The assembly of plasminogen and plasminogen activators on cell surfaces is a crucial control point for positive regulation of cell surface proteolytic activity necessary in both physiological and pathological processes requiring cell migration. The long-term goal of our laboratory is to understand the mechanisms by which plasminogen binding to cells is regulated, in order to function in physiological and pathological processes. This proposal is based on data demonstrating that up-regulation of plasminogen binding function occurs during differentiation of viable monocytes into viable macrophages. In preliminary studies, we identified three major candidate plasminogen receptors up-regulated in response to M-CSF that have not been recognized previously as plasminogen binding sites on monocytes. The objective of this application is to elucidate the role of M-CSF-up-regulated plasminogen receptors in monocyte/macrophage recruitment. The central hypothesis to be addressed is that plasminogen receptors are up-regulated during monocyte/macrophage maturation and facilitate recruitment of these cells in response to inflammatory stimuli, by promoting plasminogen activation and localizing the proteolytic activity of plasmin on the cell surface. To test this hypothesis we will I) identify the major pro- fibrinolytic plasminogen binding proteins on M-CSF-stimulated cells and quantify their expression during monocyte development in vivo and II) test the hypothesis that M-CSF-up-regulated plasminogen receptors promote plasminogen activation, extracellular matrix degradation and cell migration in vitro and in vivo. We expect that accomplishment of our specific aims will provide fundamental insights that will apply to the regulation of inflammation. Furthermore, because monocyte/macrophage recruitment and infiltration is a key feature of the atherosclerotic lesion, our results should apply to the understanding of atherosclerosis. ? ? ?
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