Epithelial Genes in Allergic Inflammation
In collaboration with Dr. Hershey’s NIAID funded Asthma and Allergic Diseases Cooperative Research Centers U19 grant, we are investigating biomarkers of disease progression from early life atopic dermatitis to asthma in children. The overarching hypothesis of this cooperative agreement is that homeostatic mechanisms that normally sustain epithelial barrier integrity, upon dysregulation, promote type 2 inflammation and contribute to the persistence and progression of allergic diseases.
Mechanisms of Progression of Atopic Dermatitis to Asthma in Children – The MPAACH Cohort
Epithelial cells are the first line of defense that interfaces with the environment and initiates the response to environmental triggers. Dysregulation may affect subsequent development of allergic inflammation and disease. Eczema or atopic dermatitis (AD) has been highlighted as the first step in the “atopic march”, whereby AD typically predates the development of other allergic disorders later in life. It has been estimated that one-third to half of patients with AD will develop asthma, however the mechanisms that promote disease progression remain unclear. We are investigating the role of synergistic biomarkers of disease progression from early life AD to school age asthma. We aim to define the key epithelial cell derived drivers of persistent immune dysregulation that promote and predict disease progression from AD to asthma among children.
Role and Regulation of TSLP in Childhood Allergic Disease
Thymic stromal lymphopoietin (TSLP) is a major epithelial cytokine that is strongly implicated in the pathogenesis of AD, allergic sensitization, and asthma. Antigen exposure in the skin in the context of TSLP is sufficient to induce AD and airway inflammation in the lung, suggesting that skin-derived TSLP is sufficient to drive the progression of AD to asthma. Evidence suggests TSLP may be an important driver of progression of a subset of early allergic phenotypes to asthma. We are working to elucidate the mechanisms by which barrier defects in human epidermal keratinocytes effect TSLP transcription; the impact of known risk and protective alleles on regulation; and the utility of markers of TSLP variation as predictors of disease progression to asthma in children.
The Children’s Respiratory and Environmental Workgroup (CREW) is part of the NIH sponsored Environmental Influences on Child Health Outcomes (ECHO) Consortium that aims to identify phenotypes of childhood asthma across 12 U.S. birth cohorts. Our site was awarded an NIH UH3 grant as a site sub-contract with ECHO/CREW to recruit a cohort of 400 children at risk for developing asthma. This is a phase II extension study from the Cincinnati Childhood Allergy and Air Pollution Study Birth Cohort (CCAAPS). We will follow these children over a period of five years to identify the relationship between childhood asthma and early-life environmental factors that cause childhood asthma and targets for future efforts aimed at preventing childhood asthma.