We have established a cDNA microarray platform for use in research focused on atherosclerosis and heart disease. Our objective is the elucidation of signalling pathways with an impact on cholesterol metabolism regulation. Specifically, we aim to discover novel genes and their encoded products that could serve as drugs, drug targets or diagnostic markers for this indication. Our specific focus is on modulating gene function to promote cholesterol efflux from peripheral tissues (reverse cholesterol transport) via HDL, thereby alleviating the potentially deleterious accumulation and oxidation of cholesterol, most notably in macrophage foam cells, that is strongly correlated with atherosclerosis.

Macrophages mediate a limited-specificity immune response that includes recognition of ‘foreign’ lipid derivatives. Macrophages display a diverse set of ‘scavenger receptors’ that bind bacterial lipopolysaccharides (LPS), phospholipids inappropriately exposed on apoptotic cells and oxidized forms of LDL cholesterol. The resulting signal transduction events and transcriptional programs are overlapping but distinct. Whereas LPS induces a transcriptional program constituting an inflammatory response, the binding and phagocytosis of apoptotic cells results in a non- (or anti-) inflammatory response. It appears that oxidized LDL or oxidized cholesterol metabolites stimulate an inflammatory response that becomes chronic and pathological as they accumulate to high levels in macrophage foam cells.

A full understanding of the transcriptional programs and signalling cascades mediated by related scavenger receptor ligands will enable the identification of unique components of each signalling program, which may provide opportunities for drug development. In addition to targeting genes involved in an abherent inflammatory response to cholesterol accumulation, target genes may regulate cholesterol metabolism and have an impact on efflux mechanisms.

Our current microarray analyses cover approximately 50% of the human genome (∼57,000 cDNAs from IMAGE, distributed by Genome Systems). We are collecting data on gene expression in cultured and primary monocytes/macrophage and those accompanying foam cell formation and stimulation by bacterial lipids and apoptotic cells. A future objective is the analysis of monocyte/macrophage-specific arrays for a more targeted gene discovery effort. Novel candidate genes will be confirmed and validated in physiological assays of cholesterol metabolism and macrophage function.