Metabolism of the VLDL receptor and ApoE receptor 2

VLDL 受体和 ApoE 受体 2 的代谢

• 批准号: 8213541
• 负责人: Joachim J Herz
• 金额: $ 39.68万
• 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/8213541
• 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. PUBLIC HEALTH RELEVANCE: Atherosclerosis and neurodegeneration are two major age-related diseases in our Western societies. Apolipoprotein E, a lipid and cholesterol transport protein, is a major genetic modifier for both syndromes. This application investigates the role of ApoE receptors in cellular signaling pathways that are common to both disease processes and explores the molecular mechanisms by which certain ApoE genotypes predispose to vascular and neuronal pathogenesis.

描述（由申请人提供）：脂蛋白受体在控制血浆脂质水平方面具有重要功能，并且对于保护动脉免受动脉粥样硬化和冠状动脉疾病至关重要。低密度脂蛋白 (LDL) 受体基因家族代表一类与脂质转运蛋白载脂蛋白 E 结合的受体。人类中存在 ApoE 的三种亚型：E2、E3 和 E4。 ApoE4 在遗传上与西方人群中流行的两种主要但临床上截然不同的疾病风险增加相关：动脉粥样硬化和阿尔茨海默病 (AD)。 ApoE4 基因型一方面导致循环 LDL 水平升高，另一方面导致 AD 中神经元脆弱性增加和加速退化，但其分子机制尚不清楚。然而，了解 ApoE 在这些疾病过程中的作用在我们的西方社会中具有迅速增加的社会经济重要性，在西方社会，平均预期寿命的持续增长导致了与年龄相关的血管和神经功能障碍的流行。本提案的目的是研究 ApoE 促进疾病发生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。这两种蛋白不仅是 ApoE 的受体，也是 Reelin 的受体，Reelin 是一种不可或缺的神经发育信号蛋白，可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 CNS 中的胶质细胞大量产生，我们假设它干扰 Apoer2 和 Vldlr 功能，从而促进 AD 的发病机制。有趣的是，ApoE、Reelin、Apoer2 和 Vldlr 也在血管壁周围交叉路径。 Reelin 由肝脏分泌，在血液中循环的浓度与中枢神经系统中的浓度相似。其在血液中的作用尚不清楚，但 Reelin 受体 Apoer2 和 Vldlr 在维持血管壁方面具有保护作用。该提案探讨了 Reelin 在血管壁上的功能，并研究了 ApoE 以异构体特异性方式干扰血管壁和神经元中 ApoE 受体功能和 Reelin 信号传导的分子机制。拟议的工作包括分析条件性 Reelin 基因敲除小鼠的血管生理学、天然存在和突变的 ApoE 亚型对亚细胞 ApoE 受体运输和再循环的影响，以及细胞中 Reelin 信号传导功能的详细定量测量。这些研究的结果将为我们理解动脉粥样硬化的发病机制以及 ApoE 介导的神经退行性过程提供概念上新颖的机制基础。 公共卫生相关性：动脉粥样硬化和神经变性是西方社会中两种主要的与年龄相关的疾病。载脂蛋白 E 是一种脂质和胆固醇转运蛋白，是这两种综合征的主要遗传修饰因子。该应用研究了 ApoE 受体在两种疾病过程中常见的细胞信号传导途径中的作用，并探讨了某些 ApoE 基因型易导致血管和神经元发病的分子机制。