MICRORNAS IN CIRCULATION: ONTOLOGIES OF ASTHMA SEVERITY AND TREATMENT (MICROCOAST)

循环中的 MICRORNAS：哮喘严重程度和治疗的本体论 (MICROCOAST)

• 批准号: 8865064
• 负责人: KELAN G TANTISIRA
• 金额: $ 91.07万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8865064
• 关键词: Accounting; Adrenal Cortex Hormones; Affect; Asthma; Bayesian Modeling; Biological Markers; Blood; Blood Circulation; Blood specimen; Body Fluids; Breathing; Bronchodilator Agents; Budesonide; Cell model; Cells; Childhood Asthma; Clinical; Clinical Data; Clinical Trials; Costa Rica; Data; Development; Disease; Early identification; Enrollment; Future; Gene Expression; Genes; Genetic; Genomics; Glucocorticoids; Goals; Health Care Costs; Healthcare; Immune; Individual; Inflammation; Inflammatory; Intervention; Investigation; Lead; Leukotrienes; Measures; Mediating; Methods; MicroRNAs; Modeling; Molecular; Morbidity - disease rate; Muscle function; Ontology; Participant; Pathogenesis; Pharmaceutical Preparations; Pharmacogenomics; Physiological; Play; Population; Process; Protein Biosynthesis; Pulmonary Function Test/Forced Expiratory Volume 1; RNA; Randomized; Repression; Resources; Respiratory physiology; Role; Salmeterol; Sample Size; Sampling; Serum; Severities; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Specific qualifier value; Testing; Therapeutic; Therapeutic Uses; Time; Tissues; Transcript; Translational Repression; United States; Validation; airway inflammation; arm; asthmatic; asthmatic airway; base; bench to bedside; case control; cell type; circulating microRNA; cohort; computer based statistical methods; differential expression; epigenetic regulation; genome-wide; inhibitor/antagonist; insight; mRNA Transcript Degradation; novel; prognostic; programs; protein protein interaction; public health relevance; respiratory smooth muscle; response; therapeutic target; treatment response

 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 asthma. Early miRNA studies have identified several miRNAs associated with asthma and corticosteroid treatment response. The presence of miRNAs stably expressed in blood indicate that miRNAs may be used as noninvasive biomarkers of asthma and asthma treatment response. The major goal of this project is to systematically investigate the role of circulating miRNAs in asthma severity and asthma treatment response. To accomplish this, we have specified three related but independent aims. The first aim evaluates data from the genome-wide sequencing of miRNAs in the serum of 500 asthmatics for their association with asthma severity at the time of enrollment into large clinical trial cohorts. The miRNA markers with the strongest evidence for differential expression will be tested for replication an independent clinical cohort and modeled using co-expression networks. The second aim seeks to understand the genomic basis for drug treatment response (pharmacogenomics). This aim will assess the genome-wide miRNAs for their differential expression with drug treatment response, as defined by change in lung function in response to inhaled corticosteroid medications. These miRNAs will be tested for replication in an independent clinical trial and then modeled using a Bayesian network approach for their ability to predict response to inhaled corticosteroids in asthma. Our final aim will be to interrogate the functional basis for our circulating miRNA findings in cellular models of airway smooth muscle function. Using miRNA mimics, our top miRNAs from our differential expression analyses will be tested for their ability to modulate airway smooth muscle proliferation and contractility (aim 1 miRNAs) or for their ability to mediate corticosteroid signaling (aim 2 miRNAs) in cells obtained from asthmatics. By simultaneously examining changes in gene expression, the mechanistic basis for the physiologic changes can be inferred. We believe that these findings will uncover the role of miRNAs basis for asthma severity and treatment response and lead to novel interventions to predict and alleviate this major health care problem.

 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中发挥重要作用。早期的miRNA研究已经确定了几种与哮喘和皮质类固醇治疗反应相关的miRNA。在血液中稳定表达的miRNAs的存在表明miRNAs可用作哮喘和哮喘治疗反应的非侵入性生物标志物。本项目的主要目的是系统地研究循环中miRNAs在哮喘严重程度和哮喘治疗反应中的作用。为了实现这一目标，我们确定了三个相互关联但又相互独立的目标。第一个目标是评估来自500名哮喘患者血清中miRNAs全基因组测序的数据，以确定其在入选大型临床试验队列时与哮喘严重程度的相关性。具有差异表达的最强证据的miRNA标志物将被测试用于独立临床群组的复制，并使用共表达网络建模。第二个目标旨在了解药物治疗反应的基因组基础（药物基因组学）。该目的将评估全基因组miRNAs在药物治疗反应中的差异表达，如通过响应吸入性皮质类固醇药物的肺功能变化所定义的。这些miRNAs将在一项独立的临床试验中进行复制测试，然后使用贝叶斯网络方法对其预测哮喘患者吸入皮质类固醇反应的能力进行建模。我们的最终目标将是询问我们在气道平滑肌功能的细胞模型中发现的循环miRNA的功能基础。使用miRNA模拟物，我们将测试来自我们的差异表达分析的顶级miRNA在从哮喘患者获得的细胞中调节气道平滑肌增殖和收缩性的能力（aim 1 miRNA）或介导皮质类固醇信号传导的能力（aim 2 miRNA）。通过同时检查基因表达的变化，可以推断生理变化的机制基础。我们相信这些发现将揭示miRNAs在哮喘严重程度和治疗反应中的作用，并导致新的干预措施来预测和缓解这一主要的医疗保健问题。