# Chemical approaches to understanding chondroitin sulfate glycosaminoglycans and their roles in brain plasticity and pathology

> **NIH NIH R01** · CALIFORNIA INSTITUTE OF TECHNOLOGY · 2024 · $681,131

## Abstract

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.

## Key facts

- **NIH application ID:** 10885708
- **Project number:** 2R01AG087519-09
- **Recipient organization:** CALIFORNIA INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Linda C Hsieh-Wilson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $681,131
- **Award type:** 2
- **Project period:** 2024-06-15 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10885708

## Citation

> US National Institutes of Health, RePORTER application 10885708, Chemical approaches to understanding chondroitin sulfate glycosaminoglycans and their roles in brain plasticity and pathology (2R01AG087519-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10885708. Licensed CC0.

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