During the development of atherosclerosis, monocytes are recruited to the vessel wall where theydifferentiate into macrophages and accelerate the development of this disease. Monocyte differentiation isassociated with the up-regulation of a number of macrophage receptors, including pattern-recognitionscavenger and toll-like receptors that are involved in innate immunity, as well as endocytotic and signalingreceptors such as the low density lipoprotein receptor-related protein (LRP). This LDL receptor familymember 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 ourwork revealed that LRP modulates a diverse range of physiological events. First, using oligionucleotidemicroarray data, we obtained evidence that LRP increases the gene expression of several inflammatorycytokines and chemokines, including MCP-1. Second, in collaboration with project 2, we discovered thatassociation of active tPA with LRP in the brain leads to permeability of the blood brain barrier resulting inincreased damage induced by ischemia during stroke. Third, in collaboration with project 3 we found thatLRP cooperates with the integrin Mac-1 to modulate macrophage migration thereby modulatinginflammation. The central hypothesis of this application is that LRP regulates inflammatory events in thevessel wall and the specific hypotheses to be tested are: 1) that LRP regulates inflammatory processes bymodulating the functional properties of integrins and thereby affects macrophage migration, 2) thatmacrophage LRP promotes the uptake of lipoproteins in the vessel wall and contributes to the developmentof atherosclerosis, 3) that LRP functions as an important phagocytic receptor and modulates the productionof inflammatory cytokines via a signaling mechanism involving release of LRP's ICD. These hypotheses willbe tested in the following aims: 1) Investigate the role of LRP in a vascular injury model and identifymechanisms by which LRP modulates macrophage migration 2) Investigate the hypothesis that macrophageLRP modulates lipoprotein uptake in the vessel wall thereby promoting atherosclerosis and 3) Evaluate therole of LRP in phagocytosis and determine if this event triggers signaling cascades that induce production ofinflammatory molecules.
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