Altered regulation of smooth muscle myosin in esophageal atresia

食管闭锁中平滑肌肌球蛋白的调节改变

基本信息

批准号：
9317159
负责人：
MICHAEL A PACK
金额：
$ 20.13万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-24 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9317159
关键词：
Affect Animal Model Chemicals Chromosomal Rearrangement Chromosome Deletion Complex Congenital Disorders Coupled Curative Surgery Defect Deglutition Deglutition Disorders Development Dideoxy Chain Termination DNA Sequencing Disease Distal Dizygotic Twins Eating Embryo Engineering Epithelial Esophageal Esophageal Atresia Esophageal Diseases Esophageal motility disorders Esophagus Esophagus motility Fertilization Fishes Gastroesophageal reflux disease Gene Mutation Genes Genetic Genetic Transcription Genomic DNA Goals Heritability Human Impairment Incidence Infant Intestines Laboratories Larva Left Length Lesion Live Birth MYH11 gene Malignant neoplasm of esophagus Missense Mutation Molecular Monozygotic twins Morphogenesis Mus Muscle Contraction Muscle Development Muscle Tension Mutagenesis Mutant Strains Mice Mutation Myosin ATPase Newborn Infant Nonsense Mutation Operative Surgical Procedures Oral Oxidation-Reduction Parents Pathway interactions Patients Pattern Pediatric Hospitals Phenotype Philadelphia Physiology Play Postoperative Period Primitive foregut structure Recurrence Regulation Regulator Genes Risk Factors Role Siblings Signal Pathway Signal Transduction Skeletal Muscle Smooth Muscle Smooth Muscle Myosins Symptoms Syndrome Tissue Grafts Tissues Tracheoesophageal Fistula Variant Zebrafish base cell motility drinking exome sequencing genetic analysis genetic variant genome-wide infancy insertion/deletion mutation insight interest intestinal epithelium mouse model muscle physiology mutant novel prevent pup

项目摘要

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.

项目摘要食道闭锁（EA）是食管中最常见的先天性疾病，全球范围内 3500例活产的发生率约为1个。 EA可以作为孤立的发现发生，或与其他发现结合发育异常。剩下的未治疗，EA是一种致命的疾病食管。幸运的是，婴儿期可能对EA进行手术校正。因此，EA在绝大多数中可以治愈案件。不幸的是，大多数EA患者都患有大量胃食管反流和吞咽困难食管运动受损而操作。 EA的原因尚不清楚，但是频繁作为复杂发育综合征的一部分出现，并且单卵菌与二卵的发病率更高双胞胎主张支持遗传因素。没有最终证明单个基因突变引起EA 在人类中。我们已经开发了第一个没有其他发育的孤立EA动物模型通过在平滑肌肌球蛋白重链基因（MYH11）中进行工程突变来进行异常先前显示的改变了肌球蛋白调节。在斑马鱼中，相同的突变会导致侵入性扩张肠。在小鼠中，主要的表型是EA，尽管检测到了侵入性的肠道病变。由于肌球蛋白调节的改变，该突变破坏了平滑肌收缩力。这表明这一点 MYH11和其他平滑肌调节基因中的遗传变异可能会导致EA并解释术后食管运动障碍。该提议的目的是探索EA的机制在MYH11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。