Project: Research project

Project Details


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

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 date3/1/982/29/04


  • Structural Biology


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