肛门直肠畸形（ARM）是最常见的消化道畸形，严重影响儿童的生活质量。由于ARM是复杂的多基因疾病，迄今其发病机制仍不清楚。目前研究发现Wnt5a下游信号通路在ARM发生中发挥重要作用，参与Wnt5a信号通路的下游基因非常复杂，哪些信号通路涉及ARM的发生及其作用机制仍不清楚。本项目在前期研究基础上，拟采用ARM患者的外周血和直肠组织标本以及乙烯硫脲诱导的大鼠产生的ARM胎鼠模型，检测和分析Wnt5a下游基因的表达和突变，筛选出Wnt5a下游参与ARM发生的基因，同时通过miRNA芯片研究ARM特异的miRNA表达谱，应用转基因动物模型验证miRNA和筛选出的Wnt5a下游基因与ARM的发病关系，探讨Wnt5a下游信号通路及miRNA在ARM发生中的作用机制，同时将验证结果用于研发产前筛查ARM的特异芯片，为人类ARM产前诊断、遗传干预和畸形防治奠定基础。

Congenital anorectal malformation (ARM) is the most common gastrointestinal malformations which influenced the quality of life of the patients severely. However, as ARM is a multigenerational complex disease, the pathogenesis of ARM is unknown. Recent studies have shown that downstream signaling pathways of Wnt5a play important role in the pathogenesis of ARM, but the mechanism is unknown. Downstream genes involved in Wnt5a signaling pathway are very complex. The exact signaling pathways involved in the pathogenesis of ARM remain unknown. In this study, we will use biopsies from ARM patients and ethylenethiourea (ETU) induced ARM rat fetus, focusing on the Wnt5a downstream genes which were considered to be involved in ARM development, to study the role of these genes in ARM generation. Both the expression levels and mutations will be detected. On the other hand, considering the importance of miRNAs in embryonic development, the specific miRNA profile in ARM will be studied by miRNA array. At the end, the genes and miRNAs identified and validated in animal models will be used to develop the ARMs-specific chip for prenatal screening.Our research lays a foundation for genetic intervention, prenatal diagnosis and prevention of human congenital ARM.