Disruption of CS/KSPG-Mediated Neuronal Outgrowth Inhibition

CS/KSPG 介导的神经元生长抑制的破坏

• 批准号: 9979536
• 负责人: Vitor Hugo Pomin
• 金额: $ 14.19万
• 依托单位: UNIVERSITY OF MISSISSIPPI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9979536
• 关键词: Achievement; Adult; Alkylation; Anions; Axon; Biological Availability; Bovine Cartilage; Carbohydrates; Cell Culture Techniques; Chemicals; Chondroitin Sulfate A; Chondroitin Sulfate C; Chondroitin Sulfates; Chondroitinases; Chromatography; Communities; Complex; Core Protein; Dermatan Sulfate; Digestion; Disaccharides; Down-Regulation; Enzymes; Excision; Foundations; Galactans; Glycosaminoglycans; Growth; Heparin; Heparin Lyase; Heparitin Sulfate; Hydrolase; In Vitro; Individual; Injury; Keratan Sulfate; Lead; Length; Libraries; Mass Spectrum Analysis; Mediating; Modeling; Molecular; Molecular Sieve Chromatography; NMR Spectroscopy; Natural regeneration; Nerve Regeneration; Neural Inhibition; Neuraxis; Neurites; Neuronal Plasticity; Neurons; Oligosaccharides; Outcome; Pathway interactions; Pattern; Play; Polysaccharides; Process; Proteoglycan; Publishing; Recovery; Regimen; Regulation; Rehabilitation therapy; Reporting; Research; Risk; Role; Sea Cucumbers; Site; Source; Spinal cord injury; Structure; Structure-Activity Relationship; Sulfate; System; Testing; Tissues; Training; Trisaccharides; Work; aggrecan; base; brain tissue; central nervous system injury; chondroitin sulfate glycosaminoglycan; fucoidan; immunoreaction; in vitro Model; in vivo; inhibitor/antagonist; mimetics; neural growth; neuronal growth; novel; programs; regenerative; relating to nervous system; screening; sugar; tool

Neurons in the adult mammalian central nervous system (CNS) do not regenerate after injury. One major factor reported to contribute to reduced regenerative potential is the inhibitory effect of chondroitin sulfate (CS) and keratan sulfate (KS)-containing proteoglycans (CS/KSPGs) on neuronal outgrowth and neural plasticity. Of note, the effects of CS and KS in aggrecan are neither additive nor synergistic, which suggests that CS and KS may act together in a single or closely related set of pathways. Disruption of either glycosaminoglycan (GAG)-target interaction should increase neuronal regeneration and rehabilitation. We propose to develop new tools to understand in detail the structure-activity relationship (SAR) of CS and KS oligosaccharide responsible for modulation of the neuronal outgrowth inhibition in vitro. For this, we will exploit in our research sulfated glycan oligosaccharides of unique and regular structures. The extensive library of structurally defined GAG and GAG-mimetic oligosaccharides (especially those derived from marine sources) will allow us to disrupt the CS/KS-dependent down-regulation effect in neural outgrowth. At the end of this project, besides understanding the structural requirements, particularly sulfation patterns and chain lengths, of sulfated glycans in the process of axon inhibition, we will be also able to present a library of sugars that can be beneficial to modulate the inhibitory process of neural growth when exogenously applied in the system. This project not only adds new information to the community regarding the actual contribution of CS and KS of aggrecan in neuronal outgrowth inhibition but will also offer new molecular tools to be used for controlling this process.

成年哺乳动物中枢神经系统（CNS）中的神经元在受伤后不会再生。一个专业 据报道，导致再生潜力降低的因素是硫酸软骨素 (CS) 的抑制作用 和含有硫酸角质素 (KS) 的蛋白聚糖 (CS/KSPG) 对神经元生长和神经可塑性的影响。的 请注意，CS 和 KS 在聚集蛋白聚糖中的作用既不是相加的也不是协同的，这表明 CS 和 KS 可以在单一或密切相关的一组途径中一起作用。糖胺聚糖（GAG）与靶标相互作用的破坏应该会增加神经元的再生和康复。我们建议开发新工具 详细了解 CS 和 KS 寡糖的构效关系 (SAR) 体外神经元生长抑制的调节。为此，我们将在研究中利用硫酸聚糖 具有独特且规则结构的寡糖。结构明确的 GAG 和 GAG 模拟寡糖（尤其是来自海洋来源的寡糖）的广泛库将使我们能够破坏神经生长中 CS/KS 依赖性下调效应。在这个项目结束时，除了了解 硫酸化聚糖在加工过程中的结构要求，特别是硫酸化模式和链长 轴突抑制，我们还将能够提供一个糖库，有利于调节 当外源性应用于系统时神经生长的抑制过程。该项目不仅增加了新 向社区提供有关聚集蛋白聚糖的 CS 和 KS 在神经元中的实际贡献的信息 生长抑制，但也将提供新的分子工具用于控制这一过程。