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.

隔膜是必不可少的哺乳动物骨骼肌，因为它对于呼吸至关重要，并且是障碍物 在胸腔和腹腔之间。隔膜发育缺陷是先天性的原因 diaphragmatic疝（CDHS），一种常见的先天缺陷（1：3000出生），导致严重的发病率和50％ 死亡。鉴于隔膜的功能重要性以及CDH的频率和严重程度 对隔膜发育的理解正常和疝气过程至关重要。使用鼠标，我们 明确地确定了胸膜折叠，瞬态胚胎结构和肌肉 结缔组织成纤维细胞源自它们，严重调节隔膜肌肉的发育 （Merrell等人，2015年）。此外，我们表明这些成纤维细胞中GATA4中的突变引起CDH。 尽管有条件的GATA4小鼠突变体对于剖析PPF和GATA4在 CDH，它们不代表CDH的遗传和表型特征。我们已经确定了 创建了GATA4的新的肌科等位基因，这些等位基因忠实地概括了基因型和表型 人CDH的特征。根据这些新的GATA4等位基因的初步数据，我们将测试 假设GATA4以剂量依赖性的隔膜发展的发展进行调节 和CDH。维甲酸（RA）信号中的遗传和环境破坏也已被认为是 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以及diaphragm中RA和GATA4相互作用的作用 开发和CDH。我们的研究将为多方面的遗传，分子，细胞和 CDH病因及其表型和临床变异性的基础的环境机制。