Atherosclerosis is the primary etiological pathology behind the two largest sources of mortality in the Western world, myocardial and cerebral infarction. The earliest observed lesion in a developing atherosclerotic plaque is the fatty streak. One way to prevent (or perhaps reverse) the formation of the fatty streak is to inhibit the accumulation of the cells responsible for its formation. MCP-1 (Monocyte Chemoattractant Protein-1) is considered to be the major factor involved in the specific recruitment of monocytic foam cell precursors to the site of fatty streak formation. Our approach is to develop a cell-based promoter-reporter assay to find compounds which switch off the MCP-1 gene in a cell type specific manner. This requires an understanding of the cis-acting elements necessary for the regulated expression of the MCP-1 gene, and the fusion of these elements to a sensitive reporter gene (in this case, the firefly luciferase gene). In Phase I we constructed MCP-1-luciferase fusion constructs and performed transfection studies in appropriate cell lines. In Phase II we will utilize these findings to establish a high-throughput drug screen to identify inhibitors of MCP-1 gene expression. The modulation of MCP-1 gene expression has significant therapeutic potential. Compounds which decrease MCP-1 gene expression have the potential to be developed into drugs to deter or even reverse atherosclerotic plaque formation.
