Molecular mechanisms in cholesterol export.

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Atherosclerosis is the disease which narrows arteries and causes heart attacks and stroke. It is one of the major causes of death in Australia. Although certain treatments, such as lowering blood cholesterol levels, reduce the incidence of atherosclerosis, current motality rates from this disease indicate that there is still a great need to improve our understanding and treament of the condition. In the development of atherosclerosis, some of the cells in the vessel wall accumulate large deposits of cholesterol. These cells are macrophages, derived from circulating white blood cells that have migrated into the vessel wall. Normally these cells are able to efficiently export excess cholesterol, but this process seems to fail in atherosclerosis. This project will study the molecular mechanism for cholesterol export from macrophages, concentrating on a the mechnisms by which recently identified cholesterol pumps operate. These are located in cell membranes, including at the cell surface, which is the site at which cholesterol is transferred to acceptors such as HDL and apoAI. By understanding how these pumps work, and how their activities are controlled, we will be better able to devise ways to increase their efficiency in atherosclerosis, and so to prevent the tissue cholesterol accumulation that drives this disease.