The studies proposed in this project will enhance understanding of the cellular and extracellular factors that modulate the flux of cholesterol between cells and serum. This bi-directional movement of cholesterol is one of the major mechanisms by which cellular cholesterol homeostasis is maintained and the efflux of cholesterol from cells is the first step in the process by which excess peripheral cholesterol is returned to the liver for excretion.
Specific Aim 1 will use cyclodextrins to: 1) examine the kinetics and mechanism of transport of plasma membrane cholesterol to the endoplasmic reticulum, 2) probe the distribution of cholesterol in fast and slow kinetic pools within the plasma membrane, 3) examine the factors regulating the efflux of synthesized sterols and cholesterol derived from lysosomes and 4) relate the kinetic pools of plasma membrane cholesterol to physical lipid domains through the use of x-ray diffraction and NMR techniques.
Specific Aim 2 will focus on the lipoprotein-related factors that modulate bi-directional flux by: 1) expanding our studies showing that cyclodextrins can shuttle cholesterol between cells and lipoproteins and that phospholipid vesicle can function as cholesterol sinks to determine if there are natural shuttles and sinks in serum, 2) study how phospholipid enrichment changes bi-directional cholesterol flux and the sink/shuttle capacity of serum, 3) establish the roles of LCAT and CETP in the modulation of cholesterol efflux from fast and slow pools, and 4) investigate differences among sera in their sink/shuttle capacity and correlate these differences to serum parameters and the regulation of cell cholesterol flux. The information gained from these studies will enhance our understanding of the processes involved in cholesterol accumulation in the vessel wall and will provide insights on interventions to modulate the progression and regression of atherosclerotic plaque.
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