Project 1: Systems level complexity of ITAM signaling Project PI: Wilson Summary Important immunoreceptors of T cells, B cells, mast cells, basophils, dendritic cells and other immune cells bear ITAMs (Immuno Tyrosine-Based Activation Motif) in their cytoplasmic tails. After tyrosine phosphorylation by Src kinases, phospho-ITAMs recruit Syk/ZAP-70 kinases to propagate positive signaling associated with key adaptive and innate immune functions. In this project, STMC investigators apply a multiscale systems biology approach to evaluate the contributions of spatial organization and ligand multivalency on ITAM receptor signal initiation and output. The model system for Aim 1 is the high affinity receptor for receptor (FceRI) on mast cells and basophils. An innovative focus is on natural allergens, based on experiments in human basophils from atopic subjects.
Aim 2 is centered on the C-type lectin receptor, Dectin-1, that recognizes fungal pathogens. High resolution microscopy methods, coupled with quantitative evaluation of ligand- mediated aggregation, are novel features of both experimental aims. The research plan incorporates extensive computational modeling, including molecular structure/dynamics and simulations of cellular signal transduction. Mathematical models will provide predictions to be tested through the innovative application of powerful quantitative fluorescence, electron microscopy and molecular engineering methods.
This project focuses on two members of a large super family of receptors that are critical to immune function. The first receptor is the high affinity IgE receptor, that is the central player in human allergic conditions. For the first time, we will define the critical features of allergens that govern how this receptor is triggered to release histamine and other inflammatory mediators, initiating the allergic response. These critical features include 1) relative abundance of allergen-specific IgE in human allergic subjects and 2) the structural aspects of allergens that crosslink the receptors to start signal transduction. The second receptor is on specialized white cells that respond to fungal infections by recognizing complex sugars. Again, the investigators will investigate the structural aspects of the sugar presentation on the fungal cell wall and how it attracts the immune cells to engulf them. The experimentalists will work closely with mathematicians to better understand these complex processes.
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