Metabolism of the VLDL receptor and ApoE receptor 2

VLDL 受体和 ApoE 受体 2 的代谢

基本信息

批准号：
7175469
负责人：
Joachim J Herz
金额：
$ 33.28万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-02-01 至 2010-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7175469
关键词：
Adaptor Signaling Protein Adult Alzheimer&apos s Disease Amino Acids Antibodies Apolipoprotein E Atherosclerosis Behavior Binding Binding Sites Blood Vessels Brain Cerebellum Cholesterol Chromosome Pairing Class Cues Cytoplasmic Tail DLG4 gene Degenerative Disorder Development Disease Doctor of Medicine Drug Delivery Systems Drug Design Economics Embryo Extracellular Domain Family member Funding Gene Family Goals Hand Hippocampus (Brain)In Vitro Institution Knock-out LDL-Receptor Related Protein 1 Learning Lipids Lipoprotein Receptor Liposomes Liver Low Density Lipoprotein Receptor Medical Memory Metabolism Molecular Mutant Strains Mice Mutation N-Methyl-D-Aspartate Receptors Neocortex Nerve Degeneration Nervous system structure Neuraxis Neurons Neurotransmitter Receptor Pathogenesis Pathway interactions Phosphorylation Phosphotransferases Physiological Positioning Attribute Predisposition Protein Binding Protein Isoforms Receptor Gene Receptor Signaling Research Personnel Role Series Signal Pathway Signal Transduction Signaling Molecule Synapses Tissues VLDL receptor Work amyloid formation amyloid precursor protein processing apolipoprotein E receptor 2 base cell motility cholesterol transporters in vivo interdisciplinary approach mutant neurotransmission novel programs receptor trafficking transmission process

项目摘要

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.

描述（由申请人提供）：在本应用中，我们使用多学科方法来研究常见的分子机制，低密度脂蛋白（LDL）受体基因家族的脂蛋白受体一方面调节了血管壁的完整性，以及在胚胎以及成人和成人中的另一个控制大脑的功能。 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.我们表明，该信号的传播涉及一系列细胞内激酶的激活。我们还证明了相同的途径在不再控制细胞迁移的成年大脑中保持活跃，而是直接参与神经传递，学习和记忆。在成熟神经系统中的这种新作用是特别且直接的生物医学重要性，因为ApoE是一种与该类别的脂蛋白受体结合的胆固醇转运分子，并且可以干扰其信号传导功能，因此与阿尔茨海默氏病（AD）有很强的相关。因此，在下一个资金期间的重点将是对AD的分子发病机理以及从这些发现引起的动脉粥样硬化的概念意义。具体而言，我们将研究VLDLR和APOER2如何与APOE相互作用，信号分子和神经递质受体在成人大脑和血管壁中的突触中的神经递质受体以及脂蛋白受体如何在体内整合这种多样的功能。这可能为动脉粥样硬化和AD的理性药物设计和治疗提供了新的目标，这是医学和社会经济重要性增加的疾病。