完全性肺静脉异位引流(TAPVC)是一种罕见先天性心脏病，危害严重。胚胎时期肺静脉发育异常可导致TAPVC，TAPVC病人肺静脉的血管生成是否出现异常及其分子机制鲜有报道。采用全外显子测序技术及生物信息学分析方法在78例TAPVC病人中筛查出TAPVC新发致病基因HMGA2及SNAI1，二者在血管生成中的作用及机制还不清楚。前期静脉环实验、肺静脉内皮细胞迁移成管及Tip Cell球体出芽等实验证实二者可回补由于TAPVC导致的血管生成能力减弱。斑马鱼Morpholino敲降HMGA2及SNAI1，出现静脉节间血管及脑部中央动脉发育迟缓。我们将进一步在斑马鱼中研究HMGA2是如何通过SNAI1及其下游靶基因导致斑马鱼血管生成异常的；并在内皮细胞中深入研究HMGA2调控SNAI1的机制。本项目从人群样本到细胞，再到斑马鱼，深入探讨其中机制，拟为厘清TAPVC发病原因提供理论依据。

Total anomalous pulmonary venous connection (TAPVC) is a rare form of congenital heart disease which results in poor postoperative survival. The abnormal development of pulmonary venous in embryo stage contributes to the occurrence of TAPVC. However, the molecular mechanism underlying TAPVC remains unknown. It is not clear whether there is abnormal angiogenesis of pulmonary veins in TAPVC patients. We screened novel pathogenic genes, HMGA2 and SNAI1, in 78 patients with TAPVC using whole-exome sequence and bioinformatics analysis. SNAI1 is a downstream gene of HMGA2, but their effects on vascular development were unclear. Our preliminary results have shown that overexpression of HMGA2 and SNAI1 in pulmonary venous endothelial cells can rescue the reduction of angiogenesis caused by TAPVC by venous ring assay, cell migration and tube formation assay and tip cell spheroid-sprouting assay. Knockdown of HMGA2 and SNAI1 in zebrafish led to growth stunt of intersegmental venous vessel and central cerebral artery. We planned to use morpholino, CRISPR/CAS9 and RNA-seq technics in zebrafish to explore the mechanism of HMGA2 regulating SNAI1 and causing abnormal vascular development. From human sample to cell, then to zebrafish, we intend to investigate the specific mechanism of HMGA2 regulating SNAI1, and provide the theoretical basis for clarifying the etiology of TAPVC.