DESCRIPTION (Adapted from Investigator's Abstract): An allergic response is initiated when allergen molecules direct the clustering of surface bound IgE-receptors, which is accompanied by the activation of one or more tyrosine kinases and subsequent release of histamine, prostaglandins, leukotrienes and cytokines. These agents cause the vascular, muscular and inflammatory responses which result in the clinical symptoms of allergy. The binding of allergens to IgE molecules is the consequence of specific atomic interactions. The polyvalency of allergens result in the aggregation of Ige-receptors and non-covalently associated cytoplasmic kinases. The increased local concentration of kinases and their cognate protein substrates results in a level of phosphorylation above the local concentration of kinases and their cognate protein substrates results in a level of phosphorylation above the threshold required to stimulate multiple signaling pathways and cause release of the mediators of the allergic response. X-ray crystallographic studies will provide the first high resolution crystal structures of prominent allergens. The structural information, when combined with epitope mapping, will provide the sequences, positions and detailed conformations of the epitopes responsible for IgE binding and receptor aggregation. The design of molecules which display reactive epitopes with well defined structural constraints will allow for the evaluation of local epitope concentration and inter-epitope separation on the kinetics and extent of IgE-mediated effector release. These studies will provide novel information about the chemical and physical determinants responsible for epitope recognition and will establish a structural data base for the design of novel univalent peptidomimetic therapeutics targeted to block the initial step in the allergic response. The studies involving structurally defined molecules will provide the first systematic structural study on IgE-receptor clustering events. This includes the effects of local epitope density and inter-epitope spacing on the efficiency of signal transduction. This system will serve as a paradigm for other signal transduction pathways involving receptor clustering events. The four specific aims are: to determine the high resolution X-ray structures of wide spread allergens such as Birch pollen profilin and PhIp2, a major grass pollen allergen; to determine the relevant IgE reactive epitopes of the allergens; to design univalent haptens for allergy therapy; and to determine the basic features of receptor clustering.
|Effective start/end date||3/1/98 → 2/29/04|
- Structural Biology
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