Recruitment of monocyte/macrophages into the subendothelial space is a mandatory step in the transition between vascular health and atherosclerotic lesion formation. Accumulation of lipids within the cytoplasm induces the transformation of macrophages into metabolically inert foam cells. Efflux of cholesterol from the macrophages cannot only delay foam cell formation but also activates reverse cholesterol transport. Apolipoprotein (apo) AI is one of the major physiologic determinants of cholesterol efflux from cells, but is not expressed by tissue macrophages. In previous studies, the applicant has shown that macrophage production of apoE (another acceptor of intracellular cholesterol) directly influences lesion formation in inbred C57BL/6 mice. Dr. Fazio hypothesizes that, if given the ability to produce apoAI, macrophages would be more efficient in getting rid of cholesterol and in activating HDL metabolism. To this end, his group has produced several lines of transgenic mice expressing the human apoAI under the control of a macrophage-specific promoter. In addition, they have developed a viable method for transduction of bone marrow with a retrovirus carrying the apoAI cDNA, and shown that transplantation of transduced marrow into irradiated mice will result in expression of apoAI from macrophages. The objectives of this research program are: i) To create and characterize transgenic mice with the ability to produce apoAI from the macrophage; ii) To evaluate the effect of macrophage apoAI expression on lipids and atherosclerosis in C57BL/6 mice and in mice lacking either the apoAI or the apoE gene; iii) To evaluate the effect of macrophage apoAI in ACAT-1-/- mice, a model of free cholesterol toxicity and inappropriate efflux; iv) To evaluate the feasibility of marrow transduction as a method for ex vivo delivery of apoAI to the macrophage. These studies can be expected to delineate the biology of foam cell formation and the importance of cholesterol efflux in atherogenesis. Moreover, these studies may lay the basis for a gene therapy approach to atherosclerosis.
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