Genetic and Environmental Regulation of Diaphragm Development and Congenital Diaphragmatic Hernias

膈发育和先天性膈疝的遗传和环境调节

• 批准号: 10376302
• 负责人: Gabrielle Kardon
• 金额: $ 47.99万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10376302
• 关键词: Abdominal Cavity; Affect; All-Trans-Retinol; Alleles; Birth; Cells; Cervical; Characteristics; Clinical; Code; Complex; Congenital Abnormality; Congenital diaphragmatic hernia; Connective Tissue; Data; Defect; Development; Diet; Dose; Embryo; Embryonic Structures; Enhancers; Environmental Monitoring; Etiology; Extracellular Matrix; Fibroblasts; Frequencies; GATA4 gene; Genes; Genetic; Genetic study; Genotype; Heart; Hernia; Human; Human Characteristics; Human Genetics; Introns; Left; Location; Modeling; Molecular; Morbidity - disease rate; Mouse Strains; Mus; Muscle; Mutagenesis; Mutant Strains Mice; Mutation; Outcome; Oxides; Patients; Penetrance; Perinatal mortality demographics; Phenotype; Play; Prevalence; Protocols documentation; Regulation; Reporter; Research; Respiration; Respiratory Diaphragm; Retinoids; Role; Series; Severities; Signal Transduction; Skeletal Muscle; Somites; Source; Teratogens; Testing; Thoracic cavity structure; Tissues; Tretinoin; Vitamin A; base; conditional mutant; insight; mortality; mouse genetics; novel

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.

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。横隔膜发育缺陷是先天性 横隔性疝气(CDHS)，一种常见的出生缺陷(1：3000出生)，导致严重的发病率和50% 死亡率。鉴于横隔膜的功能重要性以及CDH的频率和严重性， 了解横隔膜的正常和脱出过程中的发育是至关重要的。利用老鼠的遗传学，我们 明确证实了胸膜腹膜皱褶、暂时性胚胎结构和肌肉 来源于它们的结缔组织成纤维细胞对横隔肌的发育起着至关重要的调节作用 (Merrell等人)2015年)。此外，我们发现这些成纤维细胞中的Gata4突变导致了CDH。 尽管条件性Gata4小鼠突变体对于剖析PPFS和Gata4在 CDH不能代表CDH的遗传和表型特征。我们已经确定并 创造了新的Gata4亚型等位基因，忠实地概括了基因和表型 人类先天性巨结肠的特征。基于这些新的Gata4等位基因的初步数据，我们将测试 Gata4以剂量依赖的方式调节横隔膜发育的假说 和CDH。维甲酸(RA)信号的遗传和环境干扰也被认为是 脱氢表雄酮的重要来源。利用一系列小鼠遗传等位基因和协议来调节母体 维生素A，我们将明确测试RA以及RA和Gata4在横隔膜中的作用 发展与鼎晖。我们的研究将提供对多方面的遗传、分子、细胞和 CDH病因学的环境机制及其表型和临床变异性。