The low density lipoprotein receptor-related protein (LRP) is a large endocytic receptor present on the surface of most cell types, where it binds extracellular ligands and targets them to lysosomes for degradation The fact that most LRP ligands are generated during inflammation and/or wound repair processes led us to speculate that the function of LRP may extend beyond that of a catabolic one, and that association of certain of these ligands with LRP may generate a cellular response. In this regard, we have observed that reconstitution of the LRP gene into central hypothesis of this application is that binding of molecules generated during inflammation and wound repair of LRP can trigger the production of inflammatory cytokines and chemokines therapy altering the progression of inflammatory diseases such as atherosclerosis. The specific hypotheses to be tested are: 1) that the certain ligands interact with LRP to stimulate production of mediators of the inflammatory response, that specific cytosolic molecules, (e.g. protein kinase Calpha) interact with the cytoplasmic domain of LRP and participate in LRP- mediated signaling activities, and 3) that LRP can modulate cytokine production by macrophages, and thereby alter the progression of inflammatory diseases such as atherosclerosis. These hypothesis will be tested in the following aims: 1. Determine if LRP functions as a signaling receptor leading to secretion of inflammatory cytokines and chemokines, and identify ligands that trigger this response. 2. Determine if association of PKCalpha with LRP's contribution to macrophage function using tissue specific LRP knockouts in a mouse model.
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