Development of the Diaphragm and Congenital Diaphragmatic Hernias (CDH)

膈肌发育和先天性膈疝 (CDH)

基本信息

批准号：
9923458
负责人：
Gabrielle Kardon
金额：
$ 31.44万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9923458
关键词：
Abdominal Cavity Bioinformatics Birth Cells Clinical Clonal Expansion Coculture Techniques Complex Congenital Abnormality Congenital diaphragmatic hernia Connective Tissue Data Defect Development Embryo Embryonic Structures Enzymes Etiology Exhibits Fibroblasts Frequencies GATA4 gene Gene Expression Gene Silencing Genes Genetic Genetic Predisposition to Disease Genetic study Germ-Line Mutation HGF gene Hernia Human Image Injections Lesion Molecular Morbidity - disease rate Morphogenesis Mosaicism Mus Muscle Muscle Development Mutagenesis Mutation Outcome Patients Penetrance Phenotype Research Respiration Respiratory Diaphragm Role Sampling Severities Signal Transduction Skeletal Muscle Somatic Mutation Source Teratogens Testing Thoracic cavity structure Tissues Tretinoin base experimental study innovation insight migration mortality mouse genetics novel novel strategies overexpression progenitor protein expression recruit therapeutic target two-photon whole genome

项目摘要

The diaphragm is an essential mammalian skeletal muscle, as it is vital for respiration and serves as a barrier between the thoracic and abdominal cavities. Development of the diaphragm requires the integration of multiple tissues that derive from several embryonic sources. Defects in diaphragm development are the cause of congenital diaphragmatic hernias (CDHs), a common birth defect (1:3000 births) that results in severe morbidity and 50% mortality. Given the diaphragm's functional importance and the frequency and severity of CDH, an understanding of diaphragm development normally and during herniation is critical. Recently, using mouse genetics, we definitively established that the pleuroperitoneal folds, transient embryonic structures, and the muscle connective tissue fibroblasts derived from them critically regulate development of the diaphragm muscle (Merrell et al. 2015). Furthermore, we showed that mutations in these fibroblasts cause CDH. However, the molecular signals from the fibroblasts that regulate muscle development normally and are defective in CDH are not yet known. Based on preliminary studies, we hypothesize that connective tissue fibroblasts are an important source of secreted signals that recruit muscle progenitors into the developing diaphragm; regulate muscle morphogenesis; and are mis-regulated in CDH. In addition, our mouse studies (Merrell et al. 2015) suggest the novel hypothesis that somatic mosaic mutations in connective tissue fibroblasts are critical for the etiology of CDH – a hypothesis that may explain the genetic complexity and phenotypic variability of CDH. We propose to use mouse genetic studies and CDH patient samples to test these hypotheses. Our research will elucidate the genetic, molecular, and cellular mechanisms regulating the development of the diaphragm and CDH and provide important insights into potential therapeutic targets to treat CDH.

隔膜是哺乳动物必不可少的骨骼肌，因为它对于呼吸至关重要并充当屏障胸腔和腹腔之间的隔膜的发育需要整合。来自多个胚胎来源的多个组织的缺陷是原因。先天性膈疝 (CDH) 是一种常见的出生缺陷（1:3000 出生），可导致严重的考虑到隔膜的功能重要性以及发生的频率和严重程度，发病率和死亡率为 50%。 CDH，了解膈肌正常发育和疝出期间的情况至关重要。通过小鼠遗传学，我们明确地确定了胸腹膜皱襞、瞬时胚胎结构和来自它们的肌肉结缔组织成纤维细胞对膈肌的发育至关重要此外，我们发现这些成纤维细胞的突变会导致 CDH。来自成纤维细胞的分子信号，正常调节肌肉发育，但 CDH 存在缺陷尚不清楚。根据初步研究，我们认为结缔组织成纤维细胞是一种。募集肌肉祖细胞进入发育中的膈肌调节的分泌信号的重要来源；肌肉形态发生；并且在 CDH 中受到错误调节。此外，我们的小鼠研究（Merrell 等人，2015）提出了新的假设，即结缔组织成纤维细胞中的体细胞嵌合突变对于 CDH 的病因学——这一假设可以解释 CDH 的遗传复杂性和表型变异性。建议使用小鼠遗传学研究和 CDH 患者样本来检验这些假设。阐明调节膈肌发育的遗传、分子和细胞机制 CDH 并为治疗 CDH 的潜在治疗靶点提供重要见解。