APOB RNA EDITING, GENE TRANSFER AND LIPOPROTEIN METABOLI

这项提议的主题是阐明载脂蛋白的生物学。 B(ApoB)mRNA的编辑，为apoB的调控提供了新的见解 制作。最终目标将是确定目标基因(S) 负责动脉粥样硬化和开发人类基因疗法 治疗高胆固醇血症。主要关注点将涉及使用 腺病毒载体作为载脂蛋白B基因编辑载体的研究 研究脂蛋白代谢和鉴定apoB基因的酶 编辑机制。 载脂蛋白B mRNA编辑是一种独特的转录后修饰 导致mRNA发生单碱基改变，但基因不发生改变。这 过程处于发育、特定物种和特定组织的过程中 代谢调节。必不可少的成分apoB mRNA编辑酶， 管理这一机制的机制最近被克隆了。它扮演着一个中心角色 在调节脂蛋白代谢中的作用。 研究将解决载脂蛋白B mRNA编辑酶在 腺病毒载体作为基因转移对载脂蛋白B生产的调控 车辆。最后一组研究将集中在 ApoB基因编码酶的性质。特别值得关注的是 定义催化域，富含亮氨酸的基序的作用，以及 ApoB mRNA编辑酶磷酸化的调控。 总而言之，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 生物发生学。它还将为人类的基因治疗提供一种工具 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.