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.
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