ventricular septal defect, and a secundum atrial septal defect using transthoracic echocardiography on 5-day-old homozygous mice. Double knockout mice for hesr1 and hesr2 showed vascular anomalies that are strikingly similar to that of the zebrafish gridlock mutants. Hesr1 and hesr2 function synergistically in epithelial- mesenchymal transformation during atrioventricular valve formation and maintenance of trabecular cells in the ventricles, and in arterial-venous differentiation of blood vessels.

Notch信号通路通过局部细胞间相互作用调节后生动物的细胞命运决定。Notch信号传导影响细胞增殖、分化，并且是从苍蝇到人类的进化上保守的调节系统。它的功能障碍导致了各种各样的发育缺陷和成人病理。我们研究了分裂相关（hesr）基因，编码基本螺旋-环-螺旋转录抑制因子，这是下游目标的Notch信号。虽然斑马鱼的gridlock突变体，小鼠hesr 2的同源物，导致动脉成熟缺陷，hesr 2敲除小鼠失去动脉成熟缺陷。相反，我们发现小鼠心脏形态异常，房室瓣发育不良，室间隔缺损，并使用经胸超声心动图5天大的纯合子小鼠继发性房间隔缺损。hesr 1和hesr 2双基因敲除小鼠显示出血管异常，这与斑马鱼的交通堵塞突变体惊人地相似。Hesr 1和Hesr 2在房室瓣形成期间的上皮-间充质转化和心室中小梁细胞的维持以及血管的动静脉分化中协同起作用。

项目成果

小久保博樹, 富田幸子, 富松宏文, 他3名: "心血管形成におけるhesr遺伝子の機能解析"第2回 心臓血管形態形成研究会. 5 (2003)

Hiroki Kokubo、Sachiko Tomita、Hirofumi Tomimatsu 等 3 人：“hesr 基因在心血管形成中的功能分析”第二届心血管形态发生研究组 5 (2003)。

Mesp1-non-expressing cells contribute to the ventrcicular cardiac conduction system

Mesp1非表达细胞有助于心室心脏传导系统

• 发表时间: 2006
• 期刊: Developmental Dynamics 235
• 作者: Kitajima S;Miyagawa-Tomita S;et al.
• 通讯作者: et al.

富田幸子, 吉田-今中恭子, 杉村洋子, 冨澤康子, 中澤 誠: "マウスの心電図計測法"冠疾患学会雑誌. (印刷中). (2004)

富田幸子、吉田今中恭子、杉村洋子、富泽康子、中泽诚：“小鼠心电图测量方法”，冠状动脉疾病学会杂志（正在出版）（2004 年）。

Notchシグナルと心内膜床形成

Notch信号传导和心内膜床形成

• 发表时间: 2006
• 期刊: 分子心血管医学 (印刷中)
• 作者: 浅沼 俊彦;別府 慎太郎;宮川-富田幸子 ら
• 通讯作者: 宮川-富田幸子 ら

hesr, a mediator of the Notch signaling in heart and vessel development

hesr，心脏和血管发育中 Notch 信号传导的调节者

• 发表时间: 2005
• 期刊: Trends Cardiovasc Med 15(5)
• 作者: Kokubo H;Miyagawa-Tomita S;et al.
• 通讯作者: et al.