DISEASE AND HEALTH: ASTHMA RESILIENCE THROUGH MICRORNA ATTRIBUTES (DHARMA)

 描述（由申请人提供）：哮喘影响全球超过3亿人。microRNA（miRNAs）是一类小的非编码核糖核酸（RNA），通过基因反式阻遏或RNA沉默来调节蛋白质合成。越来越多的研究表明，miRNAs控制着每种细胞类型中的信号通路并调节炎症。因此，miRNAs可能在哮喘的发病机制和易感性中发挥重要作用。早期的miRNA研究已经鉴定出几种与哮喘相关的miRNA。在血液中稳定表达的miRNAs的存在表明miRNAs可用作哮喘易感性和恢复力的非侵入性生物标志物。该项目的主要目标是制定一个基于循环miRNAs的哮喘发病率和恢复力的预测生物标志物测试。为此，我们确定了三个协调一致的具体目标。第一个目标是评估来自Viva项目的139名有反复喘息病史的儿童血清中miRNAs的全基因组测序数据，并确定与随后的哮喘易感性和四年后的恢复力的相关性。然后使用贝叶斯网络方法将miRNA标记物并入miRNA的预测集合中。第二个目的是在一个独立的有反复喘息病史的儿童人群中前瞻性地验证预测性试验，这些儿童参加了维生素D治疗哮喘减少试验（VDAART）。目前可从儿童早期获得血清，并将在未来三年内测量哮喘发病率结果。在Project Viva中开发的贝叶斯预测miRNA模型将在VDAART中进行测试，并在必要时进行完善。纵向miRNA测量将允许直接的哮喘弹性与哮喘易感性测试，以确保预测性miRNA保持生物学相关性。我们的最终目标是审问 维生素D的联合作用，也具有潜在的哮喘易感性生物标志物的潜力，以及测量的miRNA对哮喘易感性和恢复力的影响。这将通过Viva项目和VDAART中的统计建模以及通过在气道来源的平滑肌和上皮细胞上使用miRNA模拟物和抑制剂以及维生素D来完成。通过检查基因表达的变化，可以获得对所观察到的临床关联的机械理解。我们相信这些发现将揭示miRNAs在哮喘易感性和恢复力中的作用，并将导致新的干预措施，包括miRNA靶向，以预测和缓解这一主要的医疗保健问题。

 DESCRIPTION (provided by applicant): Asthma affects over 300 million individuals worldwide. MicroRNAs (miRNAs) are small noncoding ribonucleic acids (RNAs) that regulate protein synthesis by way of gene trans-repression or RNA silencing. A growing number of studies demonstrate that miRNAs control signaling pathways in every cell type and regulate inflammation. Thus, miRNAs likely play a profound role in the pathogenesis of, and susceptibility to, asthma. Early miRNA studies have identified several miRNAs associated with asthma. The presence of miRNAs stably expressed in blood indicates that miRNAs may be used as noninvasive biomarkers of asthma susceptibility and resilience. The major goal of this project is to formulate a predictive biomarker test for asthma incidence and resilience based on circulating miRNAs. To accomplish this, we have specified three coordinated specific aims. The first aim evaluates data from the genome-wide sequencing of miRNAs in the serum of 139 children from Project Viva with a history of recurrent wheezing and determines association with the subsequent asthma susceptibility and resilience four years later. The miRNA markers will then be incorporated into a predictive set of miRNA using a Bayesian network approach. The second aim seeks to prospectively validate the predictive test in an independent population of children with a history of recurrent wheezing participating in the Vitamin D Antenatal Asthma Reduction Trial (VDAART). Serum is currently available from early childhood and asthma incidence outcomes will be measured over the next three years. The Bayesian predictive miRNA models developed in Project Viva will be tested in VDAART and refined if necessary. Longitudinal miRNA measurements will permit direct asthma resilience vs. asthma susceptibility testing to assure that the predictive miRNA remain biologically relevant. Our final aim will be to interrogate the joint effects of vitamin D, which also has potential biomarker potential for asthma susceptibility, and the measured miRNA on asthma susceptibility and resilience. This will be done via statistical modeling within Project Viva and VDAART, as well as via using miRNA mimics and inhibitors and vitamin D on airway derived smooth muscle and epithelial cells. By examining changes in gene expression, a mechanistic understanding for the observed clinical associations can be garnered. We believe that these findings will uncover the role of miRNAs in asthma susceptibility and resilience and will lead to novel interventions, including miRNA targeting, to predict and alleviate this major health care problem.