Chemical approaches to understanding chondroitin sulfate glycosaminoglycans and their roles in brain plasticity and pathology - Project Summary/Abstract This project will focus on chondroitin sulfate glycosaminoglycans (CS GAGs), a class of polysaccharides that plays important roles in development, immunity, viral invasion, cancer, and central nervous system (CNS) injury. CS GAGs undergo spatiotemporally regulated sulfation, giving rise to diverse regiospecific sulfation patterns. However, efforts to identify functions for specific sulfation motifs have been hampered by the structural complexity of CS GAGs and a lack of tools to study them. In this grant, we will combine the power of organic chemistry and neurobiology to overcome these challenges and identify novel functions for specific motifs in the CNS. The broad objectives of this program are to: (1) advance a fundamental understanding of the structure-function relationships of CS GAGs; (2) identify new functions for specific CS sulfation motifs in the brain, building on our recent discoveries in neuroplasticity, memory, remyelination and immunity; and (3) develop new chemical approaches to study and manipulate GAG-mediated processes, with the goal of reducing neuroinflammation and stimulating plasticity and neuronal repair. During the last granting period, we developed new chemical tools to modulate specific GAG sulfation motifs and generated conditional knockout mice lacking the CS-A and CS-E motifs in the brain. Our studies revealed exciting new functions for CS 4-O-sulfation in the regulation of perineuronal nets (PNNs), specialized ECM structures that restrict plasticity, and social memory. We also found that the CS-E motif contributes to neuroinflammation and axon remyelination. In the present grant, we will build on these exciting findings and continue to develop new molecules for manipulating CS sulfation (Aims 1a, 1b, and 3b) and ECM remodeling (Aim 1). Using these approaches, we will study how CS sulfation regulates signaling pathways important for excitatory synaptogenesis (Aim 2a). We will also investigate the impact of CS sulfation on the polarization of immune cells toward pathogenic phenotypes that drive neuroinflammation (Aim 3a) and the maturation of cells critical for axon remyelination (Aim 4a). Finally, we will explore the potential to use our sulfation and ECM remodeling agents to control PNNs, attenuate neuroinflammation, and promote remyelination (Aims 2b, 3b, and 4b). These studies are expected to advance a fundamental understanding of GAGs and expand current paradigms for how CS GAGs are viewed, demonstrating that specific motifs act as sequence-specific ligands and actively regulate processes important for neurodegenerative diseases such as Alzheimer's disease and multiple sclerosis. If successful, these studies could ultimately identify novel therapeutic targets or strategies for stimulating synaptic plasticity and neuronal repair.
