PROJECT SUMMARY/ABSTRACT The overall goals of our Childhood Asthma in Urban Settings (CAUSE)-Leadership Center proposal are to provide administrative leadership and support to develop and conduct collaborative research to address high priority unmet needs for childhood asthma in urban communities, including: a) developing strategies to prevent asthma, b) improving treatment and inhibiting progression, c) reducing severe exacerbations, and d) defining endotypes of respiratory health and disease. Four hypotheses are proposed to accomplish these goals. First, supplementation with immune modulating bacteria in infancy will prevent the early life perturbations in the gut microbiome that have been associated with risk for the development of allergic sensitization and asthma, and will promote airway mucosal immune development. Second, given the importance of cockroach (CR) allergy and exposure to asthma morbidity in urban children, CR immunotherapy will improve asthma control and reduce disease progression. Third, we propose that transcriptional analysis of airway cells will define T2-low mechanisms that contribute to both non-atopic and atopic asthma and provide new insights into treatment. Finally, multi-omics evaluation of airway cells and secretions obtained during severe exacerbations leading to ED visits and hospitalizations will reveal novel mechanistic pathways to inform improved treatment and prevention. We propose five protocols to test these hypotheses: 1. Urban Environment and Childhood Asthma study (URECA) 2. Effects of a Microbial Supplement (STMC-103H) on Microbial Colonization and Immune Development 3. Cockroach (CR) Immunotherapy (IT) in Urban Children with Moderate-Severe Asthma Protected by Omalizumab 4. Pathogenesis and Mechanisms of T2-low (Non-Atopic) Asthma 5. Severe Asthma Exacerbations in the Emergency Department (ED) and Hospital: Identifying Targets for Prevention and Treatment It is our expectation that our proposed CAUSE research program will provide critical information needed to recognize asthma phenotypes and endotypes in urban children, improve treatment of asthma and establish direction for prevention. Collectively, these studies will continue the rigorous programmatic approach of the NIAID Asthma Networks towards achieving the long-term goals of disease modification and prevention of disease in high-risk children of low-income families living in urban communities.

PROJECT NARRATIVE Asthma disproportionately affects children in urban communities in the United States and imposes a great personal and health care burden. Despite treatment advances, a significant proportion of patients do not achieve disease control and continue to have high levels of morbidity and currently no intervention has proven to either prevent or cure this disease. By identifying and addressing these unmet needs in this application, we propose to improve current asthma care in urban children, pursue disease modification, and ultimately develop effective strategies to prevent asthma.