DLL1基因异常与法洛氏四联症发病关系的分子机制研究

法洛四联症（TOF）是最常见的青紫型先天性心脏病，研究其发生机制有重要意义。课题组前期研究发现DLL1 基因在TOF心脏组织中表达下调且外显子测序并未发现功能性突变，我们推测是其调控区异常影响基因表达。鉴于DLL1基因是NOTCH信号通路关的键基因，因此，我们提出的假说是：DLL1基因及其介导的信号通路异常是TOF发生的重要因素，本研究拟开展以下研究：（1）在TOF患儿心肌组织以及斑马鱼体内中观察DLL1基因表达异常与疾病发生的关系；（2）在基因水平以及表观遗传学水平对DLL1基因增强子的功能进行验证，探索引起DLL1基因表达异常的分子机制；（3）在人类多能干细胞（hiPSCs）中研究DLL1基因与心肌细胞分化以及心脏发育的关系。本研究不仅有助于阐明TOF的发生机制，而且可为其他出生缺陷的研究提供可借鉴的研究思路和方法。

TOF is one of the most common cyanotic congenital heart defects. It is important to study the pathogenesis of TOF. Our previous study demonstrated the genes DLL1 decreased in TOF. However, mutation rate of DLL1 in patients was very low. We made a hypothesis: abnormal expression of DLL1 gene might contribute to TOF. We plan to launch the following researches, including (1) to illustrate the relationship between congenital heart disease and aberrant patterns of DLL1 expression in TOF patients and in zebrafish; (2) to analysis the function of the enhancers in DLL1; (3) to figure out the relationship between DLL1 and cardiogenesis in human induced pluripotent stem cells (hiPSCs). The research thinking and method will provide references for other birth defects.