Disruption of CS/KSPG-Mediated Neuronal Outgrowth Inhibition

成年哺乳动物中枢神经系统(CNS)中的神经元在损伤后不能再生。一大专业 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 和含有硫酸角蛋白(KS)的蛋白多糖(CS/KSPGs)对神经元生长和神经可塑性的影响。的 值得注意的是，CS和KS在集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共同作用。糖胺多聚糖(GAG)-靶相互作用的中断应能增加神经元的再生和康复。我们建议开发新的工具 详细了解壳寡糖和硫代低聚糖的构效关系 神经元体外生长抑制的调控。为此，我们将在我们的研究中开发硫化多糖 具有独特和规则结构的低聚糖。广泛的结构定义的GAG和GAG模拟寡糖(特别是那些来自海洋来源的低聚糖)的文库将使我们能够破坏神经生长中依赖CS/KS的下调效应。在本项目结束时，除了了解 硫化葡聚糖加工过程中的结构要求，特别是硫酸盐化模式和链长 轴突抑制，我们也将能够提出一个糖库，可以有益于调节 当外源应用于系统时，抑制神经生长的过程。这个项目不仅增加了新的 关于聚集素的CS和KS在神经元中的实际贡献的信息 抑制生长，但也将提供新的分子工具用于控制这一过程。

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.