Modeling the premature airway with neonatal airway basal cells

用新生儿气道基底细胞模拟早产儿气道

基本信息

批准号：
10303254
负责人：
Paul Hubert Lerou
金额：
$ 25.2万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
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：
2021-06-11 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10303254
关键词：
37 weeks gestation ATAC-seq Affect Age Air Asthma Attention Automobile Driving Autopsy Basal Cell Biological Biological Models Birth Bronchopulmonary Dysplasia Cell Line Cell physiology Cells Childhood Chromatin Cilia Complement Data Defect Development Disease Elderly Epigenetic Process Epithelial Epithelial Cells Exhibits Experimental Models Foundations Future Gene Expression Genes Genetic Transcription Gestational Age Goals Host Defense Human Immune response Immune system Immunity Impairment Incidence Infant Infection Inflammation Inflammatory Inflammatory Response Inhalation Kinetics Life Link Liquid substance Live Birth Lung Lung diseases Measures Memory Methods Modeling Molecular Molecular Profiling Morbidity - disease rate Mucociliary Clearance Neonatal Newborn Infant Pathway interactions Patients Phenotype Predisposition Pregnancy Premature Infant Prevention Prevention strategy Production Recurrence Regulator Genes Respiratory Syncytial Virus Infections Respiratory Tract Infections Respiratory syncytial virus Risk Risk Factors STEM field Severities Signal Pathway Signal Transduction Structure System Systems Biology Testing Viral Respiratory Tract Infection adaptive immune response airway epithelium cell type cohort cytokine differential expression experimental study high risk improved infancy infection risk innovation interest lung development pathogen premature preterm newborn pulmonary function respiratory respiratory morbidity response response to injury stem cells transcriptome transcriptome sequencing treatment strategy

项目摘要

PROJECT SUMMARY/ABSTRACT Prematurity affects one in nine live births in the US and is a well-described risk factor for more severe and recurrent respiratory infection during infancy and development of asthma. While it is clear that gestational age at birth and age at infection influence severity of respiratory infection, host immunologic response, and risk of long-term impact on lung development and function, our understanding of the mechanism driving these associations remains poorly understand. Limited human infant autopsy studies have revealed aberrations in the development and function of the airway epithelium, which serves as the first line barrier of defense against inhaled pathogens. Models of newborn airway epithelium to study why premature babies are at higher risk of infection and long-term ramifications, such as asthma, are lacking. We have developed a method of isolating airway basal cells from respiratory secretions of newborns born prematurely and at term. These cells can be expanded long-term and retain the ability to differentiate into pseudo-stratified airway epithelium making them a powerful system to model pre-term and full-term airways. In preliminary experiments, cilia differentiated from basal cells isolated from premature newborns are longer, beat slower, are less dense, and have decreased linear mucociliary flow compared to full-term infant controls. We also found that developmental and immunity related gene expression pathways are differentially expressed in pre-term basal cells. Using our innovative method of isolating and growing epithelial cells derived from patient-specific basal cells we will study how prematurity alters airway epithelium function. We will define the airway basal cell defect due to prematurity by phenotyping pre- and full-term basal cells. Basal cells lines from pre- and full-term infants will be differentiated in air-liquid interface culture and their differentiation potential, epithelial and cilliary function will be comprehensively evaluated. We will also study how prematurity impacts the inflammatory response of differentiated basal cells following RSV infection. Finally, gene co-expression networks and chromatin accessibility will be used to identify the molecular signature associated with the basal cell prematurity defect related to differentiation and RSV-infection response. The successful execution of these aims will establish patient-specific derived airway basal cells as a practical and biologically relevant model system. In addition, our results will provide a better understanding of the molecular mechanisms linking prematurity and early life RSV infection with longer-term morbidities such as asthma, which are important for improving prevention and treatment strategies.

项目概要/摘要在美国，九分之一的活产婴儿都会受到早产的影响，并且是导致更严重和更严重的早产的一个明确的风险因素。婴儿期反复呼吸道感染和哮喘的发展。虽然孕周是明确的出生时和感染时的年龄影响呼吸道感染的严重程度、宿主免疫反应和感染风险对肺发育和功能的长期影响，我们对驱动这些机制的理解协会仍然知之甚少。有限的人类婴儿尸检研究揭示了异常现象气道上皮的发育和功能，作为防御的第一道屏障吸入病原体。新生儿气道上皮模型用于研究早产儿为何面临更高的风险不存在感染和哮喘等长期后果。我们开发了一种隔离方法气道基底细胞来自早产儿和足月新生儿的呼吸道分泌物。这些细胞可以是长期扩张并保留分化为假复层气道上皮的能力，使它们一个强大的系统，可以模拟早产儿和足月气道。在初步实验中，纤毛分化为从早产儿中分离出的基底细胞更长、跳动更慢、密度更小并且数量减少与足月婴儿对照相比，线性粘液纤毛流动。我们还发现发育和免疫相关基因表达途径在早产基底细胞中差异表达。使用我们的创新分离和培养源自患者特异性基底细胞的上皮细胞的方法，我们将研究如何早产会改变气道上皮功能。我们将通过以下方式定义因早产引起的气道基底细胞缺陷：对足月前和足月基底细胞进行表型分析。来自早产儿和足月婴儿的基底细胞系将被分化在气液界面培养及其分化潜力、上皮和纤毛功能将综合评价。我们还将研究早产如何影响炎症反应 RSV感染后分化的基底细胞。最后，基因共表达网络和染色质可及性将用于识别与基底细胞早产缺陷相关的分子特征与分化和 RSV 感染反应有关。这些目标的成功执行将建立患者特异性衍生气道基底细胞作为实用且生物学相关的模型系统。此外，我们的结果将有助于更好地理解早产和早期生命 RSV 之间的分子机制感染导致哮喘等长期疾病，这对于改善预防和治疗非常重要治疗策略。