Development of novel human stem cell derived models of beta-propeller protein-associated neurodegeneration for disease modelling and drug screening

Research Opportunity
PhD students
Location
Royal Children’s Hospital/Murdoch Childrens Research Institute
Primary Supervisor Email Number Webpage
A/Prof Paul Lockhart paul.lockhart@mcri.edu.au 8341 6322 Personal web page
Co-supervisor Email Number Webpage
Prof Martin Delatycki martin.delatycki@vcgs.org.au Personal web page

Summary Development of novel human stem cell derived models of beta-propeller protein-associated neurodegeneration for disease modelling and drug screening

Project Details

Beta-propeller Protein-Associated Neurodegeneration (BPAN) is a rare, X-linked neurological disorder characterised by intellectual disability, seizures and ataxia in early childhood. The condition progresses rapidly leading to development of Parkinsonism, dystonia and cognitive impairment in adolescence/early adulthood. Children affected by BPAN display brain iron accumulation at an early age, leading to classification of BPAN under a group of disorders known as neurodegeneration with brain iron accumulation (NBIA5).

BPAN is caused by pathogenic variants in the WDR45 gene which encodes the WD repeat-containing protein 45. The protein plays an important role in autophagy, a biochemical mechanism that regulates degradation and recycling of cellular components. However, very little is known about the cellular effects of variants in WDR45 on the nervous system and how it causes BPAN. Hence, there are no drugs available that can cure or slow the progression of BPAN.

In this project we will use patient-derived induced pluripotent stem cells (iPSC) to generate brain cell cultures in order study disease-specific mechanisms and test potential drug treatments. The first step will be to examine the effects of pathogenic variants on electrophysiological, biochemical and morphological properties of differentiated cells, with a focus on neurons. Drugs targeting relevant pathways (e.g. autophagy, iron metabolism, etc.) will be used to determine their effectiveness in modulating disease phenotype in the neuron. This will help establish the validity of our culture model as a vital preclinical tool for BPAN drug screening. The prospective candidate will get the opportunity to learn a range of laboratory techniques including stem cell culturing, differentiation of stem cells into neurons, electrophysiology, immunocytochemistry, microscopy, drug screening assays, real-time qPCR and western blot analysis.



Faculty Research Themes

Child Health

School Research Themes

Child Health in Medicine



Research Opportunities

PhD students
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.

Research Node

Royal Children’s Hospital/Murdoch Childrens Research Institute

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