Multi-omics of the Frequent Exacerbator Asthmatic

频繁加重哮喘的多组学

• 批准号: 10596089
• 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/10596089
• 关键词: Acute; Affect; Asthma; Biological; Characteristics; Child; Childhood; Childhood Asthma; Chronic; Clinical; Clinical Research; Complex; County; DNA; Data; Deterioration; Disparity; Economics; Family; Frequencies; Genes; Goals; Health; Health Care Costs; High Prevalence; Infrastructure; Medicaid; Methylation; 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; 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 哮喘是美国一种常见、复杂且昂贵的儿科慢性疾病，导致近 200 万人患病 每年的急症护理就诊费用和 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，而且哮喘发病率和患病率差异也最大 死亡。在俄亥俄州汉密尔顿县，超过 36,000 名儿童患有哮喘，其中超过 14,000 名儿童享受医疗补助 - 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给患者和家人带来压力的主要原因。 虽然恶化是控制不佳和严重哮喘的一个显着特征，但恶化率 即使在轻度哮喘患者中也可能很高，并且哮喘发作频率可以保持不变 尽管强化控制治疗。事实上，儿科研究表明病情恶化仍在继续 尽管基线症状控制良好，但仍会发生。哮喘的常见恶化表型（定义为 2 次或以上恶化/年），已被描述，但对该哮喘亚组知之甚少， 不成比例地影响城市人口，并导致相当大的哮喘发病率和 医疗费用。没有特定的临床特征可以可靠地区分频繁发生和 不常见的加剧因素凸显了系统级方法的必要性。我们中心的特定项目 将填补这一理解上的空白。我们的初步数据揭示了差异表达和差异 儿童鼻上皮中的甲基化基因是常见的加重者并突出生物 涉及常见加剧表型背后的不同机制的途径。我们将 检验假设：频繁的加重者是哮喘的一种独特的内型，其特征在于宿主 区分常见加重因素的鼻上皮转录组和/或 DNA 甲基组模式 来自不经常加重的哮喘儿童，并且这些模式在一定程度上是由 通过独特的鼻腔微生物模式。我们提出了利用基于多个系统的创新策略 采用鼻上皮转录组学对宿主鼻生物组和甲基化组模式进行分层的方法 急性发作期间（使用类固醇之前）。我们有独特的准备来开展这项工作 研究归功于我们作为俄亥俄州小儿哮喘中心的一部分建立的庞大基础设施 存储库和我们的多学科团队。我们研究的总体目标是改善人们的生活 来自居住在城市社区的低收入家庭的哮喘儿童。我们提出 2 个目标：(1) 通过开展网络范围内的 CAUSE 临床研究项目，为总体 CAUSE 目标做出贡献 参与 CAUSE 指导委员会和其他网络职能； (2) 开展中心—— 与 CAUSE 目标一致的具体项目侧重于常见的哮喘加重表型。