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Transcriptional clues to esophageal atresia pathogenesis

食管闭锁发病机制的转录线索

基本信息

批准号：
10192781
负责人：
MICHAEL A PACK
金额：
$ 8.13万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10192781
关键词：
Affect Animal Model Architecture Chromosome abnormality Complex Congenital Disorders Data Defect Deglutition Deglutition Disorders Development Disease Distal Dizygotic Twins Eating Embryo Engineering Enteral Esophageal Atresia Esophageal Diseases Esophageal motility disorders Esophagus Esophagus motility Etiology Fishes Functional disorder Funding Ganglia Gastroesophageal reflux disease Gene Expression Gene Expression Regulation Gene Mutation Genes Genetic Genetic Transcription Goals Human Impairment In Vitro Incidence Infant Interstitial Cell of Cajal Intestines Left Length Lesion Live Birth MYH11 gene Malignant neoplasm of esophagus Modeling Morbidity - disease rate Morphology Mus Muscle Muscle Contraction Muscle Development Mutagenesis Mutant Strains Mice Mutation Myosin ATPase Neonatal Nerve Nerve Fibers Nervous System Physiology Nervous system structure Neuroglia Neurons Neurotransmitters Newborn Infant Operative Surgical Procedures Oral Pathogenesis Pathway interactions Patients Phenotype Play Primary Cell Cultures Primitive foregut structure Regulation Regulator Genes Risk Factors Role Siblings Signaling Protein Smooth Muscle Striated Muscles Stromal Cells Supporting Cell Symptoms Syndrome Tissue Grafts Wild Type Mouse Zebrafish base cell motility cell type cohort density differential expression drinking experimental study genetic variant insight macrophage mouse model mutant nerve supply neuromuscular function novel prevent pup response transcriptome sequencing

项目摘要

Project Summary Esophageal atresia (EA) is the most common congenital disorder of the esophagus with a worldwide incidence of about 1 in 3,500 live births. EA can occur as an isolated ﬁnding, or in combination with either syndromic or non-syndromic developmental anomalies. Left untreated, EA is a fatal disorder because the atretic segment obstructs the esophagus. Fortunately, it can be cured surgically in nearly all infants, however the majority suffer from severe gastroesophageal reﬂux and dysphagia as a result of impaired esophageal motility. Although the cause of EA is not known, a genetic component is predicted based on its occurrence in complex developmen- tal syndromes and its higher incidence in monozygotic vs. dizygotic twins. No single gene mutations have been conclusively shown to cause EA. We have developed the ﬁrst animal model of isolated EA 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 predomi- nant 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 its associated esophageal motility disorders. Preliminary transcriptional proﬁling studies of esophagi from Myh11 mutants before the EA phenotype is de- tected showed altered regulation of genes involved in nervous system and striated muscle development. This suggest that defects in esophageal neuromuscular function may be an intrinsic defect associated with EA that arises independently of atresia. Supporting this, immunostainings show altered esophageal nerve ﬁber density, reduced number and size of esophageal ganglia and altered striated muscle development in mutant esophagi The goal of this proposal is to expand these ﬁndings by examining these and other gene expression changes in older Myh11 mutants, by quantifying changes in neuronal density and neuronal subtypes, and by conducting in vitro functional analyses in primary cultures of esophageal neurons.

项目摘要食道闭锁(EA)是最常见的先天性食道疾病，在世界范围内发病率较高。大约每3,500名活产婴儿中就有1名。EA可以作为孤立的ﬁNding发生，也可以与综合征或非综合征性发育异常。如果不治疗，电针是一种致命的疾病，因为闭锁节段阻塞食道。幸运的是，几乎所有的婴儿都可以通过手术治愈，但大多数婴儿会遭受痛苦。由严重的胃食道Re、ﬂ、UX和吞咽困难引起的食道动力减退。尽管 EA的原因尚不清楚，根据其在复杂发育过程中的出现情况预测遗传成分 TAL综合征及其在同卵双生子和异卵双生子中的较高发生率。还没有发现单基因突变最终证明是导致EA的原因。我们通过工程方法建立了分离的EA的ﬁ第一动物模型。我们之前发现的平滑肌肌球蛋白重链基因(MYH11)突变会改变肌球蛋白监管。在斑马ﬁsh中，相同的突变会导致肠道侵袭性扩张。在小鼠中，主要是- NANT表型为EA，但可检测到侵袭性肠道病变。突变破坏了顺畅由于肌球蛋白调节改变而导致的肌肉收缩能力。这表明MYH11和MYH11的遗传变异其他平滑肌调节基因可能导致电针及其相关的食道运动障碍。 Ea表型消失前MYH11突变株食道转录水平的初步ﬁ研究 TECT显示，神经系统和横纹肌发育相关基因的调控发生了变化。这提示食道神经肌肉功能缺陷可能是与电针相关的固有缺陷独立于闭锁而产生。支持这一点的是，免疫染色显示食道神经ﬁ-ber密度改变，突变食管神经节数目和大小减少及横纹肌发育改变这项提议的目标是通过检查这些和其他基因表达变化来扩展这些ﬁ编码在年长的MYH11突变体中，通过量化神经元密度和神经元亚型的变化，以及通过传导原代培养的食管神经细胞的体外功能分析。