Improved Prediction of Response to Asthma Medication Using Small Molecules

使用小分子改进对哮喘药物反应的预测

• 批准号: 8906921
• 负责人: Nichole A Reisdorph
• 金额: $ 38.29万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-07 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8906921
• 关键词: Adolescent; Adrenal Cortex Hormones; Adult; African; African American; Aftercare; Ancillary Study; Asthma; Biological Markers; Breathing; Characteristics; Child; Chronic; Clinical; Clinical Medicine; Clinical Research; Clinical Trials; Cluster Analysis; Complement; Cross-Over Trials; Data; Death Rate; Disease; Dose; Drug Targeting; Emergency department visit; Funding; Health; Hospitalization; IL4 gene; IL5 gene; IgE; Individual; Inflammation; Inflammatory; Interleukin-13; Leukotriene E4; Leukotrienes; Lipoxins; Lung; Measures; Medical Genetics; Metabolic; Modeling; Molecular; Morbidity - disease rate; Outcome; Outcome Measure; Pathogenesis; Patient Self-Report; Patients; Pharmaceutical Preparations; Phenotype; Plasma; Population; Prostaglandins; Pulmonary Function Test/Forced Expiratory Volume 1; Relative (related person); Research; Role; Running; Sampling; Severities; Shock; Sphingolipids; Sputum; Staging; Subgroup; Symptoms; Techniques; Testing; Treatment Protocols; Urine; abstracting; asthmatic; base; cohort; cost; improved; inflammatory marker; metabolomics; novel; novel marker; periostin; population based; predictive modeling; prospective; racial difference; research clinical testing; respiratory; response; small molecule; urinary

DESCRIPTION (provided by applicant): The BARD clinical trial aims to determine the most appropriate add-on therapy for Black individuals who are not responding to low dose inhaled corticosteroids (ICS). This unique cohort offers repeated sampling across 4 treatment regimens and provides an opportunity to compare response in children and adults. Using samples obtained at baseline and following 4 treatment regimens, this ancillary study proposes to significantly augment clinical and genetic data from BARD with mechanistic information through quantitation of Th2, inflammatory, and resolving markers and through the use of complementary metabolomics techniques. We hypothesize that ICS-responsive individuals will have a Th2-high phenotype, reflected in increased IL4, IL13, IL5, IgE, and periostin. We have previously found a relationship between urinary leukotriene E4 (uLTE4) and asthma, and between sphingolipids and COPD. Therefore we will test the hypothesis that LTE4 and other pro-inflammatory molecules are increased in ICS- responsive individuals. Because asthma is a heterogeneous condition, knowing the dynamics of multiple molecules will be required in order to fully understand mechanism, and we will utilize an unbiased metabolomics approach to discover new markers. We expect that response to medication can be predicted based on the relative abundance of Th2, inflammatory, and other disease-related molecules and that levels will revert to normal levels in response to medication. Finally, we expect that groups of individuals will cluster based on mechanistic differences. Therefore, in specific aim 1 (SA1), we will quantitate Th2, inflammatory, and resolving markers and will perform metabolomics on baseline plasma, sputum (adults only), and urine samples. In SA2 we will develop prediction models, perform cluster analysis, and correlate results from sputum, plasma, and urine. In SA3 we will use longitudinally collected urine samples to determine the effect of increased ICS therapy on specific molecules. This high impact clinical study will provide an unprecedented opportunity to determine if plasma markers can be used to predict response to therapy, thereby answering urgent questions in clinical medicine.

描述（由申请人提供）：BARD临床试验旨在确定对低剂量吸入皮质类固醇（ICS）无反应的黑人个体最合适的附加治疗。这个独特的队列提供了4种治疗方案的重复采样，并提供了比较儿童和成人反应的机会。使用在基线和4种治疗方案后获得的样本，该辅助研究提出通过定量Th2、炎症和消退标志物以及通过使用补充代谢组学技术，利用机制信息显著增强来自BARD的临床和遗传数据。我们假设ICS应答个体将具有Th2高表型，反映在IL 4、IL 13、IL 5、IgE和骨膜蛋白增加。我们先前已经发现尿白三烯E4（uLTE4）和哮喘之间的关系，以及鞘脂和COPD之间的关系。因此，我们将检验LTE4和其他促炎分子在ICS应答个体中增加的假设。由于哮喘是一种异质性疾病，因此需要了解多个分子的动力学，以充分了解机制，我们将利用无偏见的代谢组学方法来发现新的标记物。我们预计对药物的反应可以根据Th2、炎症和其他疾病相关分子的相对丰度来预测，并且水平将恢复到对药物的正常水平。最后，我们预计，群体的个人将集群的基础上的机械差异。因此，在特定目标1（SA1）中，我们将定量Th2、炎症和消退标志物，并将对基线血浆、痰液（仅成人）和尿液样本进行代谢组学分析。在SA2中，我们将开发预测模型，进行聚类分析，并将痰液、血浆和尿液的结果相关联。在SA3中，我们将使用纵向收集的尿液样本来确定增加ICS治疗对特定分子的影响。这项高影响力的临床研究将提供一个前所未有的机会，以确定血浆标志物是否可用于预测治疗反应，从而回答临床医学中的紧迫问题。