During the development of atherosclerosis, monocytes are recruited to the vessel wall where they differentiate into macrophages and accelerate the development of this disease. Monocyte differentiation is associated with the up-regulation of a number of macrophage receptors, including pattern-recognition scavenger and toll-like receptors that are involved in innate immunity, as well as endocytotic and signaling receptors such as the low density lipoprotein receptor-related protein (LRP). This LDL receptor family member is widely expressed and plays important roles in lipoprotein metabolism, degradation of proteases, and in signaling pathways. During the previous funding period of this program project grant the results of our work revealed that LRP modulates a diverse range of physiological events. First, using oligionucleotide microarray data, we obtained evidence that LRP increases the gene expression of several inflammatory cytokines and chemokines, including MCP-1. Second, in collaboration with project 2, we discovered that association of active tPA with LRP in the brain leads to permeability of the blood brain barrier resulting in increased damage induced by ischemia during stroke. Third, in collaboration with project 3 we found that LRP cooperates with the integrin Mac-1 to modulate macrophage migration thereby modulating inflammation. The central hypothesis of this application is that LRP regulates inflammatory events in the vessel wall and the specific hypotheses to be tested are: 1) that LRP regulates inflammatory processes by modulating the functional properties of integrins and thereby affects macrophage migration, 2) that macrophage LRP promotes the uptake of lipoproteins in the vessel wall and contributes to the development of atherosclerosis, 3) that LRP functions as an important phagocytic receptor and modulates the production of inflammatory cytokines via a signaling mechanism involving release of LRP's ICD. These hypotheses will be tested in the following aims: 1) Investigate the role of LRP in a vascular injury model and identify mechanisms by which LRP modulates macrophage migration 2) Investigate the hypothesis that macrophage LRP modulates lipoprotein uptake in the vessel wall thereby promoting atherosclerosis and 3) Evaluate the role of LRP in phagocytosis and determine if this event triggers signaling cascades that induce production of inflammatory molecules.
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