Metabolism of the VLDL receptor and ApoE receptor 2

描述(由申请人提供)：脂蛋白受体在控制血脂水平方面具有基本功能，对于保护动脉免受动脉粥样硬化和冠状动脉疾病的影响至关重要。低密度脂蛋白(LDL)受体基因家族是一类与载脂蛋白E结合的受体，在人类群体中存在三种不同的载脂蛋白E亚型，即E2、E3和E4。载脂蛋白E4在基因上与我们西方人群中流行的两种主要但临床上截然不同的疾病的风险增加有关：动脉粥样硬化和阿尔茨海默病(AD)。载脂蛋白E4基因型一方面导致循环低密度脂蛋白水平升高，另一方面导致AD患者神经元易损性增加和加速变性，其分子机制尚不清楚。然而，了解载脂蛋白E在这些疾病过程中的作用，在我们西方社会具有迅速增长的社会经济重要性，在西方社会，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功能障碍的流行。本研究的目的是研究载脂蛋白E促进疾病发生和发展的分子和细胞机制，并确定载脂蛋白E受体Vldlr和ApoER2在这一过程中的作用。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，通过激活成人大脑中的Vldlr和ApoER2进一步控制突触的可塑性。APOE由中枢神经系统中的神经胶质细胞大量产生，我们推测它干扰了ApoER2和Vldlr功能，从而参与了AD的发病。有趣的是，ApoE、Reelin、ApoER2和Vldlr也在血管壁的外周相交。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。它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。该方案探索了Reelin在血管壁的功能，并研究了ApoE以异构体特异性的方式干扰ApoE受体功能的分子机制，以及血管壁和神经元中的Reelin信号。这项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，自然发生的和突变的ApoE亚型对亚细胞ApoE受体运输和循环的影响，以及对细胞中Reelin信号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载脂蛋白E介导的神经退变过程提供一个全新的机制基础。 公共卫生相关性：动脉粥样硬化和神经退行性变是我们西方社会中与年龄相关的两种主要疾病。载脂蛋白E是一种脂质和胆固醇运输蛋白，是这两种综合征的主要遗传修饰物。这项应用研究了载脂蛋白E受体在两种疾病过程中共同的细胞信号通路中的作用，并探索了某些载脂蛋白E基因型易导致血管和神经发病的分子机制。

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.