Congenital disorders of glycosylation (CDG) comprise more than 200 individually rare inherited metabolic disorders and represent one of the most rapidly expanding groups of inborn errors of metabolism. While abnormalities of protein glycosylation have traditionally been considered the primary disease mechanism, many CDG patients present with severe neurological manifestations that remain only partially understood.
Recent work from our research group has identified glycosphingolipids (GSLs), including gangliosides, as a potentially critical but underexplored disease mechanism in CDG. Because glycosphingolipids constitute the majority of glycan structures in the central nervous system and are essential for neuronal development, signalling and synaptic function, understanding their dysregulation may open entirely new therapeutic avenues.
This PhD project forms part of a larger translational research programme aimed at developing mechanism-based treatments for CDG. The successful candidate will work at the intersection of rare disease research, neuroscience, systems biology, metabolomics and lipidomics.
RESEARCH OBJECTIVES
Objective 1 - Defining glycosphingolipid abnormalities in CDG
The candidate will perform comprehensive glycosphingolipid and ganglioside profiling in an extensive collection of patient-derived fibroblasts representing multiple CDG subtypes. Using state-of-the-art lipidomics and tracer-based metabolomics, metabolic bottlenecks and pathway rerouting events will be identified. Treatment options will be explored.
Objective 2 - Investigating disease mechanisms and therapeutic opportunities
Key findings will be validated in neuronal-relevant cellular models generated through CRISPR-mediated genetic engineering and pharmacological perturbation approaches. Multi-omics integration (lipidomics, metabolomics, proteomics and transcriptomics) will be used to identify pathogenic mechanisms and nominate therapeutic interventions, including glycosphingolipid supplementation and drug repurposing strategies.
The project builds upon unique patient cohorts, extensive preliminary data, and internationally recognised expertise in congenital disorders of glycosylation.
