Expanding the molecular understanding, and advancing personalised therapeutics for KIF1A-Associated Neurological Disorders

Research Opportunity
PhD students
Department / Centre
Paediatrics
Location
Royal Children’s Hospital/Murdoch Childrens Research Institute
Primary Supervisor Email Number Webpage
Dr Simranpreet Kaur simran.kaur@mcri.edu.au 03-83416268 Personal web page
Co-supervisor Email Number Webpage
Prof John Christodoulou john.christodoulou@mcri.edu.au Personal web page
A/Prof Wendy Gold wendy.gold@sydney.edu.au

Summary Background Kinesin-3 family member 1A (KIF1A) encodes a neuron-specific kinesin motor protein essential for ATP-dependent anterograde axonal transport of synaptic cargos along the microtubule network in brain cells. The N-terminal motor domain of KIF1A forms the “head” that “walks” along the microtubules in a stepwise manner for anterograde transportation of specific cargos docked at the C-terminal “tail” domain using energy from ATP hydrolysis. Variants in the KIF1A gene have been found to result in a complex spectrum of neurodegenerative conditions, collectively referred to as KIF1A-associated neurological disorders (KANDs). In this proposal, we will address a wide gap in our understanding of KIF1A at the molecular and therapeutic level. Success in this project has the scope to accelerate the long-term vision of scientific therapeutics-based research to improve the health of children battling with the progressive KAND disorder and related neurological disorders.

Project Details

Hypothesis(es) and Aims
Hypothesis:
Enhancement of the molecular understanding of KIF1A and generation of tools to evaluate the trafficking of defective KIF1A will accelerate novel therapeutic options for KIF1A-related disorders.
Aims:
Aim 1: Multi-omics approach to understand biological pathway(s) implicated in KAND
a)To perform proteomics, phospho-proteomics, transcriptomics, and metabolomics using KIF1A-mutant patient organoids.
b)Through these multi-omic studies, to identify novel genes, proteins, metabolites and cellular pathways that are specifically dysregulated in KIF1A-mutant patient organoids (relative to controls).
c)To validate key novel targets using molecular and biochemical techniques.
d)To identify novel KIF1A-specific cargos critical for neuronal survival and function.
Aim 2: Small-molecule based personalised drug discovery for KAND.
a)To develop a stable COS-7 cell-based model to study different KIF1A patient specific variants.
b)To identify small-molecules for KAND using high-throughput drug screening technologies in COS-7 cell based model.
c)To use in-silico computer-aided drug design to identify drug-like small molecules for KAND therapeutics.
d)To validate the selected hit compounds in KIF1A patient-specific iPSC-derived neuronal cell models.
Aim 3: Generating tools for AAV-based therapeutics for KAND.
a)To develop a KIF1A mini-gene using COS-7 cell-based model.
b)To test the function of the KIF1A mini-gene in-vitro in stably transfected COS-7 cells-based model 
c)To validate the function of the KIF1A mini-gene in KIF1A patient-derived neurons.

Faculty Research Themes

Neuroscience

School Research Themes

Neuroscience & Psychiatry, 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.

Department / Centre

Paediatrics

Research Group / Unit / Centre

Neurodevelopmental Genomics Research

Research Node

Royal Children’s Hospital/Murdoch Childrens Research Institute

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