Altered regulation of smooth muscle myosin in esophageal atresia

项目总结 摘要食道闭锁是世界范围内最常见的先天性食道疾病。 发病率约为每3,500名活产儿中就有1名。EA可以作为单独的发现出现，也可以与其他 发育异常。如果不进行治疗，电针是一种致命的疾病，因为闭锁段阻碍了 食管。幸运的是，在婴儿期手术矫正EA是可能的。因此，EA在绝大多数情况下是可以治愈的 案件的数量。不幸的是，大多数电针患者术后都有明显的胃食道反流和吞咽困难。 手术是食道运动受损的结果。EA的原因尚不清楚，但它经常发生 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更高 双胞胎支持遗传因素。目前还没有确凿的证据表明单一基因突变会导致EA 在人类身上。我们已经建立了第一个无其他发育的孤立EA的动物模型。 通过设计我们已有的平滑肌肌球蛋白重链基因(MYH11)的突变来实现异常 先前的研究显示改变肌球蛋白的调节。在斑马鱼中，相同的突变会导致侵入性扩张 肠子。在小鼠中，主要的表型是EA，尽管检测到了侵袭性的肠道病变。 由于肌球蛋白调节的改变，该突变破坏了平滑肌的收缩能力。这表明 MYH11和其他平滑肌调节基因的遗传变异可能导致EA和 手术后食道动力障碍。这项建议的目标是探索EA的两种机制 在MYH11小鼠模型中，并使用外显子组测序确定EA患者中的新遗传变异。

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.