Multi-omics of the Frequent Exacerbator Asthmatic

频繁加重哮喘的多组学

• 批准号: 10197294
• 负责人: Gurjit K. Khurana Hershey
• 金额: $ 45.2万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-09 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10197294
• 关键词: Acute; Affect; Asthma; Biological; Characteristics; Child; Childhood; Childhood Asthma; Chronic; Clinical; Clinical Research; Complex; County; DNA; Data; Deterioration; Economics; Family; Foundations; Frequencies; Genes; Goals; Health; Health Care Costs; High Prevalence; Infrastructure; Medicaid; Morbidity - disease rate; Nasal Epithelium; Nose; Ohio; Pathway interactions; Patients; Pattern; Phenotype; Public Health; Research Project Grants; Risk; Site; Steroids; Stress; Subgroup; Symptoms; System; Testing; Therapeutic Intervention; Translational Research; Urban Community; Urban Population; Visit; acute care; asthma exacerbation; asthmatic; base; cost; design; differential expression; experience; high risk; hospitalization rates; improved; inner city; innovation; lower income families; methylome; methylomics; microbial; mortality; multidisciplinary; multiple omics; novel; psychologic; pulmonary function; repository; research study; social; success; targeted treatment; transcriptomics

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.

抽象的 哮喘是美国常见，复杂且昂贵的儿科慢性病，导致近200万 急性护理访问和每年820亿美元的总成本。城市低收入家庭的孩子 社区的哮喘患病率最高，哮喘发病率最大 死亡。在俄亥俄州汉密尔顿县，超过36,000名儿童患有哮喘，其中14,000人是医疗补助 保险率高10倍。哮喘恶化，急性发作增加 肺功能的哮喘症状和恶化，是患者和家庭压力的主要原因。 虽然恶化是控制较差和严重哮喘的突出特征，但加剧率 即使患有轻度哮喘和哮喘恶化频率的患者也可能很高 尽管进行了密集的控制器疗法。确实，小儿研究表明，恶化继续 尽管控制良好，但仍会发生。哮喘的频繁恶化表型（由 已经描述了2个或以上的加重/年），但对此哮喘亚组知之甚少 不成比例地影响城市人口，并负责大量的哮喘发病率和 医疗保健费用。没有特定的临床特征可以可靠地区分频繁和 非频繁的加剧者强调了对系统级方法的需求。我们的中心特定项目 将填补这一差距。我们的初步数据揭示了差异表达和差异 频繁恶化并突出生物学的儿童的鼻皮上上皮中的甲基化基因 涉及频繁恶化表型基础的不同机制的途径。我们将 测试假设：频繁的恶化是哮喘的独特内部型，以主机为特征 鼻上皮转录组和/或DNA甲基甲基组模式，区分频繁的恶化 从不常见的哮喘儿童出发，这些模式在某种程度上触发了 通过不同的鼻微生物模式。我们提出了一种利用多个基于系统的创新策略 该层的方法具有鼻上皮转录组学的鼻腔生物组和甲基化模式 在急性加重期间（服用类固醇）。我们有独特的准备进行 由于我们已确立为俄亥俄州小儿哮喘的一部分的巨大基础设施而导致的研究 存储库和我们的多学科团队。我们研究的总体目的是改善 居住在城市社区的低收入家庭哮喘的儿童。我们提出2个目标：（1） 通过进行网络范围的临床研究项目来促进总体原因目标 并参加因果指导委员会和其他网络职能； （2）进行中心 - 特定的项目与因素目标一致，该目标集中在频繁的恶化哮喘表型上。