MICRORNAS AND EARLY LIFE EXPOSURES IN THE DEVELOPMENTAL ORIGIN 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，子宫内暴露会影响基因组，导致对哮喘的易感性增加。子宫内吸烟（IUS）暴露与哮喘易感性有关；然而，这种关联的生物学机制尚未完全阐明。众所周知，MicroRNAs （miRNAs）可以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是子宫正常发育不可或缺的一部分，发育过程中miRNA表达异常会导致出生后疾病，这表明在发育过程中受到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，在IUS暴露于人类肺部发育的背景下，以及在哮喘的发育起源中，miRNAs的作用尚未得到研究。我们提出了一种新的整合基因组学方法，结合人类受试者的miRNAs、基因表达和DNA甲基化，研究miRNAs及其整合网络（INs）在肺部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通过IUS暴露表达和修饰的mirna和INs，这些mirna和INs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mirna及其INs在人类肺部发育中的作用的认识以及IUS暴露的特征外，该项目还将有助于确定治疗哮喘的新型治疗药物的途径。

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.