The IL-4R alpha participates in allergic responses at several levels by functioning as a receptor component for IL-4 and IL-13. IL-4 regulates the differentiation of T-cells to the TH2 type and directs class switching in B-cells to IgE. In addition, IL-4 and IL-13 regulate the adhesive characteristics of endothelial cells thereby promoting tissue infiltration by allergic inflammatory cells, such as eosinophils. These responses are elicited by binding to high affinity receptor complexes and initiating a series of signals dictated by the IL-4Ra. Interestingly, a polymorphism (Q576R in the cytoplasmic region of the huIL-4R alpha has been associated with severity of asthma in patients suggesting that IL-4R alpha signaling strength may play a role in human disease. However, the precise mechanism by which the IL-4R alpha activates and regulates STAT6 signaling is still unclear. as is the extent to which the IL-4Ra participates in the pathogenesis of allergic reactions. Therefore, our broad goal of this renewal application, is to understand the molecular mechanisms of signaling through the IL-4Ra and its contribution to the pathogenesis of asthma. We propose that the kinetics and duration of STAT6 activation may play an important role in the IL-4 and IL-13-induced signaling of allergy-related responses and that signaling by the LL-4Rcz in non-lymphoid cells in the lung substantially contributes to the pathogenesis of allergic asthma. We propose 4 specific aims designed to test these hypotheses as follows. First, we will determine the kinetics and half-life of the IL-4 (and IL-13) -induced activation of STAT6. Second, we plan to determine the mechanism of STAT6 down-regulation. in addition, we plan to define the interaction of the IL-4Ra with signaling molecules potentially involved in the regulation of STAT6. Finally, we will determine the role of STAT6 and the IL-4R alpha in the pathogenesis of asthma.
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