Epigenenomic and transcriptomic networks in normal and defective lung development

正常和有缺陷的肺发育中的表观基因组和转录组网络

• 批准号: 9144829
• 负责人: Darrell N. Kotton
• 金额: $ 54.61万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9144829
• 关键词: Binding; Binding Sites; Biological Models; Biopsy; Birth; Brain; Candidate Disease Gene; Cell Line; Cells; ChIP-seq; Child; Code; Collaborations; Complex; Congenital Abnormality; DNA; DNA Binding; Data; Data Set; Databases; Defect; Development; Developmental Biology; Disease; Distal; Dose; Dyspnea; Elements; Endoderm; Engineering; Enhancers; Epithelial; Epithelial Cells; Fetal Lung; Functional disorder; Gene Expression; Genes; Genetic Polymorphism; Genetic Programming; Goals; Health; Histones; Human; In Vitro; Infant; Interstitial Lung Diseases; Knock-in; Label; Lead; Life; Link; Location; Lung; Lung Transplantation; Lung diseases; Maps; Morbidity - disease rate; Mutation; National Heart, Lung, and Blood Institute; Neonatal; Pathogenesis; Pluripotent Stem Cells; Population; Publishing; RNA Sequence Analysis; Regulator Genes; Regulatory Element; Reporter Genes; Research Personnel; Scientist; Series; Skin; Sorting - Cell Movement; Staging; Stem cells; Supportive care; Survivors; Syndrome; System; Systems Biology; Technology; Thyroid Gland; Time; Transcript; Untranslated RNA; base; chromatin immunoprecipitation; epigenome; epigenomics; genome-wide; histone modification; human embryonic stem cell; in vitro Model; in vivo; induced pluripotent stem cell; lung development; mortality; novel; prevent; progenitor; programs; promoter; response; targeted treatment; time use; transcription factor; transcriptome; transcriptomics

 DESCRIPTION (provided by applicant): Congenital or neonatal lung diseases cause considerable morbidity and mortality in infants and lead to life-long lung dysfunction and dyspnea in survivors. The emerging field of systems biology has great potential to illuminate the complex gene regulatory networks and interacting mechanisms that control normal lung development and go awry during abnormal development leading to disease. This approach first requires access to databases that define the genetic programs of lung development, yet to date no databases required by systems scientists have been prepared from pure human lung lineages during normal or diseased lung development. This proposal prepares the databases and initiates the analytical and computational approaches required to found a developmental systems biology study of lung child birth defects. We seek to understand normal and diseased human lung development by preparing the first dynamic human lung developmental databases of gene expression and global histone modifications using differentiation of induced pluripotent stem cells (iPSCs) in culture In this proposal, we bring together lung developmental biologists, stem cell biologists, clinicians, physicists, and computational researchers to apply this new in vitro model system to map the epigenome and transcriptome of normal human lung development and to construct gene regulatory networks of development using naturally occurring or engineered perturbations in NKX2.1 that are known to lead to lung birth defects. In aim 1, we define the global epigenomic and transcriptomic programs emerging during normal human lung development using a novel human embryonic stem cell (ESC)/iPSC in vitro model system able to recapitulate the developmental sequence of lung epithelial lineage specification and differentiation. In Aim 2 we identify dynamic candidate gene regulatory networks, histone-DNA interactions, and enhancer/promoter elements using time-series data obtained during the establishment of normal lung epithelial cell fate. In aim 3 we develop systems developmental biology approaches for understanding the pathogenesis of lung child birth defects using disease-specific iPSCs generated from children with lung birth defects.

 描述（由适用提供）：先天或新生儿肺部疾病会导致婴儿的注意事项发病率和死亡率，并导致生存中终生的肺功能障碍和呼吸困难。系统生物学的新兴领域具有巨大的潜力，可以照亮复杂的基因调节网络以及控制正常肺发育并在异常发育过程中出现问题的相互作用机制。这种方法首先需要访问定义肺发育遗传程序的数据库，但迄今为止，在正常或肺部肺部发育期间，系统尚未从纯人类肺谱系中编写系统科学家所要求的数据库。该建议准备数据库，并启动寻找肺部儿童出生缺陷的发育系统生物学研究所需的分析和计算方法。我们试图通过准备基因表达和全球组蛋白修饰的第一个动态人类肺发育数据来理解正常和剖析的人类肺发育，该数据使用诱导的多能干细胞（IPSC）在该建议中的培养中进行了区分，我们将肺部生物学家，干细​​胞生物学家，临床生物学和计算模型的谱图融合在一起在AIM 2中使用自然发生或工程的扰动构建发展和构建基因调节网络，我们确定动态候选基因调节网络，组蛋白DNA相互作用以及增强子/启动子/启动子元素，使用在正常肺上皮细胞命运的建立过程中获得的时间序列数据。在AIM 3中，我们开发了系统发育生物学方法，以使用肺出生缺陷的儿童产生的疾病特异性IPSC了解肺部儿童出生缺陷的发病机理。