Asthma is a disease of chronic inflammation marked by periodic bouts of acute exacerbations of airway obstruction, and early sub-clinical eosinophilic pulmonary inflammation precedes the development of asthma in children. Why certain individuals develop asthma and factors contributing to the severity of acute exacerbations remain poorly understood. The ST6Gal-1 sialyltransferase constructs the sialyl 12,6 to Gal21,4GlcNAc glycan structures. Our preliminary data point to a previously unrecognized role of ST6Gal-1 in modulating experimental allergic airway inflammation. Mutant mice with ST6Gal-1 deficiencies have exaggerated acute allergic airway inflammation. Expression of recombinant ST6Gal-1 in vivo can attenuate the pulmonary eosinophilia, suggesting a therapeutic potential for ST6Gal-1. Following induction of experimental allergic airway inflammation, wild-type mice with normal ST6Gal-1 expression profiles had significantly depressed circulatory ST6Gal-1 levels. Therefore, natural circulatory ST6Gal-1 levels and serum sialylation products may have potential in identifying persons at risk for allergic airway disease and as a marker for disease severity. This is an exploratory proposal to test the hypothesis that ST6Gal-1 can regulate allergic respiratory inflammation and to evaluate ST6Gal-1 as a marker for asthma disease severity and as a therapeutic target. Specifically, we propose to 1) determine the extent that pulmonary inflammation and asthma-like pathologies are affected in mutant mice with deficiencies in ST6Gal-1;2) determine the extent that pulmonary inflammation and pathologies can be mitigated by in vivo supplementing of ST6Gal-1;and 3) assess the relationship of circulatory ST6Gal-1 levels in patients with atopic asthma during exacerbations and asymptomatic periods, and normal volunteers. The goal of the proposed research is to generate the foundation data for future efforts that will focus on developing ST6Gal-1 as a potential early predictor and prognostic marker of allergic airway disease and as a therapeutic target for drug development.
PROJECT NARRATIVE Asthma is a disease of chronic inflammation marked by recurring acute bouts of airway obstruction. Our preliminary studies have revealed a previously unrecognized role for the ST6Gal-1 sialyltransferase in modulating the severity of the acute pulmonary inflammation underlying asthma. This is an exploratory proposal to determine the extent that asthma-related pathologies are affected by ST6Gal-1, and to evaluate the potential of ST6Gal-1 as a prognostic marker in atopic asthma and as a target for drug development.
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