T-helper 2-low pediatric asthma endotypes: omics, biomarkers, and clinical characteristics

ABSTRACT Kristina Gaietto, MD, MPH, is an Instructor of Pediatrics in the Division of Pulmonary Medicine at the University of Pittsburgh Medical Center Children's Hospital of Pittsburgh (CHP). Her proposal presents a five-year mentored clinical scientist research career development plan to improve diagnostic methods for and elucidate pathogenic mechanisms of T-helper 2 (T2)LOW asthma endotypes in children. A growing body of evidence suggests that T2LOW asthma, which is comprised of T-helper 17 (T17)HIGH and T2LOW/T17LOW endotypes, constitutes over half of childhood asthma. However, T2LOW asthma has been poorly characterized and lacks targeted treatment options compared to T2HIGH asthma, resulting in disparate care for children with T2LOW asthma. Leveraging her and her colleagues’ innovative discovery of pediatric nasal epithelial transcriptomic endotype profiles, based on expression of eight previously identified “signature genes”, her Aims will 1) identify serum protein biomarkers for T2LOW endotypes, 2) test if exposure to violence and violence-related distress are associated with the T17HIGH endotype, and 3) assess if endotype profile changes after 6-12 months, and if so, which exposures or characteristics are associated with endotype transitions. She has already found that aggregate serum concentration of three T17 signature gene proteins is associated with the T17HIGH transcriptomic endotype profile, and that exposure to violence is associated with T17HIGH asthma in Puerto Rican youth, providing compelling preliminary data for her proposal. She will utilize existing biospecimens from four established studies of children with asthma to carry out Aims 1-2 and will recruit a cohort of pilot cohort of 30 children to complete Aim 3. This proposal builds upon Dr. Gaietto's prior research on asthma, psychosocial stress, and endotypes; her strong foundation in epidemiology, biostatistics, and Statistical Analysis System (SAS) coding; and her increasing experience in transcriptomics and R coding. Her career development plan incorporates additional training in proteomics, machine learning, and study design and preparation of an R01 proposal. She has assembled a superb multidisciplinary team to provide guidance as she carries out her Aims: Juan Celedón, MD, DrPH (asthma transcriptomics, epidemiology), Wei Chen, PhD (multi-omics data processing, machine learning), Anna Marsland, PhD (biological responses to stress), John Alcorn, PhD (T17 immune responses), and James Floyd, MD, MS (proteomics). She will carry out her proposal at the University of Pittsburgh, an ideal environment with abundant resources and a strong track record of securing NIH funding. This award will prepare her to submit an R01 application for a longitudinal study of pediatric endotypes in a large, multiethnic cohort of youth to functionally validate the biomarkers identified in this proposal and to study if and how asthma endotypes transition over time, and which exposures, such as chronic psychosocial stress, influence transitions between endotypes.