Electronic Thesis and Dissertation Repository

Thesis Format

Monograph

Degree

Master of Science

Program

Neuroscience

Supervisor

Brown, Arthur

Abstract

Chondroitin sulfate proteoglycans (CSPGs) inhibit of neural regeneration in the central nervous system after injury. Our laboratory identified SRY-BOX Transcription Factor 9 (SOX9) as a key driver of genes involved in CSPG synthesis. Conditional SOX9 ablation reduces CSPG levels and improves locomotor recovery post-spinal cord injury (SCI) in mice by enhancing axon sprouting. This thesis identifies and evaluates novel small molecule inhibitors of SOX9, focusing on the lead compound TD874. Through in silico screening and in vitro assays, we identified several SOX9 inhibitors and assessed their effects on SOX9 target gene expression and metabolic stability. TD874 emerged as the most promising candidate, significantly inhibiting SOX9 target genes and showing favourable pharmacokinetic properties in vivo. TD874 treatment markedly reduced SOX9 target gene expression in the injured spinal cord, highlighting its potential as a therapeutic agent for SCI. Future studies will optimize TD874 formulations, and evaluate its pharmacodynamics and efficacy.

Summary for Lay Audience

Spinal cord injuries (SCI) can lead to severe and often permanent disabilities, largely because certain molecules, called chondroitin sulfate proteoglycans (CSPGs), block the regrowth of damaged nerves. Our research has found that a specific protein, SOX9, is crucial in producing these CSPGs. In previous studies, removing SOX9 in mice led to lower levels of CSPGs and better recovery of movement after spinal cord injury, mainly because it provided favourable, less inhibitory, environment for the nerves to grow in. This thesis focused on finding new drugs that can inhibit SOX9 and reduce harmful CSPGs. We used computer-based methods to screen for potential drugs and then tested them in the lab. The most promising drug we found is called TD874. This drug significantly reduced the activity of genes controlled by SOX9 and showed good properties when tested in living animals. Importantly, treatment with TD874 led to a noticeable decrease in SOX9 activity in injured spinal cords, suggesting it could be a useful treatment for SCI. Future work will focus on improving how TD874 is formulated, understanding how it works in more detail, and testing its ability to lower CSPG levels and improve recovery in more advanced animal models of spinal cord injury.

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Available for download on Wednesday, July 01, 2026

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