The theme of this proposal is to elucidate the biology of apolipoprotein B (apoB) mRNA editing and provide new insights in the regulation of apoB production. The ultimate goal will be to define the target gene(s) responsible for atherosclerosis and to develop human gene therapy for treatment of hypercholesterolemia. The main focus will involve using adenovirus vector as a gene transfer vehicle to deliver apoB mRNA editing enzyme to study lipoprotein metabolism and to characterize apoB mRNA editing mechanism. ApoB mRNA editing is a unique post-transcriptional modification which results in a single base change in the mRNA, but not the gene. This process is under developmental, species-specific, and tissue-specific metabolic regulation. The essential component, apoB mRNA editing enzyme, that governs that mechanism has been cloned recently. It plays a central role in the regulation of lipoprotein metabolism. Studies will address the role of apoB mRNA editing enzyme in the regulation of apoB production using adenovirus vector as a gene transfer vehicle. A final group of studies will be focused on the characterization of apoB mRNA editing enzyme. of particular interest will be to define the catalytic domain, the role of Leucine-rich motifs, and the modulation of phosphorylation of apoB mRNA editing enzyme. Taken together, these studies should provide a fundamental basis concerning the molecular and biology of apoB mRNA editing and lipoprotein biogenesis. It will also provide us a tool for human gene therapy for the treatment of atherosclerosis.
