A high throughput drug screen to identify candidate targets for the treatment of Neurofibromatosis Type 1.

Research Opportunity
PhD students
Department / Centre
Paediatrics
Location
Royal Children’s Hospital/Murdoch Childrens Research Institute
Primary Supervisor Email Number Webpage
Dr Kiymet Bozaoglu kiymet.bozaoglu@mcri.edu.au Personal web page
Co-supervisor Email Number Webpage
Prof Paul Lockhart paul.lockhart@mcri.edu.au Personal web page
A/Prof Jonathan Payne jonathan.payne@mcri.edu.au

Summary NF1 is a single-gene disorder caused by a loss-of-function mutation in the NF1 gene resulting in a reduction of the protein neurofibromin. Cognitive deficits occur in approximately 80% of children with the genetic syndrome, neurofibromatosis type 1 (NF1), making them the greatest cause of disability for individuals with this lifelong genetic condition. These manifest as academic failure due to learning disabilities (70%), attention deficit-hyperactivity disorder (ADHD; 40%) and a significantly increased risk for autism spectrum disorder (ASD; 25%).

Project Details

NF1 is a single-gene disorder caused by a loss-of-function mutation in the NF1 gene resulting in a reduction of the protein neurofibromin. Cognitive deficits occur in approximately 80% of children with the genetic syndrome, neurofibromatosis type 1 (NF1), making them the greatest cause of disability for individuals with this lifelong genetic condition. These manifest as academic failure due to learning disabilities (70%), attention deficit-hyperactivity disorder (ADHD; 40%) and a significantly increased risk for autism spectrum disorder (ASD; 25%).     

Current therapies, whether medication or behavioural interventions, are often ineffective because they use 'trial and error' approaches targeting symptoms, rather than the cause. Therefore is an urgent need to discover new therapeutics for the impairing neurodevelopmental symptoms experienced by children with NF1.   

This drug screening project aims to identify compounds that may modulate neurofibromin expression using patient derived stem cell lines.. Cells will be differentiated into neuronal cells and then used to perform a high throughput drug screen. Functional readouts from the screen will include assessment of neurofibromin steadystate levels as well as structural readouts including neurite development, length and number of neurons in the cultures. Once candidate compounds have been identified, validation assays will be performed in NF1-patient derived stem cell models to determine whether the compound treatment/s can ameliorate neuronal deficits. Extensive functional analyses will be performed including the assessment of neuron growth and maturation (using immunofluorescence assays), neuron function (using multi electrode arrays and calcium imaging) as well as biochemical assays such western blotting, real time PCR and ELISAs to determine biological changes in our patient lines versus control lines.    



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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.

Department / Centre

Paediatrics

Research Node

Royal Children’s Hospital/Murdoch Childrens Research Institute

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