APOLIPOPROTEIN E BINDING TO RECEPTORS

载脂蛋白 E 与受体的结合

基本信息

批准号：
3082462
负责人：
DAVID A CHAPPELL
金额：
$ 5.4万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
1988
资助国家：
美国
起止时间：
1988-08-15 至 1992-08-14
项目状态：
已结题

项目摘要

The interaction of lipoproteins with lipoprotein receptors is a fundamental factor influencing the levels of plasma lipoproteins and delivery of lipids to tissues. Abnormalities affecting this interaction may involve either the receptor or the lipoprotein ligands and lead to accelerated arteriosclerosis. This is the case in two hereditary disorders, familial hypercholesterolemia, in which the apo-B,E(LDL) receptor is defective, and familial dysbetalipoproteinemia (type III hyperlipoproteinemia), in which the ligand apolipoprotein (apo-) E is defective. Using current techniques, it is not possible to quantitate defects in lipoprotein receptor-ligand interactions on a molar basis in vivo. The major goal of this proposal is to develop methods that allow estimation of lipoprotein receptor number and rate of association with lipoprotein ligands in vivo. The liver is the major site of receptor-mediated clearance of lipoproteins and will be studied in detail. Radiolabeled lipoproteins will be injected in experimental animals and their distribution in vivo monitored continuously using gamma camera imaging. A three-compartment model consisting of ligand in extrahepatic blood, hepatic blood, and ligand bound to receptors will be designed and validated. The proposed studies will focus primarily on apo-E-containing lipoproteins. Comparisons will be made between normal apo-E and mutants of apo-E that are defective in receptor binding. Kinetic modeling of receptor-mediated uptake in vivo is a novel approach to the investigation of lipoprotein metabolism that could introduce a new dimension to our understanding of the interaction between lipoprotein receptors and ligands. ultimately it could lead to diagnostic tests for familial hypercholesterolemia and other hyperlipidemic disorders associated with abnormal lipoprotein receptor function. We will delineate more precisely the in vitro determinants of receptor binding by normal and mutant forms of apo-E. The effect on binding of the number of apo-E molecules per particle, the lipid composition, and the presence of other apolipoproteins will be investigated on native and synthetic lipoproteins in vitro. We will correlate in vitro receptor binding data with the metabolic fate of lipoproteins containing apo-E in vivo. Human subjects with mutations in apo-E will be studied to gain insight into the normal role of this protein. Our goal determine the origin of beta-very low density lipoproteins, a potentially atherogenic lipoprotein that is the hallmark of defective function of apo-E in vivo.

脂蛋白与脂蛋白受体的相互作用是影响血浆脂蛋白水平的基本因素并将脂质递送到组织。异常影响这一点相互作用可能涉及受体或脂蛋白配体并导致加速动脉硬化。就是这样在两种遗传疾病中，家族性高胆固醇血症， Apo-B，E（LDL）受体有缺陷和家族性脂肪难度蛋白血症（III型高脂蛋白血症），其中配体载脂蛋白（apo-）E有缺陷。使用电流技术，不可能定量脂蛋白缺陷受体 - 配体相互作用在体内摩尔。专业该建议的目标是开发允许估算的方法脂蛋白受体数量和与体内脂蛋白配体。肝脏是受体介导的脂蛋白清除率，将在细节。放射性标记的脂蛋白将在实验中注射动物及其在体内分布不断监测伽玛相机成像。一个组成的三室模型肝外血，肝血和配体的配体受体将经过设计和验证。提出的研究将主要关注含Apo-E的脂蛋白。将进行比较 APO-E在受体结合中有缺陷。动力学建模受体介导的体内摄取是一种新颖的方法调查脂蛋白代谢，可能引入我们对我们对互动之间相互作用的理解的新维度脂蛋白受体和配体。最终可能导致家族性高胆固醇血症和其他的诊断测试与异常脂蛋白有关的高脂症受体功能。我们将更精确地描述体外正常和突变形式的受体结合的决定因素 apo-e。对Apo-E分子数量的结合的影响根据粒子，脂质组成和其他载脂蛋白将在本机和合成上进行研究体外脂蛋白。我们将与体外受体结合相关联与含有apo-e的脂蛋白的代谢命运的数据体内。将研究Apo-E中具有突变的人类受试者深入了解该蛋白的正常作用。我们的目标确定β非常低密度脂蛋白的起源，A 潜在的动脉粥样硬化脂蛋白是 apo-e体内的功能有缺陷。