The objective of this research proposal is to delineate the overall contribution and potential mechanisms that complement utilizes to mediate the pathogenesis of allergic lung disease.
The specific aims of this proposal are driven by the central hypothesis that complement activation products regulate key features of allergen-induced airway disease, including airway hyperresponsiveness (AHR) and acute airway inflammation. The results of this proposal will facilitate the evaluation of complement as a possible therapeutic target in the treatment of asthma. An allergen-induced model of pulmonary allergy in mice with specific complement deficiencies will be used to identify the complement pathways, activation fragments, and receptors that are potentially important in mediating the pathogenesis of allergic lung disease. The complement-deficient animals that are subjected to the model will be examined for attenuation of pathological and physiological hallmarks of asthma, including AHR, airway mucus hypersecretion, elevated IgE levels and lung eosinophils. The Th2 cytokines (IL-4, IL-5, IL-13) that have been proposed to play a pivotal role in asthma will also be examined for altered expression. In addition to the murine experimental allergic model, studies with human T-cells as well as other leukocytes isolated from patients with allergic lung disease will be used to examine potentially altered complement mediated cellular responses in asthma.
Four specific aims are proposed to accomplish the research goals: 1) to examine the importance of each complement activation pathway in eliciting the asthma associated responses in an allergen-induced model of pulmonary allergy, 2) to determine how the complement anaphylatoxin receptors (C3aR and C5aR) affect the asthma associated responses in an allergen-induced model of pulmonary allergy, 3) to determine how the fifth complement component (C5) affects the asthma associated responses in an allergen-induced mouse model of pulmonary allergy, and 4) to determine the biological effects of the complement anaphylatoxins (C3a and C5a) in regulating T-cell mediated responses in asthma. ? ?
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