Basophil and mast cell mediator release is a central feature of both acute and chronic allergic reactions. Future therapeutic approaches that depend on regulating secretion from these two cell types will require a detailed knowledge of the mechanisms that regulate the response of these cells to stimulation. This proposal will focus on IgE-mediated secretion from human basophils, examining patient populations in aims 2 and 4 and elucidating signaling pathways in these cells in aims 1 and 3. With the large number of possible signaling pathways suggested by studies in mast cell/basophil cell lines, we have chosen to focus on those which specifically down-regulate ongoing IgE-mediated secretion. There are four aims.
Aim 1 will address the issue of the loss of signaling elements as a result of activation, a form of long term down-regulation. The loss of syk kinase has already been documented in our recent studies and this aim will expand these observations, leading to tests in aim 2 of whether a chronic state of down-regulation can be induced in maturing basophils and whether clinical desensitization (such as used to prepare patients for penicillin use) results from a similar process. In the third aim, we will examine the process of late down-regulation we have called nonspecific desensitization. This form of down-regulation appears to involve regulation of phosphatidyl inositol 3,4,5 phosphate (PIPS).
Sub aims will determine the signaling elements that connect the presence of PIPS to the activation of p21ras/Raf-1, determine the activation and regulation of SHIP1/2, and determine the mechanisms underlying the long term memory (or prior activation) that appear related to SHIP.
In aim 4, a synthesis of our current understanding suggests syk and SHIP expression will be two predictors of two independent characteristics of the IgE-mediated response in human basophils, the cells' sensitivity to stimulation and the maximum release obtainable. A population of subjects will be examined for this relationship.
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