The hypothesis to be tested is that overexpression of scavenger receptors (ScR) in either macrophages or endothelium will reduce atherogenesis. To test this hypothesis transgenic mice will be developed in which ScR activity is either up- or downregulated with cell-specific promoters. The hypothesis is that ScR activity may be a beneficial local clearance mechanism for removal of modified extracellular lipoprotein deposits, and that the absence of an ordered endocytic process may enhance extracellular lipid deposition and promote harmful cytotoxic and phagocytic activity. While the benefit of ScR activity in macrophages may be debated, there is solid evidence that a receptor to remove lipoproteins from the subendothelial space would be beneficial. Therefore, the studies are designed to test the relative ability of macrophage ScR versus endothelial ScR to impact atherogenesis by clearing extracellular lipid deposits. The following aims are proposed:
Aim 1. To determine whether cell-specific high-level expression or functional knockout of ScR activity in macrophages influences development of atherosclerotic lesions. In association with changes in atherosclerotic lesions, a number of biological effects of ScR regulation will be addressed. 1) Do changes in ScR activity affect the extent of extracellular lipid accumulation? 2) Do increases in ScR activity reduce the extent of cholesterol crystal formation? 3) Are changes in ScR activity negated by the activity of other receptors of similar ligand specificity? 4) Do changes in ScR activity affect macrophage adhesion to extracellular matrix and endothelium? 5) Do changes in macrophage ScR activity affect the production of autoantibodies against modified lipoproteins? Aim 2: To determine whether cell-specific high-level expression or functional knockout of ScR activity in the endothelium influences development of atherosclerotic lesions. As in Aim 1, predicted changes in atherosclerosis will be related to biological activities of ScR. These properties will include subendothelial deposition of lipid droplets and changes in plasma concentrations of modified lipoproteins.
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