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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.

膈肌是哺乳动物必不可少的骨骼肌，因为它对呼吸至关重要，并起到屏障的作用