IL-13 is a key mediator of allergic asthma. IL-13 mediates its effects via a complex receptor system, which includes IL-4Ra (IL-4 receptor alpha chain) and two other cell surface proteins, IL-13Ra1 and IL-13Ra2, which specifically bind IL-13. IL-4Ra and IL-13Ra1 are required for IL-13 signaling, however, little is known the role of IL-13Ra2 in IL-13 responses. IL-13Ra2 has been postulated to be a decoy receptor since it binds IL-13 with high affinity, but does not initiate signaling. Recently, we have observed that over expression of IL- 13Ra2 in the lungs of mice was associated with increased AHR and that IL-13Ra2 deficient mice displayed decreased AHR in allergen-induced model of allergic inflammation. These observations support a more complex role for IL-13Ra2. The central hypothesis of this proposal is that IL-13Ra2 is not a simple decoy receptor, but rather contributes to IL-13 responses. The primary objective of these studies is to elucidate the biologic function(s) of IL-13Ra2 and the mechanisms by which IL-13Ra2 exerts its effects.
The first aim will elucidate the effects of IL-13Ra2 in vivo on IL-13 and IL-4 responses. We will compare allergic inflammation and AHR following IL-13 or IL-4 treatment, and following allergen sensitization and challenge in transgenic mice over expressing IL-13Ra2 in the lungs, IL-13Ra2 deficient mice, and wild type in response to mice and determine how the level of IL-13Ra2 expression alters its contribution to IL-13 responses.
Aim 2 will elucidate the mechanism by which IL-13Ra2 influences IL-13 responses. We will determine whether IL- 13Ra2 alters the kinetics of Stat6 or IRS-2 activation or deactivation in vivo. IL-13Ra2 exists in 3 forms: on the cell surface, in intracellular pools and as a soluble receptor. We will elucidate whether a particular form is related to specific functions of IL-13Ra2. We will also utilize in vitro transfection model to elucidate the role of IL-13Ra2 in IL-13 responses. We will compare transfectants expressing different levels of IL-13Ra2 to determine whether the level of its expression effects its function.
Aim 3 will examine whether internalization of IL-13Ra2 is necessary for its contribution to IL-13 signaling. The experiments proposed herein will provide important novel information about the role of IL-13Ra2 in allergic inflammation, the mechanism by which it exerts its affects, and whether it may be a useful pharmacologic target to modulate the asthma phenotype. ? ? ? ? ?
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