The objective of this project is to define the mechanism controlling cholesterol deposition and mobilization in foam cells the presence of foam cells is a hallmark of atherosclerosis. The foam-cell phenotype results from the formation of numerous cytoplasmic neutral lipid droplets or inclusions, consisting mostly of cholesteryl ester (CE). This CE undergoes a continuous cycle of hydrolysis and re-esterification mediated by neutral cholesteryl ester hydrolases and acyl-CoA: cholesterol acyl transferase. Project 3 will examine several poorly understood aspects of cholesterol metabolism in model macrophage foam cells, with a particular focus on the metabolism of CE.
The Specific Aims are: 1) To elucidate the structure and formation of inclusions by studies of their composition, with particular attention to the surface proteins and phospholipids, and by studies of the mechanism of incorporation of CE synthesized in the endoplasmic reticulum into inclusions. 2) To examine the control of CE hydrolysis, by identification and molecular cloning of lipases with potential involvement in CE metabolism, and determining the effects of altered expression of these lipases and other components of the droplet surface identified under Aim 1. 3) To determine the intracellular locations of the free cholesterol generated by cytoplasmic CE hydrolysis, and to examine how this localization is affected by agents that perturb sterol trafficking and vesicular transport. 4) To establish the metabolic consequences of the accumulation of cholesterol produced CD hydrolysis, and to compare these responses to those provoked by direct uptake of exogenous cholesterol via the plasma membrane. The information gained in these studies will be relevant to the pathological events in the progression and regression of atherosclerosis, and will aid the development of prevention and treatment protocols.
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