The overall objective of this R21 application, which is a step toward attainment of our long-term goal, is to prove/refute the concept that fluorescent plasma oxidative stress products (FPOP) are biologically relevant biomarkers of diesel exhaust particle (DEP) exposure-induced oxidative stress and/or markers of disease severity in asthmatic children. Currently, there remains an incomplete understanding of the extent to which DEP from truck traffic modifies asthma and comorbid allergic disease. The lack of biological markers of DEP exposure, which would enable physicians to make the distinction between actual exposure in one child and biologically relevant or effective DEP exposure leading to disease in another child, continues to hamper development of therapies to prevent or attenuate disease. To test the hypothesis that high levels of DEP exposure will significantly increase systemic oxidative stress and that measurement of oxidative stress will better predict risk of severe childhood asthma and allergic disease burden than estimation of actual DEP exposure alone, the following two specific aims will be pursued: 1) to determine if systemic oxidative stress products are internal markers of biologically relevant DEP exposure in asthmatic children (exposure-biomarker relationship), and 2) to determine if systemic oxidative stress products are predictive of more severe childhood asthma and greater allergic disease burden (biomarker-disease relationship). The study capitalizes on the distinctive Cincinnati Children's Hospital Medical Center Pediatric Asthma and Allergy Study, unique ability to measure levels of systemic oxidative stress products and estimate DEP exposure in a highly exposed and significantly affected community. Primary outcomes will include the level of systemic oxidative stress products (Aim 1) and asthma defined by physician diagnoses/pulmonary function tests, symptom scores and quality of life measures (Aim 2). Secondary outcomes will include the burden and severity of existing co-morbid allergic conditions. To identify children at risk for more severe asthma and allergic disease burden, the predictive values of systemic oxidative stress products and estimated DEP exposure on severe asthma will be directly compared. The influences of polymorphisms in genes within the antioxidant/oxidative stress and inflammatory pathways, demographic factors and other important inflammatory oxidative stress-inducing exposures will be evaluated as potential confounders and/or modifiers. Regardless of the findings, this proposed exploratory R21 is significant because it will diminish the risk associated with more definitive studies seeking to discover biomarkers to identify children predisposed to more severe asthma and allergic disease following environmental exposures. If the endeavor supports the central hypothesis, completion of the study will open the door for efforts seeking first to better characterize relationships between DEP exposure, oxidative stress and asthma and ultimately to optimize asthma prevention approaches, develop and tailor novel therapies, and strengthen public health policies based on knowledge of environmental exposure.
This R21 proposal is significant to public health because it will determine if products of oxidative stress are biologically relevant biomarkers of diesel exhaust exposure-induced oxidative stress and asthma severity in children. Consequently, these and planned future efforts will underscore the importance of environmental exposures in asthma treatment, development of diagnostic tools and new evidenced-based environmental policies.
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