APOB RNA EDITING, GENE TRANSFER AND LIPOPROTEIN METABOLI

本提案的主题是阐明载脂蛋白的生物学 B（apoB）mRNA编辑，并为apoB的调控提供新的见解 生产最终目标是确定靶基因 负责动脉粥样硬化并开发人类基因疗法 高胆固醇血症的治疗。主要重点将涉及使用 腺病毒载体作为基因转移载体递送apoB mRNA编辑 研究脂蛋白代谢和表征apoB mRNA的酶 编辑机制 ApoB mRNA编辑是一种独特的转录后修饰， 导致mRNA中的单个碱基变化，而不是基因。这 这一过程是在发育、物种特异性和组织特异性下进行的 代谢调节 apoB mRNA编辑酶， 最近被克隆出来了它发挥着核心作用 调节脂蛋白代谢的作用。 研究将解决apoB mRNA编辑酶在细胞凋亡中的作用。 用腺病毒载体作为基因转移载体调节apoB的产生 车辆 最后一组研究将集中在 apoB mRNA编辑酶的表征。特别感兴趣的是， 确定催化结构域，富含亮氨酸的基序的作用，以及 apoB mRNA编辑酶磷酸化的调节。 综合起来，这些研究应该提供一个基本的基础， 关于apoB mRNA编辑和脂蛋白的分子和生物学 生物起源它还将为我们提供一种人类基因治疗的工具， 动脉粥样硬化的治疗。

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.