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。一个主要 据报道有助于降低再生潜力的因素是硫酸软骨素（CS）的抑制作用 和硫酸葡萄糖（KS） - 神经元出生和神经可塑性的含有蛋白聚糖（CS/KSPGS）。的 请注意，CS和KS在Aggrecan中的影响既不是加性的也不是协同作用，这表明CS和KS 可以在一组或密切相关的一组途径中一起起作用。糖胺聚糖（GAG） - 靶标相互作用的破坏应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寡糖的结构活性关系（SAR）负责 神经元出生抑制的调节体外。为此，我们将在我们的研究中利用硫化的聚糖 独特和规则结构的寡糖。结构定义的GAG和GAG模拟寡糖（尤其是从海洋来源衍生的）的广泛文库将使我们能够破坏CS/KS依赖性下调在神经出生中的作用。在该项目的结尾，除了了解 结构要求，尤其是硫化聚糖的硫化模式和链长度 轴突抑制，我们还将能够提出一个可以调节的糖库 当外源应用系统中时，神经生长的抑制作用。这个项目不仅添加了新的 向社区提供有关Aggrecan CS和KS在神经元中的实际贡献的信息 出现抑制作用，但还将提供用于控制此过程的新分子工具。