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.
|Hoard, Brittany; Jacobson, Bruna; Manavi, Kasra et al. (2016) Extending rule-based methods to model molecular geometry and 3D model resolution. BMC Syst Biol 10 Suppl 2:48|
|Kerketta, Romica; HalÃ¡sz, ÃdÃ¡m M; Steinkamp, Mara P et al. (2016) Effect of Spatial Inhomogeneities on the Membrane Surface on Receptor Dimerization and Signal Initiation. Front Cell Dev Biol 4:81|
|Levin, Drew; Forrest, Stephanie; Banerjee, Soumya et al. (2016) A spatial model of the efficiency of T cell search in the influenza-infected lung. J Theor Biol 398:52-63|
|Winner, Kimberly R Kanigel; Steinkamp, Mara P; Lee, Rebecca J et al. (2016) Spatial Modeling of Drug Delivery Routes for Treatment of Disseminated Ovarian Cancer. Cancer Res 76:1320-34|
|Meddens, Marjolein B M; Liu, Sheng; Finnegan, Patrick S et al. (2016) Single objective light-sheet microscopy for high-speed whole-cell 3D super-resolution. Biomed Opt Express 7:2219-36|
|Hansen, Scott G; Wu, Helen L; Burwitz, Benjamin J et al. (2016) Broadly targeted CD8âº T cell responses restricted by major histocompatibility complex E. Science 351:714-20|
|Marjon, K D; Termini, C M; Karlen, K L et al. (2016) Tetraspanin CD82 regulates bone marrow homing of acute myeloid leukemia by modulating the molecular organization of N-cadherin. Oncogene 35:4132-40|
|Fricke, G Matthew; Letendre, Kenneth A; Moses, Melanie E et al. (2016) Persistence and Adaptation in Immunity: T Cells Balance the Extent and Thoroughness of Search. PLoS Comput Biol 12:e1004818|
|Lin, Jia; Wester, Michael J; Graus, Matthew S et al. (2016) Nanoscopic cell-wall architecture of an immunogenic ligand in Candida albicans during antifungal drug treatment. Mol Biol Cell 27:1002-14|
|Termini, Christina M; Lidke, Keith A; Gillette, Jennifer M (2016) Tetraspanin CD82 Regulates the Spatiotemporal Dynamics of PKCÎ± in Acute Myeloid Leukemia. Sci Rep 6:29859|
Showing the most recent 10 out of 104 publications