): Cell migration and proliferation occur concordantly in a wide variety of normal and pathophysiological processes. For example, normal wound healing in skin requires fibroblasts to proliferate and invade the fibrin clot to regenerate dermal matrix, endothelial cells to proliferate and migrate in the wound to form new blood vessels, and overlying epithelial cells to proliferate and migrate from the wound margins across the newly-formed dermis. Both intracellular and extracellular molecular components involved in proliferation and migration are being identified at a rapid rate. Much overlap exists in the signaling molecules involved in both processes. How does the cell take information from such overlapping sets of stimuli and process it to achieve different responses? In addition to the identity of specific molecules involved, the overall context of adhesion ligand and growth factor ligand presentation must be considered to understand how a cell integrates stimuli to achieve a precise response. This includes the relative concentrations, spatial arrangements, and kinetics of ligand presentation and receptor activation. Parsing how each of these factors contribute to the overall integrated cell response is essential in developing a rational approach to genetic, pharmacologic, or biomaterials-based interventions in events mediated by these processes. The overall goal of this research is to implement a model system in which key variables can be systematically controlled by a combination of biochemical and physical means, thereby illuminating general phenomena. Biochemical approaches to probing mechanisms and interactions are fairly well developed, but physical approaches directed at the same questions are relatively lacking. The proposed work emphasizes complementary techniques and significant development of physical approaches. It focuses specifically on probing how the spatial organization, magnitude, and kinetics of growth factor receptor activation influence cell proliferation and migration, against a defined context of adhesion receptor ligation, using synthetic polymers as the means of physical control and fibroblasts stimulated via the epidermal growth factor receptor (EGFR) as a model cell system with clinical relevance.
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