CAUSE Clinical Research Center New York (CAUSE-CRC)

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Project Summary/Abstract Pediatric asthma disproportionately impacts children who live in urban communities partly due to environmental exposure to allergens, stress and air pollution. This project establishes a Clinical Research Center to conduct both network-wide and site-specific clinical studies and trials with the ultimate goal of developing effective asthma treatment or prevention approaches applicable to children residing in low-income urban settings. For a significant number of asthma patients, guideline-directed treatment does not achieve disease control, suggesting the need, and potential benefit, for treatment(s) that are personalized to the phenotype of these patients. As evident by cluster analyses in adults and children, there is a group of severe asthmatics that have fewer characteristics of type 2 inflammation and in whom type 2 cytokine-targeting biologics may be less effective. Children living in inner-cities are exposed and sensitized to allergens, particularly cockroach, triggering type 2 inflammatory response and exposed to high levels of indoor and outdoor irritants and pollutants which can trigger TH1 and TH17 neutrophilic inflammation. There is a need to have a better understanding of mechanisms of non-atopic asthma. Systemic inflammation with IL-6 as a biomarker is a mechanism that is postulated to mediate asthma severity. IL-6 is produced by cells of the immune system and secreted by airway epithelial cells and has been proposed as a potential target for asthma therapy. While cytokine and soluble receptor levels, as well as genetic studies of IL-6R have been examined in relation to asthma, the intrinsic capacity for the receptor to signal within differing phenotypic populations has not. The objective of this study is to determine whether intrinsic signaling responses to circulating IL6 and other cytokines differs between cockroach negative, lower atopic children and cockroach allergic, higher atopic children with moderate to severe asthma. We hypothesize that and the relationship of IL-6 receptor signaling to morbidity. We hypothesize that genetic polymorphisms will modify intrinsic IL-6 signaling and that IL-6 signaling will be a determinant of morbidity. The protocol will test exploratory hypotheses that pollution and stress lead to exacerbations in those with higher intrinsic signaling. To test this hypothesis, we propose a study designed to identify differences in intrinsic IL-6 signaling in children with asthma. The study will include children who: 1) are between the ages of 6 and 20 years; 2) have a history of recurrent wheeze / persistent asthma of at least one year duration; and 3) live in low-income census tracts of U.S. inner-city communities. Studies of intrinsic IL-6 signaling and SNP carrier status will be done on peripheral blood mononuclear cells (PBMC) at baseline. These studies will be done on nasal epithelial cells on a subset of participants. We propose a 12-month follow up at 3-month intervals to prospectively determine the relationship of IL-6 signaling to symptoms and exacerbations.