Apolipoproteins are components of lipoproteins that circulate in the blood and lymph, and mediate the transport and metabolism of lipids between various tissues. The regulation of the synthesis of these proteins is not well understood. The overall objective of this proposal is to characterize the molecular elements involved in the regulation of the expression of two human apolipoprotein gene complexes. The first gene complex is composed of the apo-E, apo-C-I, and apo-C-I' genes. The second complex is composed of the apo-A-IV, apo-C-III, and apo-A-I genes. The proposed studies are aimed at determining the sequence elements associated with these genes that control their expression. These control regions will be employed to identify, isolate, and characterize the intracellular components with which they interact. In particular, possible regulatory regions associated with the apo-E gene that mediate the response of the gene to intracellular cholesterol levels as well as inflammatory agents will be investigated. The structural and regulatory relationships of the apo-C-I and apo-C-I' genes will be determined. The regulation of the apo-A-IV gene in response to metabolic mediators will be characterized. Preliminary results from our laboratory indicate that multiple regulatory factors will be involved in determining the mechanisms of apolipoprotein gene expression. These studies are directed towards understanding the control mechanisms responsible for the synthesis of their mRNAs. Knowledge of this regulation should facilitate an understanding of the role of these apolipoproteins in circulating lipoproteins and their involvement in the pathogenesis of cardiovascular diseases such as atherosclerosis.
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