The proposed research has been subdivided into four sections, the specific aims of which are designed to contribute towards the long-term objective, i.e., the study of pathogenesis and regression of atherosclerosis. Section 1 aims to investigate putative interactions between two cellular populations of atheroma, i.e., macrophages and smooth muscle cells, which may result in enhanced cholesterol esterification in smooth muscle cells.
The specific aim of Section 2 is to elucidate the possible role of lipoprotein lipase in transmembrane transport of lipoprotein cholesteryl ester. Section 3 is aimed to study the contribution of extrahepatic tissues to the metabolism of VLDL and LDL cholesteryl ester and the contribution of lipoprotein cholesteryl ester to the formation of atheroma. In section 4 a model system in vivo to study the role of macrophages in the removal of atheroma lipid will be investigated. In Sections 2-4 we shall utilize a new marker for cholesteryl ester, in the form of its non-degradable analog 3H-cholesteryl linoleyl ether that we were able to synthesize at high purity and high specific activity. The labeled 3H-cholesteryl linoleyl ether will be introduced into lipoproteins using a newly developed method of biological transfer. The methodology used will involve: I. tissue culture of mouse peritoneal macrophages, bovine aortic smooth muscle cells, human skin fibroblasts and rat heart cells. II. Preparation of lipoproteins which will be isolated from human, rat or rabbit plasma or rat lymph by differential density ultracentrifugation. III. Radiochemical and chemical analysis of lipids, using TLD and GLC. IV. Determination of lipoprotein lipase activity. V. Electron microscopy and radioautography. The scientific disciplines involved in this research are cell biology and lipid biochemistry. The proposed research is health related in that it aims to investigate mechanisms operative in the pathogenesis of atherosclerosis.
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