NAXD deficiency: unravelling the pathological consequences, and evaluation of therapeutic opportunities

Research Opportunity
Honours, Master of Biomedical Science
Number of Honour Places Available
1
Number of Master Places Available
1
Department
Paediatrics
Location
Royal Children’s Hospital/Murdoch Childrens Research Institute
Primary Supervisor Email Number Webpage
Doctor Nicole Van Bergen nicole.vanbergen@mcri.edu.au Personal web page
Co-supervisor Email Number Webpage
Professor John Christodoulou john.christodoulou@mcri.edu.au Personal web page

Summary This research proposal will enhance our understanding of this new genetic disorder by uncovering molecular pathways perturbed by loss of gene function, and may provide an understanding of therapeutic targets to protect the brain when children with gene mutations suffer febrile illnesses that would otherwise overload the repair system.

Project Details

There are major gaps in our basic understanding of the inborn error of metabolism, NAXD deficiency, and no specific treatments are available. It is likely that disruption of core metabolic processes including ATP synthesis, the Krebs cycle and other pathways could be aggravated by intercurrent illnesses and challenge an already compromised energetic state.   Our research team focuses on uncovering the molecular basis of undiagnosed childhood brain disorders using genomic sequencing. We have recently identified mutations in a new gene called NAXD in young children who were born healthy and developed normally until a febrile episode or common infection triggered failure of the metabolite repair system associated with NAXD. All of these children died rapidly during such an episode. We have shown that mitochondrial energy production was severely compromised in skin cells from these children and was associated with a vast accumulation of damaged metabolites. Prior to our discovery, mutations in this gene had never been described before in humans. This work was published in Brain in January 2019.  We will utilise a number of techniques to investigate mitochondrial impairment including, but not limited to cell culture, mitochondrial inhibition assays, mitochondrial enzyme activities and respiration, protein expression, gene expression, metabolite extraction and analysis and proteomics. There is scope to expand this project from an Honours to a Masters project by the inclusion of stem cell modelling for screening of potential therapeutic agents for NAXD deficiency, using patient-derived and gene-corrected iPSC for differentiation into relevant cell types for NAXD deficiency.   This research proposal will enhance our understanding of this new genetic disorder by uncovering molecular pathways perturbed by loss of gene function, and may provide an understanding of therapeutic targets to protect the brain when children with gene mutations suffer febrile illnesses that would otherwise overload the repair system.



Faculty Research Themes

Child Health

School Research Themes

Child Health in Medicine



Research Opportunities

Honours, Master of Biomedical Science
Students who are interested in joining this project will need to consider their elegibility as well as other requirements before contacting the supervisor of this research

Graduate Research application

Honours application

Key Contact

For further information about this research, please contact a supervisor.

Department

Paediatrics

Research Node

Royal Children’s Hospital/Murdoch Childrens Research Institute

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