Atherosclerosis is a lipid-driven inflammatory disease characterized by the accumulation of lipoproteins and leukocytes in the vessel wall. Among the leukocytes, macrophages are the most numerous and contribute to the development and exacerbation of atherosclerosis decisively. Lesional macrophages derive from circulating monocytes. In the mouse, bone marrow and spleen-derived Ly-6Chigh monocytes accumulate in lesions continuously, and preferentially over the course of disease. Our recent work has shown that, in addition to monocyte influx, mature macrophages proliferate in situ. Although lesional macrophages ultimately derive from circulating monocytes, macrophage proliferation is a dominant mechanism of macrophage accumulation in established atherosclerosis. The molecular mechanisms that orchestrate monocyte influx and macrophage proliferation differ. On the one hand, production and influx of monocytes depends on growth factors and chemokines. On the other hand, local macrophage proliferation depends in part on signaling via the scavenger receptor SR-A. In the grant, we hypothesize that the relative contribution of monocyte influx and macrophage proliferation is fundamental to the development and exacerbation of atherosclerosis. We propose to profile the relative importance of recruitment and proliferation, elucidate and target the molecular mechanisms that drive these processes, and correlate macrophage proliferation with the composition of human lesions. The study is clinically relevant because targeting specific inflammatory processes in atherosclerosis is a major clinical goal. It is therefore essential to know whether and when monocyte recruitment, macrophage proliferation, or both, need to be targeted.
Atherosclerosis is a lipid-driven inflammatory disease of lipoprotein and leukocyte accumulation. Monocytes and macrophages are essential to the development and exacerbation of disease, and are therefore possible therapeutic targets. Development of atherosclerosis involves the recruitment of monocytes to the vessel wall. Recent data also show that lesional macrophage proliferation is an important mechanisms that drives the accumulation of macrophages in established disease. Is one process more important and dangerous than the other? In this grant, we will evaluate the relative importance of monocyte influx and macrophage proliferation to the development of atherosclerosis.
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