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MICRORNAS AND EARLY LIFE EXPOSURES IN THE DEVELOPMENTAL ORIGIN OF ASTHMA

哮喘发生起源中的微小颗粒和早期生活暴露

基本信息

批准号：
9883827
负责人：
Sunita Sharma
金额：
$ 68.85万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9883827
关键词：
Affect Age Alveolar Macrophages Animal Model Asthma Bayesian Method Biological Biological Markers Blood specimen Childhood DNA Methylation Data Development Disease Epigenetic Process Exposure to Expression Profiling Fetal Lung Financial Hardship Gaussian model Gene Expression Genes Genome Genomic approach Genomics Health Expenditures Hospitalization Human Human Genome Knowledge Lead Life Linear Models Lung MicroRNAs Modeling Morbidity - disease rate Network-based Pathway Analysis Pathway interactions Pattern Play Predisposition Prevention strategy Public Health Respiratory physiology Reverse Transcriptase Polymerase Chain Reaction Role Sampling Schools Severity of illness Signal Transduction Smoke Testing Therapeutic Agents Time Tissue Sample Tobacco smoke Umbilical Cord Blood United States Vitamin D Wheezing Whole Blood Work antenatal asthmatic biobank bronchial epithelium cohort differential expression early life exposure early onset epidemiologic data exposed human population genome-wide human fetal lung tissue human subject in utero lung development miRNA expression profiling new therapeutic target novel novel therapeutics postnatal prenatal prenatal exposure public health relevance sex therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Asthma is a major public health problem affecting over 23 million people in the US, resulting in excess of $50 billion in healthcare expenditures per year. There is increasing evidence suggesting that in utero exposures can influence the genome resulting in increased susceptibility to asthma. In utero smoke (IUS) exposure has been associated with asthma susceptibility; however, the biologic mechanisms underlying this association have not been fully elucidated. MicroRNAs (miRNAs) are known to fine-tune the relative expression of hundreds of target genes and provide stability to gene expression regulatory networks. Animal models demonstrate that miRNAs are integral to normal in utero development, and that abnormal miRNA expression during development results in postnatal disease, suggesting that miRNAs that are modified during development by IUS exposure may be critical determinants of asthma susceptibility later in life. However, the role of miRNAs has neither been investigated in the context of IUS exposure in human lung development, nor in the developmental origin of asthma. We propose a novel integrative genomics approach incorporating miRNAs, gene expression, and DNA methylation in human subjects to investigate the role of miRNAs and their integrative networks (INs) in lung development and asthma susceptibility. Our proposal describes our plan to: identify miRNAs and the INs that are expressed, and modified by IUS exposure in developing human lung, and are also associated with asthma susceptibility and disease severity. In addition to vastly expanding our knowledge of the role miRNAs and their INs in human lung development and the signature of IUS exposure, this project will aid in the identification of pathways for novel therapeutic agents for the treatment of asthma.

描述（由申请人提供）：哮喘是影响美国2300多万人的主要公共卫生问题，每年导致超过500亿美元的医疗保健支出。越来越多的证据表明，子宫内暴露可影响基因组，导致哮喘易感性增加。子宫内吸烟（IUS）暴露与哮喘易感性相关;然而，这种相关性的生物学机制尚未完全阐明。已知microRNA（miRNAs）微调数百个靶基因的相对表达，并为基因表达调控网络提供稳定性。动物模型表明，miRNA是子宫内正常发育的组成部分，发育过程中异常的miRNA表达导致出生后疾病，这表明在发育过程中通过IUS暴露修饰的miRNA可能是以后生活中哮喘易感性的关键决定因素。然而，miRNAs的作用既没有在IUS暴露于人类肺发育的背景下进行研究，也没有在哮喘的发育起源中进行研究。我们提出了一种新的整合基因组学方法，将人类受试者的miRNA，基因表达和DNA甲基化，以研究miRNA及其整合网络（IN）在肺发育和哮喘易感性中的作用。我们的提案描述了我们的计划：鉴定在发育中的人肺中表达并被IUS暴露修饰的miRNA和IN，并且这些miRNA和IN也与哮喘易感性和疾病严重程度相关。除了极大地扩展我们对miRNAs及其IN在人类肺发育中的作用以及IUS暴露的特征的了解外，该项目还将有助于识别用于治疗哮喘的新型治疗药物的途径。