Monocyte Heterogeneity in Experimental and Human Atherosclerosis

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DESCRIPTION (provided by applicant): Atherosclerosis is a complex chronic disease and a leading cause of myocardial infarction and stroke. At present, the dominant conceptual approaches to therapy for atherosclerosis involve manipulation of lipid metabolism and manipulation of inflammatory processes. Despite numerous efforts, mortality rates for complications of atherosclerosis continue to rise. Monocytes and macrophages are widely regarded as key cellular protagonists of atherosclerosis; not only do they promote disease through release of inflammatory mediators, but also, as lipid-rich foam cells, they become part of the disease's physical bulk. Although their indiscriminate targeting would interfere with normal homeostasis and immunity, and is therefore therapeutically nonviable, the discovery that monocytes are comprised of distinct subsets in human, mouse and other mammals suggests specialization of function, and has stimulated interest in approaches that discriminate between harmful and beneficial subsets. In this proposal we will test the hypothesis that monocyte subsets contribute differentially to atherogenesis and can be targeted selectively to image and treat the disease. Experiments will utilize classical cell biology tools, molecular profiling, and recently developed in vivo molecular imaging and therapeutic technologies that permit to interrogate monocyte biology at multiple resolutions, from the whole animal to a single cell. The project will interact closely with local imaging, immunology and cardiovascular groups and with outside collaborators. The ability to target monocyte subsets would advance our understanding of atherogenesis, and may allow us to evaluate drugs designed to selectively inhibit monocyte subset recruitment or function, and to stratify patients at risk for developing complications of atherosclerosis such as myocardial infarction or stroke.