Development of the Diaphragm and Congenital Diaphragmatic Hernias (CDH)

横隔膜是哺乳动物必不可少的骨骼肌，因为它对呼吸至关重要，是一种屏障。 在胸腔和腹腔之间。膜片的发展需要集成 来自几个胚胎来源的多种组织。原因是横隔膜发育的缺陷。 先天性隔膜疝气(CDHS)，一种常见的出生缺陷(1：3000出生)，导致严重的 发病率和50%的死亡率。鉴于横隔膜的功能重要性以及 对于先天性巨结肠，了解横隔膜的正常发育和脱出过程是至关重要的。最近，使用 小鼠遗传学，我们明确地证实了胸膜腹膜皱折、瞬时胚胎结构和 来源于它们的肌肉结缔组织成纤维细胞对横隔膜的发育起着至关重要的调节作用。 肌肉(Merrell等人)2015年)。此外，我们发现这些成纤维细胞中的突变导致了CDH。然而， CDH中调节肌肉正常发育和缺陷的成纤维细胞的分子信号 还不为人所知。根据初步研究，我们假设结缔组织成纤维细胞是一种 重要的分泌信号来源，可将肌肉祖细胞招募到发育中的横隔膜；调节 肌肉形态发生；并在CDH中调节不当。此外，我们的小鼠研究(Merrell等人。2015年) 提出结缔组织成纤维细胞的体细胞马赛克突变对 CDH的病因学--一种可能解释CDH遗传复杂性和表型变异的假说。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 阐明调节横隔膜发育的遗传、分子和细胞机制 并为治疗CDH的潜在治疗靶点提供了重要的见解。

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.