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Identifying a novel gene contributing to vascular maturation and its significance in cardiovascular diseases.

识别有助于血管成熟的新基因及其在心血管疾病中的意义。

基本信息

批准号：
23659424
负责人：
SAITO Yoshihiko
金额：
$ 2.5万
依托单位：
Nara Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Challenging Exploratory Research
财政年份：
2011
资助国家：
日本
起止时间：
2011 至无数据
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23659424/
关键词：
血管新生動脈分化 TGFβスーパーファミリー肺高血圧

项目摘要

Members of the transforming growth factorβsuperfamily play essential roles in various aspects of embryonic development and physiological organ function. Among them, bone morphogenetic protein(BMP) 9 and BMP10 regulate embryonic vascular development by activating their endothelial receptor ALK1.ALK1-mediated intracellular signaling is implicated in the etiologies of human diseases such as HHT and pulmonary hypertension, but their downstream functional proteins are largely unknown. We identified gene X to be an embryonic endothelium-enriched gene activated by BMP9 and BMP10 through the ALK1 receptor. Gene X null mice showed embryonic lethality due to impaired differentiation of arterial endothelium and defects of vascular morphogenesis. The activity of Notch-and Akt-mediated signaling, which is essential for vascular development, was down regulated in gene X null mice, suggesting that the gene X deficiency leads to vascular demise, at least in part, through dysregulation of these signaling pathways. These data indicated that gene X play indispensable roles downstream of BMP9/BMP10-ALK1 signaling during endothelial differentiation and vascular morphogenesis.Mutations in ACVRL1/ALK1 and BMPR2 cause hereditary hemorrhagic telangiectasia as well as pulmonary arterial hypertension in humans. Gene X might be involved in the mechanisms of these diseases as an additional causative gene or a modifier. To demonstrate this hypothesis we analyzed conditional KO mice of tamoxifen-induced inactivation of gene X. However cKO mice did not develop pulmonary hypertension spontaneously under unstressed conditions. We are investigating whether hypoxia induced severe pulmonary hypertension in cKO mice.

转化生长因子β超家族成员在胚胎发育和生理器官功能的各个方面发挥重要作用。其中，骨形态发生蛋白（BMP）9和BMP 10通过激活其内皮受体ALK 1来调控胚胎血管的发育。ALK 1介导的细胞内信号转导与HHT和肺动脉高压等人类疾病的发病机制有关，但其下游功能蛋白尚不清楚。我们确定基因X是一个胚胎内皮富集基因，通过ALK 1受体被BMP 9和BMP 10激活。X基因敲除小鼠表现出胚胎致死性，由于动脉内皮细胞分化受损和血管形态发生缺陷。Notch和Akt介导的信号传导的活性，这是血管发育所必需的，在基因X缺失小鼠中下调，表明基因X缺陷导致血管死亡，至少部分地，通过这些信号传导途径的失调。这些结果表明，X基因在内皮细胞分化和血管形成过程中起着重要作用，ACVRL 1/ALK 1和BMPR 2基因突变可导致遗传性出血性毛细血管扩张症和肺动脉高压。X基因可能作为一个额外的致病基因或修饰基因参与了这些疾病的发病机制。为了证明这一假设，我们分析了他莫昔芬诱导的X基因失活的条件性KO小鼠。然而，cKO小鼠在非应激条件下不会自发地发生肺动脉高压。我们正在研究是否缺氧诱导cKO小鼠严重的肺动脉高压。