Development of the Diaphragm and Congenital Diaphragmatic Hernias (CDH)

横膈膜是哺乳动物必不可少的骨骼肌，因为它对呼吸至关重要，并充当屏障 在胸腔和腹腔之间隔膜的开发需要集成 从几个胚胎来源获得的多种组织。横膈膜发育缺陷是导致 先天性腹股沟疝（CDHs）是一种常见的出生缺陷（1：3000出生）， 发病率和50%的死亡率。鉴于横膈膜的功能重要性以及 CDH，了解隔膜的正常发展和在疝是至关重要的。近日，利用 小鼠遗传学，我们明确地建立了胸膜腹膜褶皱，短暂的胚胎结构， 从它们衍生的肌肉结缔组织成纤维细胞关键地调节隔膜的发育 肌肉（Merrell等人，2015）。此外，我们发现这些成纤维细胞中的突变导致CDH。然而，在这方面， 来自成纤维细胞的分子信号，其正常调节肌肉发育并且在CDH中有缺陷 目前还不清楚。基于初步的研究，我们假设结缔组织成纤维细胞是一种 将肌肉祖细胞招募到发育中的横膈膜中的分泌信号的重要来源;调节 肌肉形态发生;并且在CDH中被错误调节。此外，我们的小鼠研究（Merrell et al. 2015） 提出了一种新的假设，即结缔组织成纤维细胞中的体细胞嵌合突变对结缔组织的形成至关重要。 CDH的病因学-一种可以解释CDH的遗传复杂性和表型变异性的假说。我们 建议使用小鼠遗传学研究和CDH患者样本来验证这些假设。我们的研究将 阐明调节横膈膜发育的遗传、分子和细胞机制， CDH，并提供了重要的见解，潜在的治疗靶点，以治疗CDH。

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.