APOLIPOPROTEIN E BINDING TO RECEPTORS

载脂蛋白 E 与受体的结合

• 批准号: 3082459
• 负责人: DAVID A CHAPPELL
• 金额: $ 5.4万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-08-15 至 1988-08-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3082459
• 关键词: apolipoproteins; biological models; blood lipoprotein biosynthesis; blood lipoprotein metabolism; cardiovascular disorder diagnosis; familial hyperlipoproteinemia type III; fibroblasts; gel electrophoresis; gel filtration chromatography; human subject; hypercholesterolemia; ligands; liver circulation; liver metabolism; mathematical model; model design /development; mutant; noninvasive diagnosis; peptide chemical synthesis; radiotracer; receptor mediated endocytosis; scintillation cameras; technetium; tissue /cell culture; ultracentrifugation; very low density lipoprotein

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一种 影响血浆脂蛋白水平的基本因素 以及脂质向组织的递送。 影响这一点的因素 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。 是这种情况 在两种遗传性疾病，家族性高胆固醇血症， 其中apo-B，E（LDL）受体是有缺陷的， β脂蛋白异常血症（III型高脂蛋白血症），其中 配体载脂蛋白（apo-）E是有缺陷的。 使用当前 技术，不可能定量脂蛋白中的缺陷， 受体-配体相互作用在体内的摩尔基础上。 主要 本提案的目标是开发出一种方法， 脂蛋白受体数量和与 体内脂蛋白配体。 肝脏是主要的部位 受体介导的脂蛋白清除，并将在 详细 放射性标记的脂蛋白将被注射到实验室中。 动物及其体内分布连续监测， 伽马照相机成像 三室模型，包括 肝外血、肝血和与之结合的配体 将设计和验证接收器。 拟议的研究 将主要关注含载脂蛋白E的脂蛋白。 将在正常的apo-E和apo-E的突变体之间进行比较。 apo-E在受体结合中有缺陷。 的动力学模拟 受体介导的体内摄取是一种新的方法， 脂蛋白代谢的研究， 新的维度来理解 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 与异常脂蛋白相关的高脂血症 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决定因素 apo-E 载脂蛋白E分子数量对结合的影响 每颗粒、脂质组成和其他物质的存在 载脂蛋白将研究天然和合成 体外脂蛋白。 我们将关联体外受体结合 数据与脂蛋白的代谢命运含有载脂蛋白E， vivo. 将研究具有apo-E突变的人类受试者， 了解这种蛋白质的正常作用。 我们的目标 确定β-极低密度脂蛋白的来源， 潜在的致动脉粥样硬化脂蛋白， 体内apo-E功能缺陷。