There are major gaps in our basic understanding of the inborn error of metabolism, NAXD deficiency, a febrile-induced infantile neurodegenerative disease, and no specific treatments demonstrating long-term benefit are available.

It is likely that disruption of core metabolic processes in this disorder, including ATP synthesis, the Krebs cycle and other pathways could be aggravated by intercurrent illnesses and challenge an already compromised energetic state.

Advances in next generation sequencing provide rapid diagnosis of critically ill infants, highlighting the need for current research to focus on understanding underlying disease mechanisms to develop timely therapeutic interventions.

Our team was the first to identify that pathogenic variants in NAXD cause a rapid and lethal neurodegenerative disease following what would normally be a mild illness. Our skilled team is perfectly positioned to better understand the biology of NAXD deficiency and to develop iPSC-based models to study NAXD disorder.

The project aims are: Aim 1: To develop a better understanding of the consequences of NAXD deficiency in relevant cell types (neurons and microglia) which will aid in understanding disease mechanisms and identifying targeted therapies. Aim 2: To screen efficacy of hits from an FDA-approved drug library, and niacin-based compounds, and test their toxicity, in relevant diseased cell types. We will address the significant knowledge gap of how genetic abnormalities in metabolite damage and repair pathways affect brain function, in particular the processes involved in repairing the central metabolic enzyme cofactor, NAD.

To do this we will use cellular models that we have developed, and will utilise a high-throughput drug repurposing program to identify potential targeted therapies to protect brain function in children with NAD metabolite repair disorders.

If you are interested in this PhD project and meet the entry requirements, send an email to Dr Nicole van Bergen (primary supervisor,nicole.vanbergen@mcri.edu.au) explaining why you would like to be considered for this opportunity and how the project fits with your experience and interests. Make sure to attach your CV and transcripts to the email. Only enquiries sent via email that follow all these instructions will be considered.

Chair in Genomic Medicine

Department of Paediatrics

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Division

Faculty of Medicine, Dentistry and Health Sciences

Primary Interest

inborn errors of metabolism

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