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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

基本信息

批准号：
10619545
负责人：
Gabrielle Kardon
金额：
$ 47.6万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
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/10619545
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 Patients Penetrance Perinatal mortality demographics Phenotype Play Prevalence Proliferating 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 Vitamin A Deficiency conditional mutant insight mortality mouse genetics novel

项目摘要

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.

隔膜是哺乳动物必不可少的骨骼肌，因为它对于呼吸至关重要并充当屏障胸腔和腹腔之间。膈肌发育缺陷是先天性的原因膈疝 (CDH) 是一种常见的出生缺陷（1:3000 出生），导致严重发病率和 50% 死亡。考虑到膈肌的功能重要性以及 CDH 的频率和严重程度，了解膈肌正常发育和疝出期间的发育至关重要。利用小鼠遗传学，我们明确确定胸腹膜皱襞、短暂胚胎结构和肌肉来自它们的结缔组织成纤维细胞严格调节膈肌的发育（梅雷尔等人，2015）。此外，我们发现这些成纤维细胞中 Gata4 的突变会导致 CDH。尽管条件性 Gata4 小鼠突变体对于剖析 PPF 和 Gata4 在 CDH，它们并不代表CDH的遗传和表型特征。我们已经确定并创建了 Gata4 的新亚等位基因，忠实地再现了基因型和表型人类 CDH 的特征。根据这些新 Gata4 等位基因的初步数据，我们将测试假设 Gata4 以剂量依赖性方式调节膈肌的发育和CDH。视黄酸 (RA) 信号传导的遗传和环境破坏也被认为是 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 在膈肌中的相互作用发展和CDH。我们的研究将为多方面的遗传、分子、细胞和 CDH 病因学及其表型和临床变异性背后的环境机制。