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

点击翻译按钮获取中文摘要

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.