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.
|Termini, Christina M; Gillette, Jennifer M (2017) Tetraspanins Function as Regulators of Cellular Signaling. Front Cell Dev Biol 5:34|
|Harmon, Brooke; Chylek, Lily A; Liu, Yanli et al. (2017) Timescale Separation of Positive and Negative Signaling Creates History-Dependent Responses to IgE Receptor Stimulation. Sci Rep 7:15586|
|Schwartz, Samantha L; Cleyrat, Cédric; Olah, Mark J et al. (2017) Differential mast cell outcomes are sensitive to Fc?RI-Syk binding kinetics. Mol Biol Cell 28:3397-3414|
|Kocha?czyk, Marek; Kocieniewski, Pawe?; Koz?owska, Emilia et al. (2017) Relaxation oscillations and hierarchy of feedbacks in MAPK signaling. Sci Rep 7:38244|
|Mrass, Paulus; Oruganti, Sreenivasa Rao; Fricke, G Matthew et al. (2017) ROCK regulates the intermittent mode of interstitial T cell migration in inflamed lungs. Nat Commun 8:1010|
|Medina, Christopher S; Manifold-Wheeler, Brett; Gonzales, Aaron et al. (2017) Automated Computational Processing of 3-D MR Images of Mouse Brain for Phenotyping of Living Animals. Curr Protoc Mol Biol 119:29A.5.1-29A.5.38|
|Graus, Matthew S; Neumann, Aaron K; Timlin, Jerilyn A (2017) Hyperspectral fluorescence microscopy detects autofluorescent factors that can be exploited as a diagnostic method for Candida species differentiation. J Biomed Opt 22:16002|
|Mahajan, Avanika; Youssef, Lama A; Cleyrat, Cédric et al. (2017) Allergen Valency, Dose, and Fc?RI Occupancy Set Thresholds for Secretory Responses to Pen a 1 and Motivate Design of Hypoallergens. J Immunol 198:1034-1046|
|Freed, Daniel M; Bessman, Nicholas J; Kiyatkin, Anatoly et al. (2017) EGFR Ligands Differentially Stabilize Receptor Dimers to Specify Signaling Kinetics. Cell 171:683-695.e18|
|Cleyrat, Cédric; Girard, Romain; Choi, Eun H et al. (2017) Gene editing rescue of a novel MPL mutant associated with congenital amegakaryocytic thrombocytopenia. Blood Adv 1:1815-1826|
Showing the most recent 10 out of 123 publications