The goal of Project 5 is to investigate the control of apolipoprotein E (apoE) gene expression in macrophages, the role of macrophage apoE in cellular cholesterol metabolism, and macrophage functions which play a role in atherosclerotic lesion formation and progression. The experimental approach to these issues will make extensive use of the trangenic core, creating new transgenic and targeted deletion mice as well as breeding with existing transgenic and gene knockout strains.
The specific aims of this project are 1) to determine the DNA elements and trans-acting factors which control the tissue specific and cholesterol regulated expression of apoE in macrophages; 2) to characterize the role and mechanism of macrophage apoE in promoting macrophage cholesterol efflux and in preventing atherosclerosis; and 3) to develop animal models to gain insight into the mechanisms of macrophage involvement in atherosclerosis by breeding atherosclerosis-prone apoE deficient mice with other mutant or transgenic strains which disrupt macrophage development or functions. This project is directly related to the central theme of the program, namely the investigation of lipid and lipoprotein metabolism and atherogenesis using cell cultaure models and genetically manipulated mice. The analysis of macrophage apoE gene expression may yield novel information about macrophage specific regulatory elements and the mechanism of cholesterol up-regulation of gene expression. Understanding the role of macrophage apoE in cholesterol efflux and which macrophage functions are involved in atherosclerosis may be of significance in developing strategies to prevent atherogenesis and lesion progression.
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