Genetic and Environmental Regulation of Diaphragm Development and Congenital Diaphragmatic Hernias

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 在胸腔和腹腔之间膈肌发育缺陷是先天性 腹股沟疝（CDHs）是一种常见的出生缺陷（1：3000出生），导致严重的发病率和50%的 mortality.考虑到膈肌的功能重要性以及CDH的频率和严重程度， 了解横膈膜的正常发育和疝形成过程是至关重要的。利用老鼠遗传学，我们 明确确定了胸膜腹膜褶皱、短暂的胚胎结构和肌肉 结缔组织成纤维细胞来源于他们至关重要的调节膈肌的发展 （Merrell等人，2015年）。此外，我们发现这些成纤维细胞中Gata4的突变导致CDH。 尽管条件性Gata4小鼠突变体对于剖析PPF和Gata4在细胞内的作用是至关重要的，但是， CDH，它们不代表CDH的遗传和表型特征。我们已经确定， 创造了Gata4的新的亚纯型等位基因，忠实地概括了基因型和表型 人CDH的特征。基于这些新的Gata4等位基因的初步数据，我们将测试 Gata4以剂量依赖性方式调节横膈膜发育的假说 和CDH。遗传和环境破坏维甲酸（RA）信号也被认为是 CDH的重要来源。使用一系列小鼠遗传等位基因和方案来调节母体 维生素A，我们将明确测试RA的作用，以及RA和Gata4在隔膜中的相互作用， 发展和CDH。我们的研究将提供深入了解多方面的遗传，分子，细胞， CDH病因学的环境机制及其表型和临床变异性。

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. 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. 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 Gata4 in these fibroblasts cause CDH. Although conditional Gata4 mouse mutants have been critical for dissecting the role of PPFs and Gata4 in CDH, they are not representative of the genetic and phenotypic characteristics of CDH. We have identified and created new hypomorphic alleles of Gata4 that faithfully recapitulate both the genotypic and phenotypic characteristics of human CDH. Based on preliminary data with these new Gata4 alleles, we will test the hypothesis that Gata4 regulates in a dose-dependent manner development of development of the diaphragm and CDH. Genetic and environmental disruptions in retinoic acid (RA) signaling have also been proposed to be an important source of CDH. Using a series of mouse genetic alleles and protocols for modulating maternal vitamin A, we will explicitly test a role for RA and as well as RA and Gata4 interactions in diaphragm development and CDH. Our research will provide insights into the multifaceted genetic, molecular, cellular, and environmental mechanisms underlying the etiology of CDH and its phenotypic and clinical variability.