Human monocytes and murine/rat macrophages metabolize charge modified lipoproteins, such as acetylated LDL and oxidized LDL, through a specific cell surface receptor termed the scavenger receptor. Metabolism of modified lipoproteins can produce massive cholestryl ester deposition as cytoplasmic droplets, giving cells the appearance of the foam cell of arterial lesions.
The specific aims of this proposal are: (a) to obtain partial sequence information for the murine scavenger receptor isolated from macrophage tumors: (b) to develop monoclonal and polyclonal antibodies specific for the receptor: and (c) to clone the scavenger receptor by either expression cloning in lambda gt11 or by transfection into cells which do not express active receptor. These studies should lead to a more complete understanding of the synthesis and regulation of the receptor, and allow localization of the receptor in different cell types, particularly those in the arterial lesion. In addition, information obtained on the amino acid sequence of the receptor will aid in ldentifying structural regions of the receptor important for function. Highly specific probes for these functional regions can then be generated. Foam cell formation is a key event in the development of the atheromatous lesions. A receptor for modified lipoproteins may play a role in this foam cell formation in vivo. The receptor may also be of importance in regulating normal macrophage functions such as secretion of proteases and prostaglandin series compounds. Combined biochemical, immunochemical, and molecular biological data will facilitate evaluation of the receptor's role in both atherogenesis and normal macrophage physiology, and may provide the necessary information for developing reagents to modulate the function of the receptor.
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