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Galectin Modulation of Glutamate Receptors and Neuronal Function

半乳糖凝集素对谷氨酸受体和神经元功能的调节

基本信息

批准号：
9210655
负责人：
GEOFFREY T SWANSON
金额：
$ 33.23万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-01 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9210655
关键词：
Acute Affinity Animals Behavior Binding Binding Proteins Brain Brain Neoplasms Cell Surface Proteins Cell Survival Cell membrane Characteristics Chronic Complement Complex Cytoplasm Dendritic Cells Dendritic Spines Development Disaccharides Exposure to Extracellular Matrix Family Galactose Binding Lectin Galactosides Galectin 1 Glioma Glutamate Receptor Glycoproteins Golgi Apparatus Hippocampus (Brain)Human Immune system Induction of Apoptosis Integrins Investigation Lectin Ligand Binding Domain Long-Term Potentiation MAP Kinase Gene Malignant neoplasm of brain Mediating Membrane Molecular Morphology Multiple Sclerosis Mus N-acetyllactosamine Neoplasm Metastasis Nerve Degeneration Nervous system structure Neurodegenerative Disorders Neuroglia Neurologic Process Neurons Oligosaccharides Pathologic Pathway interactions Peripheral Phosphotransferases Physiological Polysaccharides Preparation Process Protein Family Proteins Recombinants Research Role Signal Pathway Signal Transduction Signaling Molecule Site Slice Structure Synapses Synaptic Transmission Synaptic plasticity System Testing Transducers Tumor Cell Migration Vascularization Wound Healing angiogenesis cancer cell cell type crosslink density desensitization experimental study insight kainate knowledge base member neurogenesis neuronal excitability neurotransmission novel public health relevance receptor receptor function sugar synthetic enzyme tool

项目摘要

DESCRIPTION (provided by applicant): The purpose of this project is to understand the role of animal-derived lectins in nervous system activity. Investigation into the neuronal activities of galectins, a family of mammalian soluble galactoside-binding proteins, thus far has focused primarily on how they impact neurogenesis or act as metastatic factors for brain cancer cells. However, galectins also are known to be secreted by glia and neurons in the mature nervous system, and therefore are likely to have a physiological role in brain function. We hypothesize that galectins impact neuronal function through short-term morphological changes in dendritic spines, alterations in synaptic plasticity, and reductions in neuronal viability. These activities re mediated by engagement of intracellular signaling cascades that include ERK/MAPK. Integral proteins expressed on neuronal plasma membranes typically contain the glycan N acetyllactosamine, a common disaccharide constituent of complex oligosaccharides, and therefore could serve as targets for galectin binding and cross-linking of signaling molecules, leading to their activation and initiation of intracellular enzymatic cascades. In addition to thei actions on neurons, galectins are useful tools for understanding the relevance of N-glycans to ionotropic glutamate receptor (iGluR) function due to their allosteric modulatory actions. Accordingly, the proposed project will elucidate how galectins impact neuronal function and viability and use these proteins as glycan-specific tools in structure-function studies with recombinant iGluRs. In Specific Aim 1, we will examine galectin activity on neurotransmission and synaptic plasticity in the mouse hippocampus. Experiments in Specific Aim 2 will test the hypothesis that galectins alter neuronal structural plasticity through intracellular kinase cascades. Finally, in Specific Aim 3, we will determine the spectrum of galectin actions on iGluRs and their molecular basis. We will probe the physical characteristics of galectins that optimize their functional action on iGluRs. These studies will yield insight into the as-yet unexplored relevance of galectins to neuronal function, which also will be relevant to understanding their importance to glioma-induced alterations in neuronal excitability.

描述（由申请人提供）：本项目的目的是了解动物源性凝集素在神经系统活动中的作用。神经元活动的研究半乳糖凝集素是哺乳动物可溶性半乳糖苷结合蛋白的一个家族，迄今为止主要关注它们如何影响神经发生或作为脑癌细胞的转移因子。然而，已知半乳糖凝集素也由成熟神经系统中的神经胶质和神经元分泌，因此可能在脑功能中具有生理作用。我们假设半乳糖凝集素通过树突棘的短期形态变化、突触可塑性改变和神经元活力降低来影响神经元功能。这些活动是通过参与细胞内信号级联，包括ERK/MAPK介导的。在神经元质膜上表达的整合蛋白通常含有聚糖N乙酰乳糖胺，这是复合寡糖的常见二糖成分，因此可以作为半乳糖凝集素结合和信号分子交联的靶标，导致其激活和启动细胞内酶级联反应。除了它们对神经元的作用之外，半乳糖凝集素是用于理解N-聚糖与离子型谷氨酸受体（iGluR）功能的相关性的有用工具，这归因于它们的变构调节作用。因此，拟议的项目将阐明半乳糖凝集素如何影响神经元功能和活力，并使用这些蛋白质作为聚糖特异性工具，在重组iGluRs的结构-功能研究中。在具体目标1中，我们将研究半乳糖凝集素对小鼠海马神经传递和突触可塑性的活性。具体目标2中的实验将检验半乳糖凝集素通过细胞内激酶级联改变神经元结构可塑性的假设。最后，在具体目标3中，我们将确定半乳糖凝集素对iGluRs的作用谱及其分子基础。我们将探索半乳糖凝集素的物理特性，优化其对iGluRs的功能作用。这些研究将深入了解半乳糖凝集素与神经元功能的尚未探索的相关性，这也将有助于了解它们对神经胶质瘤诱导的神经元兴奋性改变的重要性。