Metabolism of the VLDL receptor and ApoE receptor 2

描述（由申请方提供）：脂蛋白受体在控制血浆脂质水平方面具有基本功能，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）受体基因家族代表了一类与脂质转运蛋白载脂蛋白E结合的受体。ApoE的三种亚型存在于人群中，E2、E3和E4。ApoE4在遗传上与两种主要但临床上非常不同的疾病的风险增加相关，这两种疾病在我们的西方人群中普遍存在：动脉粥样硬化和阿尔茨海默病（AD）。一方面ApoE4基因型倾向于较高的循环LDL水平，另一方面增加AD中神经元的脆弱性和加速变性的分子机制知之甚少。然而，理解ApoE在这些疾病过程中的作用在我们西方社会中具有迅速增加的社会经济重要性，在西方社会中，平均预期寿命的持续增加导致与年龄相关的血管和神经衰弱的流行。本提案的目的是研究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在该过程中的作用。这两种蛋白质不仅是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，通过激活成年大脑中的Vldlr和Apoer2进一步控制突触可塑性。ApoE由CNS中的神经胶质细胞大量产生，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、Apoer 2和Vldlr也在血管壁的外周交叉路径。Reelin由肝脏分泌，并以与CNS中存在的浓度相似的浓度在血液中循环。其在血液中的作用尚不清楚，但Reelin受体Apoer2和Vldlr在维持血管壁中具有保护作用。该提案探讨了Reelin在血管壁的功能，并研究了ApoE以同种型特异性方式干扰ApoE受体功能和血管壁和神经元中Reelin信号传导的分子机制。拟议的工作包括条件性Reelin基因敲除小鼠的血管生理学分析，自然发生的和突变的ApoE亚型对亚细胞ApoE受体运输和回收的影响，以及Reelin信号传导功能在细胞中的详细定量测量。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一个概念上新颖的机制基础。

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.