Development of novel human stem cell derived models of beta-propeller protein-associated neurodegeneration for disease modelling and drug screening
- Research Opportunity
- PhD students
- Royal Children’s Hospital/Murdoch Childrens Research Institute
|A/Prof Paul Lockhartfirstname.lastname@example.org||8341 6322||Personal web page|
|Prof Martin Delatyckiemail@example.com||Personal web page|
Summary Development of novel human stem cell derived models of beta-propeller protein-associated neurodegeneration for disease modelling and drug screening
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.
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Research NodeRoyal Children’s Hospital/Murdoch Childrens Research Institute
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