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，对生活在城市低收入地区的儿童造成不成比例的影响。 收入设置。以前的研究已经确定了多种病理生物学亚型(即内型)。 儿童哮喘，特别是呼吸道2型炎症高(T2-High)哮喘内型。内型 对哮喘的理解导致了通过个性化治疗更好地管理哮喘。然而，哮喘 内型研究仍处于初级阶段，许多儿童疾病的病理生物学机制 仍有待确定。特别是，呼吸道内型发育的时机和机制以及 与肺功能障碍的关系尚不清楚。科罗拉多大学医学院事业 临床研究中心项目WINDOWS试图确定呼吸道内型发育的关键窗口 这会导致肺功能障碍和疾病，为哮喘预防提供潜在的靶点。Windows是一种 高危城市儿童早期生命纵向队列研究绘制发育分子步骤图 导致早期肺功能缺陷，并最终导致儿童持续哮喘的呼吸道内型。 我们正在从城市低收入家庭中招募1.5-3岁的幼儿，这些家庭至少有三年的历史 对于哮喘持续风险最高的儿童，需要治疗的喘息或哮喘发作需要补充。 他们将在四年多的时间里接受年度呼吸道分子内切分型和肺功能评估。 至6-7岁，届时将确定持续性哮喘状态。鼻腔RNA序列测定 在儿童早期获得的呼吸道样本将揭示两者背后的机制 T2-高哮喘和非T2-高哮喘，这将与使用强制 振荡技术和阻抗气体描记术。比较患有和不患哮喘的受试者 将使我们能够区分与病情进展相关的呼吸道内型和肺功能表型特征 从早年的高危状态到儿童哮喘。窗口的目的是1)描述轨迹 肺功能和喘息表型从早年到儿童期的进展 幼儿患哮喘的高危人群；2)呼吸道上皮转录特征 从幼年到童年，儿童哮喘的高危儿童；以及3)确定 早期生命中呼吸道转录组特征与肺功能指标的关系及其如何 早期生命、分子和生理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呼吸道功能障碍在儿童哮喘发展中的作用 利用创新的方法研究早期生命的呼吸道生物学和生理学，这将填补 了解呼吸道弹性和哮喘预防。

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.