This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Foam cell formation from monocyte-derived macrophages is a hallmark of atherosclerosis. Atherosclerotic plaque contains foam cells that store cholesterol and cholesterol esters. Macrophage-derived foam cells are of particular importance in the development and health consequences of atherosclerotic disease, because macrophages are found in the shoulder regions of 'vulnerable' plaques, where they destabilize the 'cap' of the plaque by expressing various pro-inflammatory chemokines, cytokines, matrix-degrading metalloproteases and other mediators that tend to promote plaque rupture. Plaque macrophages are thought to be derived from blood monocytes, which are recruited into the arterial wall through adhesion molecules and chemokines. Therefore, the proposed research will investigate the differentiation of human blood monocytes to macrophages and foam cells using Affymetrix gene chip analysis of mRNA expression, flow cytometry and other techniques for validation. We hypothesize that the differentiation of macrophages into foam cells by modified low density lipoproteins (oxLDL and others) will lead to a pro-inflammatory cell phenotype that supports antigen presentation and chronic inflammation. We will also test the influence of high density lipoprotein (HDL) and statin treatment on foam cell differentiation. The current study design calls for 256 Affymetrix U133A gene chips testing mRNA expression levels in monocytes, macrophages, foam cells and dendritic cells, all derived from blood of donors. Initially our study will be limited to white males, since this group has been shown to be highly susceptible to atherosclerosis. These experiments are expensive and we would like to have a high probability of success. If significant results are found, we would like to carry on with the experiments in other groups to see if further significant results can be found.
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