Critical Windows in the Development of Asthma Endotypes and Phenotypes in High-Risk Toddlers

项目摘要 哮喘仍然是一个普遍的公共卫生问题，不成比例地影响生活在城市低收入地区的儿童， 收入设置。先前的研究已经鉴定了多种病理生物学亚型（即，内型） 儿童哮喘，特别是气道2型炎症高（T2-高）哮喘内型。内型的 对哮喘的理解导致通过个性化治疗更好地管理哮喘。然而，哮喘 内型研究仍处于起步阶段，在许多儿童中， 还有待确定。特别是，气道内型发展的时间和机制， 与肺功能障碍的关系尚未探索。科罗拉多大学医学院 临床研究中心项目WINDOWS旨在确定气道内型开发的关键窗口 导致肺功能障碍和疾病，为哮喘预防提供了潜在的目标。Windows是一个 一项针对高危城市儿童的早期纵向队列研究，绘制了发展中的分子步骤 导致早期肺功能缺陷，最终导致儿童哮喘持续存在。 我们正在招募1.5-3岁的幼儿，来自城市低收入家庭，至少有三年的历史 需要治疗的喘息或哮喘发作，以丰富哮喘持续性风险最高的儿童。 他们将被随访四年以上，每年进行气道分子内定型和肺功能评估 至6-7岁，此时将确定持续哮喘状态。鼻黏膜RNA序列分析 在儿童早期获得的气道样本将揭示这两种机制的新见解， T2高和非T2高哮喘，这将与使用强制性呼吸机测量气道阻塞相结合。 振荡技术和阻抗呼吸描记术。比较患有和未患有哮喘的受试者 将使我们能够区分与进展相关的气道内型和肺功能表型特征， 从早期的高危状态到儿童哮喘。WINDOWS的目标是1）描述轨迹 肺功能和喘息表型从生命早期到儿童期的进展， 儿童哮喘高危幼儿; 2）气道上皮细胞的转录特征 从早期生活到儿童期，儿童哮喘的高风险幼儿;和3）确定 生命早期气道转录组谱与肺功能指标之间的关系以及这些指标如何变化 早期生命分子和生理学特征与儿童哮喘的临床特征有关。 WINDOWS将通过以下方式深入了解气道功能障碍在儿童哮喘发展中的作用： 使用创新的方法来研究生命早期的气道生物学和生理学，这将填补差距， 了解气道弹性和哮喘预防。

Project Summary Asthma remains a prevalent public health concern that disproportionately affects children living in urban low- income settings. Previous studies have identified multiple pathobiological subtypes (i.e., endotypes) of childhood asthma, notably the airway Type 2 inflammation high (T2-high) asthma endotype. Endotypic understanding of asthma has led to better asthma management through personalized therapy. Yet, asthma endotype research is still in its infancy, and the pathobiologic mechanisms driving disease in many children remains to be determined. In particular, the timing and mechanisms of airway endotype development and relationships to lung dysfunction are unexplored. The University of Colorado School of Medicine CAUSE Clinical Research Center project WINDOWS seeks to identify critical windows in airway endotype development that lead to lung dysfunction and disease, providing potential targets for asthma prevention. WINDOWS is an early-life longitudinal cohort study of high-risk urban children that maps the molecular steps in the development of airway endotypes, which lead to early-life lung function deficits, and eventually persistent childhood asthma. We are recruiting toddlers age 1.5-3 years from urban, low-income families with a history of at least three wheezing or asthma episodes requiring treatment to enrich for children at highest risk of asthma persistence. They will be followed over four years with annual airway molecular endotyping and lung function assessments to age 6-7 years, when persistent asthma status will be ascertained. Sequential RNA sequencing of nasal airway samples obtained during early childhood will reveal new insights into the mechanisms underlying both T2-high and non-T2-high asthma, which will be coupled with measures of airway obstruction using the forced oscillation technique and impedance pneumography. Comparing subjects that do and do not develop asthma will allow us to distinguish airway endotype and lung function phenotype features associated with progression from an early life high risk state to childhood asthma. The aims of WINDOWS are to 1) characterize trajectories of lung function and progression of wheezing phenotypes from early life through childhood in a cohort of toddlers at high risk for developing childhood asthma; 2) transcriptionally characterize the airway epithelium from early life through childhood in toddlers at high risk for developing childhood asthma; and 3) determine the relationship between airway transcriptome profiles and measures of lung function in early life and how these early life molecular and physiologic features relate to the clinical characteristic of childhood asthma. WINDOWS will provide insights into the role of airway dysfunction in the development of childhood asthma by using innovative methods to investigate airway biology and physiology in early life, which will fill the gap in understanding airway resilience and asthma prevention.