Our long term goals are to generate synthetic or semisynthetic polymer materials that promote healing and tissue regeneration via precise control of receptor-mediated phenomena involved in cell growth and migration. A major step would be a detailed understanding of the factors that regulate cell responsiveness, not only through identity of the ligands involved, but also how the ligand presentation regulates cell responses to external clues. Evidence indicates that cell proliferation and migration are effected upon the same sets of signals via growth factor receptors and adhesion receptors, primarily integrins. Adhesion receptor occupancy and downstream signals modulate the cell behaviors that occur in response to growth factors. A prototypal growth factor receptor, the epidermal growth factor receptor (EGFR) has been shown to influence cell growth and migration in a broad range of cell types (fibroblasts, epithelial cells, mesenchymal stem cells) and healing situations (skin wound repair, liver regeneration, angiogenesis) We hypothesize that the spatial and temporal nature of EGFR activation and integrin-growth factor receptor communications determine whether the outcome of growth factor-mediated signaling is migration or proliferation. Our foundational model posits that the physical mode of ligand presentation for both adhesion and growth factor receptors will dictate whether the cell behavior is weighted more strongly to proliferation, migration or differentiation. To dissect this, we have developed an inert, PEO-PMMA comb copolymer surface for precise immobilization of growth factor receptor and integrin ligands. Successful studies from our initial funding period lead us to test the following in fibroblasts, endothelial cells and mesenchymal stem cells that form the stromal support tissues. 1. Hypothesis that EGFR cell surface signaling is preferential for cell migration over proliferation . Our initial studies suggest that ultra low affinity ligands, which signal only from the surface, induce motility but not proliferation when presented at limiting concentrations. 2. Hypothesis that level of integrin clustering alters EGF receptor signaling. We have shown that at least microclustering of integrins is required for growth factor signaling. We will now determine the molecular basis. The successful completion of these investigations will not only yield important insights into the cellular controls of integrin and growth factor-induced signaling, but also provide for the creation of synthetic biomaterials scaffolds to promote tissue regeneration. This project focuses on cells that generate the supporting stroma and vasculature. Such a repair promoting scaffold would be of value to patients with non-healing wounds, traumatic or otherwise, and tissue deficits.
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