Metabolism of the VLDL receptor and ApoE receptor 2

VLDL 受体和 ApoE 受体 2 的代谢

• 批准号: 8415969
• 负责人: Joachim J Herz
• 金额: $ 37.84万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8415969
• 关键词: Adult; Affect; Alzheimer' s Disease; Amino Acids; Aneurysm; Animal Model; Aorta; Apolipoprotein E; Arterial Fatty Streak; Arteries; Atherosclerosis; Biological Models; Biotinylation; Blood; Blood Vessels; Brain; CREB1 gene; Carrier Proteins; Cell Fractionation; Cell surface; Cells; Cholesterol; Coronary Arteriosclerosis; Development; Disease; Disease Progression; Endocytosis; Epidemic; Gene Family; Genetic; Genetic screening method; Genotype; Goals; Human; Hyperplasia; In Vitro; Kinetics; Knock-out; Knockout Mice; LDL-Receptor Related Protein 1; Lesion; Life Expectancy; Ligands; Lipids; Lipoprotein Receptor; Liver; Low Density Lipoprotein Receptor; Low-Density Lipoproteins; Maintenance; Measurement; Measures; Mediating; Metabolism; Molecular; Mouse Protein; Mouse Strains; Mus; Mutation; N-Methyl-D-Aspartate Receptors; Nerve Degeneration; Neuroglia; Neurologic; Neurons; Onset of illness; PDGFRB gene; Pathogenesis; Physiological; Physiology; Plasma; Population; Process; Property; Protein Isoforms; Proteins; Receptor Gene; Receptor Signaling; Recycling; Risk; Role; Signal Pathway; Signal Transduction; Signaling Protein; Smooth Muscle; Smooth Muscle Myocytes; Societies; Stream; Surface; Synaptic plasticity; Syndrome; Testing; VLDL receptor; Work; age related; apolipoprotein E receptor 2; apolipoprotein E-4; base; immunocytochemistry; in vivo; lipid metabolism; lipid transport; mutant; novel; public health relevance; receptor; receptor binding; receptor function; receptor recycling; reelin receptor; socioeconomics; trafficking

DESCRIPTION (provided by applicant): Lipoprotein receptors have essential functions in the control of plasma lipid levels and are critically important for protection of the arteries from atherosclerosis and coronary artery disease. The low-density lipoprotein (LDL) receptor gene family represents one class of such receptors that bind the lipid transport protein Apolipoprotein E. Three isoforms of ApoE exist in the human population, E2, E3 and E4. ApoE4 is genetically associated with increased risk for two major, but clinically very different diseases that are prevalent in our Western populations: Atherosclerosis and Alzheimer's disease (AD). The molecular mechanisms through which ApoE4 genotype predisposes to higher circulating LDL levels on one hand, and to increased neuronal vulnerability and accelerated degeneration in AD on the other, are poorly understood. Understanding the role of ApoE in these disease processes, however, is of rapidly increasing socioeconomic importance in our Western societies, where the continuing increase in average life-expectancy has led to an epidemic of age- related vascular and neurological debilities. The purpose of this proposal is to investigate the molecular and cellular mechanisms by which ApoE promotes disease onset and progression, and to determine the role of the ApoE receptors Vldlr and Apoer2 in the process. Both proteins are not only receptors for ApoE, but also for Reelin, an indispensable neurodevelopmental signaling protein that further controls synaptic plasticity by activating Vldlr and Apoer2 in the adult brain. ApoE is produced abundantly by glial cells in the CNS, where we hypothesize that it interferes with Apoer2 and Vldlr functions, thereby contributing to the pathogenesis of AD. Intriguingly, ApoE, Reelin, Apoer2 and Vldlr also cross paths in the periphery at the vascular wall. Reelin is secreted by the liver and circulates in blood in concentrations similar to those present in the CNS. Its role in the blood is unknown, but the Reelin receptors Apoer2 and Vldlr have protective roles in the maintenance of the vascular wall. This proposal explores the function of Reelin at the vessel wall and investigates molecular mechanisms through which ApoE interferes in an isoform-specific manner with ApoE receptor functions and Reelin signaling in the vascular wall and in neurons. The proposed work involves the analysis of the vascular physiology of conditional Reelin knockout mice, the effect of naturally occurring and mutant ApoE isoforms on subcellular ApoE receptor trafficking and recycling, and detailed quantitative measurements of Reelin signaling functions in cells. The results from these studies will contribute a conceptually novel mechanistic basis to our understanding of the pathogenesis of atherosclerosis, as well as ApoE-mediated neurodegenerative processes.

描述（由申请人提供）：脂蛋白受体在控制血浆脂质水平的控制方面具有重要功能，对于保护动脉的动脉粥样硬化和冠状动脉疾病至关重要。低密度脂蛋白（LDL）受体基因家族代表结合脂质转运蛋白载脂蛋白E的一类受体E。APOE的三种同工型在人群中，E2，E3和E4。 APOE4在遗传上与我们西方人群中普遍存在的两种主要疾病的风险增加有关：动脉粥样硬化和阿尔茨海默氏病（AD）。一方面，APOE4基因型易受循环LDL水平的分子机制，另一方面增加了神经元脆弱性和AD的加速变性。然而，在我们的西方社会中，了解APOE在这些疾病过程中的作用迅速增加了社会经济的重要性，在我们的西方社会中，平均预期寿命的持续增加导致了与年龄相关的血管和神经学的流行。该建议的目的是研究APOE促进疾病发作和进展的分子和细胞机制，并确定APOE受体VLDLR和APOER2在此过程中的作用。两种蛋白质不仅是APOE的受体，而且是Reelin的受体，Reelin是必不可少的神经发育信号传导蛋白，通过激活成人大脑中的VLDLR和APOER2进一步控制突触可塑性。 APOE由中枢神经系统中的神经胶质细胞大量产生，我们假设它会干扰ApoER2和VLDLR功能，从而有助于AD的发病机理。有趣的是，apoe，reelin，apoer2和vldlr也在血管壁的周围横路。 reelin被肝脏分泌，并以与中枢神经系统中存在的浓度相似的浓度循环。它在血液中的作用尚不清楚，但是reelin受体apoer2和vldlr在维持血管壁中具有保护作用。该提案探讨了reelin在血管壁上的功能，并研究了分子机制，APOE以同种异体特异性方式干扰了血管壁和神经元中的APOE受体功能和reelin信号传导。提出的工作涉及对条件reelin敲除小鼠血管生理的分析，天然发生和突变的APOE同工型对亚细胞APOE受体运输和回收利用的影响，以及细胞中reelin信号功能的详细定量测量。这些研究的结果将在概念上有助于我们对动脉粥样硬化的发病机理以及APOE介导的神经退行性过程的理解。