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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL055487-05
Application #
6043877
Study Section
Metabolism Study Section (MET)
Project Start
1996-08-01
Project End
2001-07-31
Budget Start
1999-08-01
Budget End
2000-07-31
Support Year
5
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Kentucky
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
832127323
City
Lexington
State
KY
Country
United States
Zip Code
40506
King, Victoria L; Cassis, Lisa A; Daugherty, Alan (2007) Interleukin-4 does not influence development of hypercholesterolemia or angiotensin II-induced atherosclerotic lesions in mice. Am J Pathol 171:2040-7
Whitman, Stewart C; Kurowska, Elzbieta M; Manthey, John A et al. (2005) Nobiletin, a citrus flavonoid isolated from tangerines, selectively inhibits class A scavenger receptor-mediated metabolism of acetylated LDL by mouse macrophages. Atherosclerosis 178:25-32
Kosswig, Ninetta; Rice, Stuart; Daugherty, Alan et al. (2003) Class A scavenger receptor-mediated adhesion and internalization require distinct cytoplasmic domains. J Biol Chem 278:34219-25
Urbas, Aaron; Manning, Michael W; Daugherty, Alan et al. (2003) Near-infrared spectrometry of abdominal aortic aneurysm in the ApoE-/- mouse. Anal Chem 75:3650-5
Daugherty, Alan; Whitman, Stewart C (2003) Quantification of atherosclerosis in mice. Methods Mol Biol 209:293-309
Whitman, Stewart C; Rateri, Debra L; Szilvassy, Stephen J et al. (2002) Macrophage-specific expression of class A scavenger receptors in LDL receptor(-/-) mice decreases atherosclerosis and changes spleen morphology. J Lipid Res 43:1201-8
King, Victoria L; Szilvassy, Stephen J; Daugherty, Alan (2002) Interleukin-4 deficiency promotes gallstone formation. J Lipid Res 43:768-71
King, Victoria L; Szilvassy, Stephen J; Daugherty, Alan (2002) Interleukin-4 deficiency decreases atherosclerotic lesion formation in a site-specific manner in female LDL receptor-/- mice. Arterioscler Thromb Vasc Biol 22:456-61
Webb, Nancy R; de Beer, Maria C; Yu, Jin et al. (2002) Overexpression of SR-BI by adenoviral vector promotes clearance of apoA-I, but not apoB, in human apoB transgenic mice. J Lipid Res 43:1421-8
Daugherty, A; Kosswig, N; Cornicelli, J A et al. (2001) Macrophage-specific expression of class A scavenger receptors enhances granuloma formation in the absence of increased lipid deposition. J Lipid Res 42:1049-55

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