Metabolism of the VLDL receptor and ApoE receptor 2

描述（由申请人提供）：在本申请中，我们正在使用多学科方法来研究低密度脂蛋白（LDL）受体基因家族的脂蛋白受体一方面调节血管壁的完整性，另一方面控制胚胎和成人大脑的发育和功能的共同分子机制。在第一个资助期，我们发现极低密度脂蛋白受体（VLDLR）和载脂蛋白E受体-2 （ApoER2）不仅作为胆固醇和其他脂质的转运体，而且作为发育必需的信号受体，向控制新皮层、海马体和小脑形成的迁移神经元传递重要的位置线索。我们发现这种信号的传递涉及到一系列细胞内激酶的激活。我们还证明了同样的通路在成人大脑中仍然活跃，在那里它不再控制细胞迁移，而是直接参与神经传递、学习和记忆。这种在成熟神经系统中的新作用具有特别和直接的生物医学意义，因为ApoE是一种与这类脂蛋白受体结合并能干扰其信号功能的胆固醇转运分子，在遗传上与阿尔茨海默病（AD）密切相关。因此，下一个资助期的一个重点将是这些发现对阿尔茨海默病分子发病机制和动脉粥样硬化的概念意义。具体来说，我们将研究VLDLR和ApoER2如何与成人大脑和血管壁神经元突触中的ApoE、信号分子和神经递质受体相互作用，以及脂蛋白受体如何在体内整合这些不同的功能。这可能为动脉粥样硬化和阿尔茨海默病的合理药物设计和治疗提供新的靶点，这两种疾病都具有越来越重要的医学和社会经济意义。

DESCRIPTION (provided by applicant): In this application we are using multidisciplinary approaches to investigate the common molecular mechanisms by which lipoprotein receptors of the low-density lipoprotein (LDL) receptor gene family regulate on one hand the integrity of the vascular wall, and on the other control development and function of the brain in the embryo as well as in the adult. During the first funding period we showed that the very-low-density lipoprotein receptor (VLDLR) and the Apolipoprotein E receptor-2 (ApoER2) function not only as transporters for cholesterol and other lipids, but also as developmentally essential signaling receptors that convey an important positional cue to migrating neurons that controls the formation of the neocortex, the hippocampus and the cerebellum. We showed that transmission of this signal involves the activation of a series of intracellular kinases. We also demonstrated that the same pathway remains active in the adult brain, where it no longer controls cell migration, but instead participates directly in neurotransmission, learning and memory. This novel role in the mature nervous system is of particular and immediate biomedical importance, since ApoE, a cholesterol transport molecule that binds to this class of lipoprotein receptors and can interfere with their signaling functions, is genetically strongly associated with Alzheimer's disease (AD). One focus during the next funding period thus will be the conceptual implications for the molecular pathogenesis of AD as well as atherosclerosis that arise from these findings. Specifically, we will investigate how VLDLR and ApoER2 interact with ApoE, signaling molecules and neurotransmitter receptors in the synapses of neurons in the adult brain and in the vascular wall, and how lipoprotein receptors integrate such diverse functions in vivo. This may provide novel targets for rational drug design and treatment of atherosclerosis as well as of AD, both disorders of increasing medical and socio-economic importance.