内脏异位合并先天性心脏病中DNAH8基因缺陷致病的分子机制

内脏异位合并先心病病情复杂、病死率高，其病因和发病机制与纤毛功能障碍有着密切的内在联系。基于前期研究提出以下课题假说：DNAH8基因缺陷作为纤毛运动障碍的候选基因，可能是内脏异位合并先心病重要的致病因素。本研究拟完成：①分析内脏异位合并先心病患者DNAH8基因的DNA序列、表达特征及其调控机制；②在人呼吸道上皮细胞中检测DNAH8基因突变对动力纤毛的发生、运动和超微结构的影响；③建立患者来源诱导多能干细胞hiPSCs，检测DNAH8基因突变对hiPSCs多能性、定向心肌细胞分化、形态和功能的影响；④利用模式动物观察DNAH8基因突变对胚胎动力纤毛、内脏位置和心脏发育表型的影响。研究结果有助于深入解析内脏异位合并先心病的发病机制，为今后开展早期干预研究提供依据。

Heterotaxy with congenital heart disease (heterotaxy/CHD) is a spectrum of complicated congenital anomalies with high mortality and morbidity. Studies have shown that its etiology and pathogenesis are closely related to cilia dysfunction. Based on the previous research, we propose that DNAH8 gene defect as a candidate gene for cilia motility disorder may be an important pathogenic factor of heterotaxy/CHD. This study is intended to complete the following parts: ① to analyze the DNA sequence, expression characteristics and regulation mechanism of DNAH8 gene in patients with heterotaxy/CHD; ② to detect The effects of DNAH8 gene mutation on the occurrence, movement and ultrastructure of the dynamic cilia in human respiratory epithelial cells. ③ to establish the stem cell line hiPSCs from patients and to detect the effects of DNAH8 gene mutation on hiPSCs, differentiation, morphology and function of cardiac myocytes. ④ to observe the effects of DNAH8 gene mutation on fetal dynamic cilia, visceral position and cardiac development phenotype by using zebrafish and mouse models. The results will help to illustrate the pathogenesis of heterotaxy/CHD and provide evidence for early intervention of the disease.