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

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：先天性或新生儿肺病会导致婴儿相当高的发病率和死亡率，并导致幸存者终生肺功能障碍和呼吸困难。系统生物学的新兴领域具有阐明复杂的基因调控网络和相互作用的巨大潜力。这种方法首先需要访问定义肺部发育遗传程序的数据库，但迄今为止，还没有从纯人类肺部谱系中准备出系统科学家所需的数据库。该提案准备了数据库并启动了建立儿童肺部出生缺陷的发育系统生物学研究所需的分析和计算方法，我们试图通过准备第一个动态人类肺部来了解正常和患病的人类肺部发育。利用培养物中诱导多能干细胞 (iPSC) 的分化建立基因表达和全局组蛋白修饰的发育数据库在这项提案中，我们汇集了肺发育生物学家、干细胞生物学家、群体、物理学家和计算研究人员来应用这种新的体外模型系统绘制正常人类肺部发育的表观基因组和转录组，并利用 NKX2.1 中已知会导致肺部出生缺陷的自然发生或工程扰动构建发育的基因调控网络。使用新型人胚胎干细胞 (ESC)/iPSC 体外模型系统在正常人肺发育过程中出现的转录组程序能够概括肺上皮谱系规范和分化的发育顺序。在目标 2 中，我们确定了动态。在目标 3 中，我们开发了系统发育生物学方法来了解肺儿童出生缺陷的发病机制。使用从患有先天性肺部缺陷的儿童身上产生的疾病特异性 iPSC。