Project 3 Angela Wandinger-Ness, PI Summary Receptor endocytosis is a fundamental cellular process that regulates the quality and duration of signal transduction. This project uses a systems-based approach to comparatively evaluate the endocytic trafficking of two receptors (FceRI immunoreceptor and the Epidermal Growth Factor Receptor, erbB1) in an immune cell line. The interdisciplinary team will test the hypothesis that ligand-dependent, receptor-specific signaling dictates spatial and temporal regulation of membrane trafficking machinery and pathway selection.
Three specific aims will examine how: 1) receptors are selectively internalized at the plasma membrane through clathrin-dependent and independent pathways;2) endocytic machinery responds to and is regulated by "input signals" from receptor cargo;and 3) receptor signaling is controlled by location and via specific interactions with endocytic proteins. Sophisticated spatiotemporal imaging will span nano to micron scales and will be integrated with biochemical analyses. The experimental data sets will iteratively inform rule-based mechanistic and population dynamics models. Outcomes from this research plan will reveal new information on pathway saturation limits, receptor competition for limiting components, among other parameters, that cannot be extrapolated when analyzing receptors individually.
This project will take a systems biology approach to understand how two apparently distinct cellular processes - receptor endocytosis and receptor signaling - are linked in time and space. We expect to show that these processes are tightly coupled, orchestrating the cellular responses by feedback loops and interacting regulatory steps. Experimentalists on the team will use very innovative imaging methods to capture the sequences of events and the spatial relationships of players in both pathways. We will search for unknown players through targeted genetic screening and then validate these hits with novel microscopy and biochemical approaches. The large, complex data sets will be analyzed by mathematical modeling specialists. The interdisciplinary teams will work in coordinated fashion to use computation and bench skills to understand these very complex, inter-connected 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|
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