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

• 批准号: 9030454
• 负责人: Sunita Sharma
• 金额: $ 69.19万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9030454
• 关键词: Affect; Age; Alveolar Macrophages; Animal Model; Asthma; Bayesian Method; Biological Markers; Blood specimen; Childhood; Conceptions; DNA Methylation; Data; Development; Disease; Epigenetic Process; Expenditure; Exposure to; Fetal Lung; Gaussian model; Gene Expression; Gene Targeting; Genes; Genome; Genomic approach; Genomics; Healthcare; Hospitalization; Human; Human Genome; Knowledge; Lead; Life; Linear Models; Lung; MicroRNAs; Modeling; Molecular Profiling; Morbidity - disease rate; Network-based; Pathway Analysis; Pathway interactions; Pattern; Perinatal Exposure; Play; Predisposition; Prevention strategy; Public Health; Reverse Transcriptase Polymerase Chain Reaction; Role; Sampling; Schools; Severity of illness; Signal Transduction; Smoke; Structure of parenchyma of lung; Testing; Therapeutic Agents; Time; Tissue Sample; Tobacco smoke; Umbilical Cord Blood; United States; Vitamin D; Weight; Whole Blood; Work; asthmatic; biobank; bronchial epithelium; cohort; differential expression; early life exposure; early onset; epidemiologic data; genome-wide; human subject; in utero; lung development; new therapeutic target; novel; novel therapeutics; postnatal; prenatal; public health relevance; sex; therapeutic target

 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）：哮喘是影响美国超过 2,300 万人的主要公共卫生问题，导致每年超过 500 亿美元的医疗支出 年。越来越多的证据表明，子宫内暴露会影响基因组，导致哮喘易感性增加。子宫内烟雾 (IUS) 暴露与哮喘易感性相关；然而，这种关联背后的生物学机制尚未完全阐明。众所周知，MicroRNA (miRNA) 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 是子宫发育正常过程中不可或缺的一部分，并且发育过程中异常的 miRNA 表达会导致出生后疾病，这表明在发育过程中因 IUS 暴露而改变的 miRNA 可能是以后生活中哮喘易感性的关键决定因素。然而，miRNA 的作用既没有在人类肺部发育中 IUS 暴露的背景下进行过研究，也没有在哮喘的发育起源中进行过研究。我们提出了一种新的整合基因组学方法，将人类受试者中的 miRNA、基因表达和 DNA 甲基化结合起来，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：识别在发育中的人类肺部中通过 IUS 暴露表达和修饰的 miRNA 和 IN，它们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 IN 在人类肺部发育中的作用以及 IUS 暴露特征的了解之外，该项目还将有助于确定治疗哮喘的新型治疗药物的途径。