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相互作用来调节后生动物的细胞命令决策。 Notch信号传导影响细胞增殖，分化，并且是一种从苍蝇到人类的进化保守的调节系统。它的功能障碍导致多种发育缺陷和成人病理。我们检查了分裂相关（HESR）基因的毛茸茸和增强子，并编码了基本的螺旋 - 环螺旋转录抑制因子，这些抑制因子是Notch信号传导的下游靶标。尽管小鼠HESR2的同源物的斑马突变体导致动脉成熟缺陷，但HESR2敲除小鼠失去了动脉成熟缺陷。取而代之的是，我们证明了小鼠具有心脏形态的异常，心室瓣膜的发育异常，心室间隔缺陷以及使用经胸膜超声心动图的secundum心房间隔缺陷，使用5天老的肉体性小鼠。 HESR1和HESR2的双基因敲除小鼠的血管异常与斑马鱼烤肉突变体的血管异常非常相似。 HESR1和HESR2在心室中小梁细胞以及血管中动脉相差的小梁细胞的形成和维持小梁细胞的过程中在上皮 - 间质转化中协同作用。

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)。

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）。

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.

Mouse hesr1 and hesr2 genes are redundantly required to mediate Notch signaling in the developing cardiovascular system

• DOI: 10.1016/j.ydbio.2004.10.025
• 发表时间: 2005-02-15
• 期刊: DEVELOPMENTAL BIOLOGY
• 影响因子: 2.7
• 作者: Kokubo, H;Miyagawa-Tomita, S;Johnson, RL
• 通讯作者: Johnson, RL

Targeted disruption of hesr2 results atrio-ventricular valve anomalies, leading to cardiac dysfunction and perinatal lethality

靶向破坏 hesr2 会导致房室瓣异常，导致心功能障碍和围产期死亡

• 发表时间: 2004
• 期刊: Circulation Research 95
• 作者: Kokubo H;Miygawa;Tomita S;et al.
• 通讯作者: et al.