APOLIPOPROTEIN E BINDING TO RECEPTORS

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 以及将脂质输送到组织中。影响这一点的异常现象 相互作用可能涉及受体或脂蛋白。 并导致加速的动脉硬化。情况就是这样。 在两种遗传性疾病中，家族性高胆固醇血症 其中载脂蛋白B，E(低密度脂蛋白)受体有缺陷，并有家族性 高脂蛋白血症(III型高脂蛋白血症) 配体载脂蛋白(apo-)E有缺陷。使用当前 技术，不可能对脂蛋白的缺陷进行量化 受体-配体在体内的摩尔相互作用。少校 这项提案的目标是开发允许估计的方法 脂蛋白受体的数量和关联率 体内的脂蛋白配体。肝是黄褐斑的主要部位 受体介导的脂蛋白清除，将在#年进行研究 细节。放射性标记的脂蛋白将在实验中注射 连续监测动物及其体内分布 伽马相机成像。一个由三个隔室组成的模型 在肝外血液、肝血中的配体，以及与 接收器将被设计和验证。建议进行的研究 将主要集中在含载脂蛋白E的脂蛋白上。 比较正常载脂蛋白E和突变型载脂蛋白E 受体结合缺陷的载脂蛋白E。动力学模型的建立 受体介导的体内摄取是一种新的方法 脂蛋白代谢的研究可能会导致 为我们理解相互作用提供了新的维度 脂蛋白受体和配体。最终，它可能会导致 家族性高胆固醇血症等的诊断试验 与异常脂蛋白相关的高脂血症 受体功能。我们将更准确地描绘出体外 正常形式和突变形式的受体结合的决定因素 载脂蛋白E载脂蛋白E分子数目对结合的影响 每种颗粒，脂类成分，以及其他 载脂蛋白将在天然和人工合成的基础上进行研究 体外培养的脂蛋白。我们将在体外与受体结合相关 含载脂蛋白E的脂蛋白在人体内代谢去向的数据 活着。具有载脂蛋白E突变的人类受试者将被研究 深入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性脂蛋白是 体内载脂蛋白E功能缺陷。

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.