Atherosclerosis and its complications are the leading cause of death in the United States. This process, by which arteries become narrowed and eventually occluded, is still not clearly understood, but current concepts suggest that the serum lipoproteins, especially low density lipoprotein (LDL), play an important role. Evidence is accumulating that indicates that modifications of LDL, particularly oxidation, may play a critical role in the initiation of atherosclerotic plaque formation. A receptor on the surface of macrophages, called the acetyl-LDL or scavenger receptor, appears to be responsible for the uptake of modified lipoproteins and the subsequent conversion of macrophages to cholesterol-loaded foam cells. An understanding of the process of foam cell formation is critical to any understanding of atherosclerosis, since the foam cell is one of the earliest changes noted in the development of an atherosclerotic plaque. The expression of scavenger receptors on macrophages and smooth muscle cells appears to be regulated. Differentiation of the monocyte into a macrophage is associated with a dramatic increase in receptor activity and recent evidence suggests that several cytokines can induce a substantial increase in smooth muscle cell scavenger receptors. The research proposed in this grant is intended to identify the molecular genetic signals that control scavenger receptor expression in both macrophages and smooth muscle cells. Gene constructs encoding various fragments of the control regions in the scavenger receptor's promoter will be linked to a reporter gene will be made. These constructs will then be transfected into macrophages, smooth muscle cells, and non-vascular cell types in order to determine the specificity of control elements. Once this process has been well characterized, similar gene constructs will be injected into transgenic mice in order to confirm, in vivo, the observations that have been made in vitro. With this accomplished, it should then be possible to study foam cell formation in the transgenic animal by feeding a high fat/high cholesterol diet. Using native and mutated transgene constructs, it is anticipated that these studies will lead to new insights into the process of atherosclerotic plaque development and the role that scavenger receptors play in that process. This information has the potential to open up new therapeutic avenues whose exploration could lead to advances in the prevention of coronary heart disease.
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