Cytokines & transcriptomes in rhinovirus bronchiolitis and risk of incident asthma

细胞因子

基本信息

批准号：
9144857
负责人：
Kohei Hasegawa
金额：
$ 25.5万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-15 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9144857
关键词：
4 year old Adrenal Cortex Hormones Affect African American Age Allergic Ancillary Study Antibodies Aspirate substance Asthma Biological Markers Breathing Bronchiolitis CCL7 gene Cells Child Childhood Childhood Asthma Chronic lung disease Cohort Studies Collaborations Data Diagnosis Early identification Educational workshop Enrollment Epithelial Experimental Models Foundations Funding Gene Expression Gene Expression Profile Goals Health Hispanics Hospitalization Individual Infant Infection Interleukin-13 Interleukin-4 International Intervention Interview Knowledge Link Lower Respiratory Tract Infection Mediator of activation protein Medical Records Messenger RNA MicroRNAs Mus National Heart, Lung, and Blood Institute Natural Immunity Outcome Parents Physicians Population Preventive Intervention Primary Prevention Recurrence Reporting Research Research Personnel Respiratory syncytial virus Rhinovirus Risk Role Signal Pathway Specimen Systems Biology TSLP gene Testing Th2 Cells Time United States National Institutes of Health Validation Wheezing allergic response asthmatic biobank biomarker identification cohort critical period cytokine early childhood follow-up high risk indexing infancy innovation interest lung development novel marker patient population prevent primary outcome prospective response targeted treatment therapeutic target transcriptome transcriptomics

项目摘要

DESCRIPTION (provided by applicant): Rhinovirus (RV) lower respiratory infection in early childhood, such as RV bronchiolitis, is associated with a high risk of incident asthma. However, it remains unclear which infants with RV bronchiolitis will develop asthma and which will not; this knowledge gap has hindered primary prevention efforts. Our long-term goal is to develop primary prevention interventions for infants at high risk of asthma. The overall objective of this R21 application is, in the airway of 151 infants hospitalized with RV bronchiolitis, to discover modifiable factors that predict incident asthma. We will achieve this objective by using the biorepository from a 17-center, prospective cohort study called the 35th Multicenter Airway Research Collaboration (MARC-35) (U01 AI- 87881; Camargo, PI) that completed enrollment of 925 infants hospitalized with bronchiolitis. In this diverse U.S. cohort (~52% African-American or Hispanic), investigators have collected nasopharyngeal aspirate at the index hospitalization. Follow-up data include biannual parent interviews and annual review of medical records, which provide >90% follow-up to date. For timing reasons, the primary outcome of this R21 application is physician-diagnosed asthma by age 4 years. The central hypothesis is that, in the 151 infants with RV bronchiolitis, activated microRNA (e.g., miR-147b, miR-375) - thymic stromal lymphopoietin (TSLP) - T helper (TH)2 cytokine pathway signaling is a predictor of incident asthma. The hypothesis has been generated from strong preliminary data using the MARC-35 biorepository. The rationale for the proposed research is that identification of very early (infanc) markers of incident asthma will enable early prediction of asthma risk, thereby providing a new and potentially critical window for primary intervention. The central hypothesis will be tested by pursuing two specific aims: 1) To determine the relations of airway cytokines (TSLP, TH2 cytokines) in infants with RV bronchiolitis to risk of incident asthma; and 2) To use a transcriptomic approach to identify a global gene expression profile (i.e., mRNA and microRNA) in the airway of infants with RV bronchiolitis that predicts incident asthma. The approach is highly innovative because the proposed R21 will use specimens of infants during RV infection (median age, 3.7 months) and thereby focus on very early identification of increased asthma risk during a critical period of lung development; and because the study will support a new avenue for primary prevention through developing targeted interventions (e.g., anti-TSLP antibody, microRNA-targeting therapy). The study advances research on the primary prevention of asthma, and matches well with the goals indicated by the 2013 NHLBI Workshop on the Primary Prevention of Chronic Lung Diseases.

描述（由申请人提供）：儿童早期的鼻病毒（RV）下呼吸道感染，例如 RV 细支气管炎，与发生哮喘的高风险相关。然而，尚不清楚哪些患有 RV 细支气管炎的婴儿会发展为哮喘，哪些不会。 ; 这知识差距阻碍了初级预防工作。我们的长期目标是为哮喘高危婴儿制定初级预防干预措施，该 R21 应用的总体目标是在 151 名因 RV 细支气管炎住院的婴儿的气道中发现可改变的方法。我们将通过使用名为第 35 届多中心气道研究合作 (MARC-35) 的 17 中心前瞻性队列研究的生物样本库来实现这一目标。（U01 AI-87881；Camargo，PI）完成了 925 名因细支气管炎住院的婴儿的入组。在这个多样化的美国队列中（约 52% 为非洲裔美国人或西班牙裔），研究人员收集了住院期间的鼻咽抽吸物。包括每年两次的家长访谈和每年一次的病历审查，迄今为止提供超过 90% 的随访。由于时间原因，此 R21 申请的主要结果是。医生在 4 岁时诊断出哮喘。核心假设是，在 151 名患有 RV 细支气管炎的婴儿中，激活的 microRNA（例如 miR-147b、miR-375）- 胸腺基质淋巴细胞生成素 (TSLP) - T 辅助细胞 (TH)2细胞因子事件途径信号传导是哮喘的预测因素该假设是根据 MARC-35 生物数据库的有力初步数据得出的。拟议的研究是，识别哮喘事件的极早期（婴儿）标志物将能够早期预测哮喘风险，从而为初级干预提供一个新的、潜在的关键窗口，将通过追求两个具体目标来检验中心假设：1）。确定患有 RV 细支气管炎的婴儿的气道细胞因子（TSLP、TH2 细胞因子）与哮喘发生风险的关系；2) 使用转录组学方法来确定 RV 细支气管炎婴儿中的整体基因表达谱（即 mRNA 和 microRNA）。该方法具有高度创新性，因为拟议的 R21 将使用 RV 感染期间的婴儿样本（中位年龄为 3.7 个月），从而重点关注关键时期哮喘风险增加的早期识别。由于该研究将通过开发有针对性的干预措施（例如抗 TSLP 抗体、microRNA 靶向治疗）来支持一级预防的新途径，因此该研究推进了哮喘一级预防的研究。与 2013 年 NHLBI 慢性肺病一级预防研讨会提出的目标非常吻合。