Disruption of CS/KSPG-Mediated Neuronal Outgrowth Inhibition

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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.