Altered regulation of smooth muscle myosin in esophageal atresia

项目摘要 食管闭锁是最常见的先天性食管疾病， 发病率约为1/3，500活产。EA可以作为一个孤立的发现，或与其他 发育异常如果不及时治疗，EA是一种致命的疾病，因为闭锁段阻碍了呼吸道。 食道幸运的是，在婴儿期就可以手术矫正EA。因此，绝大多数EA是可治愈的 案件。不幸的是，大多数EA患者患有显著的胃食管反流和吞咽困难， 由于食管运动受损而手术切除。EA的原因尚不清楚，但其频繁 作为复杂发育综合征的一部分发生，其在单合子与双合子中的发生率较高 双胞胎赞成遗传因素。没有单一的基因突变已被最终证明会导致EA 在人类身上。我们已经开发了第一个孤立的EA发生而没有其他发育的动物模型。 通过在平滑肌肌球蛋白重链基因（Myh 11）中进行突变， 改变肌球蛋白调节。在斑马鱼中，相同的突变导致了 肠子在小鼠中，主要的表型是EA，尽管检测到侵袭性样肠道病变。 由于肌球蛋白调节的改变，该突变破坏了平滑肌的收缩性。这表明 MYH 11和其他平滑肌调节基因的遗传变异可能导致EA， 术后食管动力障碍。本研究的目的是探讨EA的作用机制 在Myh 11小鼠模型中，并使用外显子组测序鉴定EA患者的新遗传变异。

PROJECT SUMMARY Esophageal atresia (EA) is the most common congenital disorder of the esophagus with a world-wide incidence of about 1 in 3,500 live births. EA can occur as an isolated finding, or in combination with other developmental anomalies. Left untreated, EA is a fatal disorder because the atretic segment obstructs the esophagus. Fortunately, surgical correction of EA is possible in infancy. EA is thus curable in the vast majority of cases. Unfortunately most EA patients suffer from significant gastroesophageal reflux and dysphagia post- operatively as a result of impaired esophageal motility. The cause of EA is not known, however its frequent occurrence as part of complex developmental syndromes, and its higher incidence in monozygotic vs. dizygotic twins argues in favor of genetic factors. No single gene mutations have been conclusively shown to cause EA in humans. We have developed the first animal model of isolated EA occurring without other developmental anomalies by engineering a mutation in the smooth muscle myosin heavy chain gene (Myh11) that we have previously shown alters myosin regulation. In zebrafish, the identical mutation causes invasive expansion of the intestine. In mice the predominant phenotype is EA, although invasive-like intestinal lesions are detected. The mutation disrupts smooth muscle contractility as a result of altered myosin regulation. This suggests that genetic variants in MYH11 and other smooth muscle regulatory genes could cause both EA and account for post-surgical esophageal motility disorders. The goal of this proposal is to explore both the mechanism of EA in the Myh11 mouse model and to identify novel genetic variants in EA patients using exome sequencing.