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：
8531641
负责人：
GEOFFREY T SWANSON
金额：
$ 32.27万
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 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8531641
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 Neurons Oligosaccharides 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 Vascularization Wound Healing angiogenesis base cancer cell cell type crosslink density desensitization insight kainate knowledge base member neurogenesis neuronal excitability neurotransmission novel public health relevance receptor receptor function research study 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）：该项目的目的是了解动物衍生的凝集素在神经系统活动中的作用。调查对神经元活动的调查到目前为止，乳糖素是哺乳动物可溶性半乳糖苷结合蛋白的家族，主要集中于它们如何影响神经发生或充当脑癌细胞的转移性因子。然而，甘肠蛋白也已被成熟神经系统中的神经胶质和神经元分泌，因此很可能在脑功能中具有生理作用。我们假设半乳糖素通过树突状刺的短期形态变化，突触可塑性的改变以及神经元生存能力的降低来影响神经元功能。这些活动是通过包括ERK/MAPK在内的细胞内信号传导级联反应来介导的。在神经元质膜上表达的积分蛋白通常包含糖N乙酰乳糖胺，这是复杂寡糖的常见二糖，因此可以用作元素结合的靶标和信号分子的交联，从而导致其活化和启动的elacellular enz eNz eNz eNZENZENZASCADES。除了对神经元的作用外，半乳糖蛋白是理解N-聚糖与离子型谷氨酸受体（IGLUR）功能相关性的有用工具，这是由于其变构调节作用。因此，拟议的项目将阐明半乳肠蛋白如何影响神经元功能和生存力，并将这些蛋白质用作重组iGlurs的结构功能研究中的聚糖特异性工具。在特定的目标1中，我们将检查小鼠海马中神经传递和突触可塑性的半乳糖素活性。特定目标2中的实验将测试甲状腺蛋白通过细胞内激酶级联反应神经元结构可塑性的假设。最后，在特定的目标3中，我们将确定卵黄作用在iGlurs及其分子基础上的频谱。我们将探测甲状腺素的物理特征，以优化其对iGlurs的功能作用。这些研究将深入了解甘肠蛋白与神经元功能的尚未探索的相关性，这也将与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有关。