Multi-omics of the Frequent Exacerbator Asthmatic

摘要 在美国，哮喘是一种常见、复杂且代价高昂的儿科慢性疾病，导致近200万人 每年的急诊费用和820亿美元的总费用。城市低收入家庭子女 社区的哮喘患病率最高，哮喘发病率和 死亡率。在俄亥俄州的汉密尔顿县，超过36,000名儿童患有哮喘，其中14,000人是医疗补助计划。 保险的住院率高出10倍。哮喘加重，急性发作增加 哮喘症状和肺功能恶化是患者和家庭压力的主要原因。 虽然恶化是控制不佳和严重哮喘的一个显著特征，但恶化的比率 即使在轻度哮喘和哮喘加重的患者中也可以保持较高的频率不变 尽管进行了密集的控制器治疗。事实上，儿科研究显示病情恶化仍在继续 尽管基线症状控制良好，但仍会发生。哮喘的一种经常加重的表型(定义为 2个或更多的恶化/年)，但对这一哮喘亚群知之甚少，它 对城市人口的影响不成比例，并导致相当大的哮喘发病率和 医疗保健成本。没有特定的临床特征可以可靠地区分频发和 非频繁加重者强调了系统级方法的必要性。我们针对中心的项目 将填补这一理解上的空白。我们的初步数据显示，不同的表达和不同的 经常加重并突出生物学特征的儿童鼻上皮甲基化基因 涉及不同机制的通路，这些机制构成了频繁恶化表型的基础。我们会 检验假设：频繁加重者是一种不同的哮喘内型，以宿主为特征 鼻腔上皮转录和/或DNA甲基组模式区分频繁恶化 不是经常加重的哮喘儿童，这些模式在一定程度上是被触发的 通过截然不同的鼻腔微生物模式。我们提出了一种利用基于多个系统的创新策略 鼻腔生物组和甲基组模式与鼻腔上皮转录分离的层次化方法 在急性加重期间(在使用类固醇之前)。我们做好了进行这项工作的独特准备 由于我们建立了巨大的基础设施，作为俄亥俄州儿科哮喘的一部分 存储库，以及我们的多学科团队。我们研究的总体目标是改善人们的生活 来自生活在城市社区的低收入家庭的哮喘儿童。我们提出了两个目标：(1) 通过开展全网事业临床研究项目，为实现整体事业目标作出贡献 并参加事业指导委员会和其他网络职能；(2)开展中心- 与原因目标相一致的特定项目，重点放在经常加重的哮喘表型。

ABSTRACT Asthma is a common, complex and costly pediatric chronic condition in the U.S., resulting in nearly 2 million acute-care visits and $82 billion in overall costs each year. Children of low-income families in urban communities have the highest prevalence of asthma and the greatest disparities in asthma morbidity and mortality. In Hamilton County, OH, over 36,000 children have asthma, >14,000 of whom are Medicaid- insured with a 10-fold higher rate of hospitalization. Asthma exacerbations, acute episodes of increased asthma symptoms and deteriorations in lung function, are a major cause of stress for patients and families. While exacerbations are a prominent feature of poorly controlled and severe asthma, exacerbation rates can be high even in patients with mild asthma and asthma exacerbation frequency can remain unchanged despite intensive controller therapy. Indeed, pediatric studies have revealed that exacerbations continue to occur despite good baseline symptom control. A frequent exacerbator phenotype of asthma (defined by 2 or more exacerbations/year), has been described, but little is known about this asthma subgroup, which disproportionately affects urban populations and is responsible for considerable asthma morbidity and healthcare costs. No specific clinical characteristics can reliably discriminate between frequent and nonfrequent exacerbators highlighting the need for systems level approaches. Our center-specific project will fill this gap in understanding. Our preliminary data reveal differentially expressed and differentially methylated genes in the nasal epithelial of children who are frequent exacerbators and highlight biologic pathways that implicate distinct mechanisms that underlie the frequent exacerbator phenotype. We will test the hypothesis: the frequent exacerbator is a distinct endotype of asthma that is characterized by host nasal epithelial transcriptomic and/or DNA methylomic patterns that distinguish the frequent exacerbator from asthmatic children who are not frequent exacerbators, and that these patterns are, in part, triggered by distinct nasal microbial patterns. We propose an innovative strategy utilizing multiple systems-based approaches that layer host nasal biome and methylome patterns with nasal epithelial transcriptomics taken during an acute exacerbation (before administration of steroids). We are uniquely poised to conduct this study due to the tremendous infrastructure that we have established as part of the Ohio Pediatric Asthma Repository, and our multidisciplinary team. The overall objective of our studies is to improve the lives of children with asthma from low-income families who live in urban communities. We propose to 2 aims: (1) To contribute to the overall CAUSE goals by conducting network-wide CAUSE clinical research projects and participating in the CAUSE Steering Committee and other network functions; (2) To conduct a center- specific project aligned with CAUSE goals focused on the frequent exacerbator asthma phenotype.