Lipoprotein (LP) accumulation in the artery wall is a crucial early step in atherogenesis and is thought to result from increased LP flux across the endothelial cell barrier and increased retention of LPS within the subendothelial cell matrix. The factors that control these processes include the amounts and composition of circulating LPS, their interaction with the artery wall, their alteration by endothelial cells (EC) and macrophages, and their association with matrix molecules leading to entrapment within the artery. A central hypothesis of this project is that artery wall lipoprotein lipase (LpL) has a major impact on all of those factors. How LPL impacts, in a proatherogenic way, upon the interaction between Lp and the artery wall will be investigated. This project includes 3 specific aims that will assess atherosclerosis development in genetically altered mice with differences in arterial wall LpL explore how LpL alters macrophage functions: directly assess mechanisms for Lp accumulation in arteries and relate these mechanisms with atherogenic risk in humans.
In Aim 1 atherogenesis will be studied in mice with macrophages that express increased amounts or no LpL. In addition, the effects of increased lipolysis at the artery wall will be determined using transgenic mice with increased arterial wall LpL.
In Aim 2 we will study the biological and pathological roles of macrophage LpL, focusing on the role of fatty acids as an energy source. A second objective will be to study how LpL affects matrix association of other proteoglycan- binding proteins.
Aim 3 proposes to study how Lp size and composition, which are significantly affected by LpL activity, modulate Lp accumulation in normal and atherosclerotic mouse aortas. This information will be correlated with Lp profiles and variants in genes for apolipoproteins and lipid enzymes in humans. This project includes collaborations with all the other projects in this SCOR. With Project 1, we will study the cooperative roles of sphingomyelinase and LpL. With Project 3, we will assess the roles of lipolysis versus CETP in producing atherogenic LPS. Experiments to determine the effects of LpL on production of atherogenic LPS in diabetic mice will involve a collaboration with Projects 3 and 4. Because interferon gamma modulates LpL production by macrophages, several experiments will be done cooperatively with investigators in Project 5. Studies in this Project to determine genetic polymorphisms associated with CHD risk in humans will provide data that will be used in other Projects. All of the proposed core units, including Pathology, Molecular Biology, and Clinical- Biostatistics will be required for these experiments.
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