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20022024

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Personal profile

Biography

I am the Professor of Neurobiology and Neurochemistry, and Deputy Dean (Research & Innovation) in the Faculty of Medicine, Health & Human Sciences. I lead the Neurochemistry & Molecular Therapeutics Group within the Macquarie University Centre for Motor Neuron Disease Research.

My main areas of research interest involve a multi-disciplinary approach to understanding the biochemical, molecular and cellular mechanisms that underpin how neurons respond to injury or neurodegenerative disease, and how non-neuronal cells (glia) are involved in modulating this process.   More recently, we have taken our understanding of disease mechanisms to develop molecular therapies for Motor Neuron Disease (MND, also known as amyotrophic lateral sclerosis or ALS). We have developed gene therapies for MND/ALS, which have been licensed to Celosia Therapeutics. I am the co-Founder and Chief Scientific Officer of CelosiaTX.

I completed my PhD in molecular biology in 2003, and have since led a research team at the University of Tasmania (2004-2013) and at Macquarie University since 2013.

Research interests

In 2013, I co-led the creation of the Centre for Motor Neuron Disease Research at Macquarie University.  This Research Centre takes a multidisciplinary approach to unravelling the molecular origins of MND through identifying the genetic and epigenetic causes of MND, biochemical and proteomic evaluation of protein defects in MND, cell biology and animal models of disease, and patient biomarker studies and clinical trials. My current research program involves a multidisciplinary approach including proteomics, molecular and cellular biology, synthetic biology and molecular bioengineering, neuropathology and neuroimaging, and animal models of MND/neurodegeneration. I work closely with valued collaborators Dr Albert Lee and A/Professor Marco Morsch. Several of my current research projects are described briefly below:

Understanding the role of abnormal protein aggregates in MND disease mechanisms | This program of research aims to understand how mutations in MND proteins cause them to inappropriately aggregate and accumulate inside motor neurons, and how this leads to degeneration. Our studies have focused upon characterizing a new MND gene (CCNF) we have identified in a project led by Professor Ian Blair and A/Professor Kelly Williams (Williams et al, Nature Communications, 2016). Our research has now mapped out in precise detail how the resultant mutant cyclin F protein causes specific defects in the ubiquitin-proteasome system, ultimately leading to inappropriate accumulation of proteins that causes apoptosis (Lee et al, 2017; 2018; Hogan et al, 2017). A key discovery was the identification of TDP-43 as a specific ubiquitylation substrate of cyclin F (Rayner et al, 2022), and the corresponding demonstration that cyclin F is an endogenous regulator of TDP-43 homeostasis. 

Developing AAV gene therapies for MND | We have determined that therapeutic overexpression of cyclin F can clear pathological accumulation of TDP-43 in experimental models of MND. Through this process, we have bioengineered therapeutically-optimised variants of cyclin F. We have also used some innovative synthetic biology approaches to create molecular switches that can be used to control the levels of therapeutic gene expression. We are currently undertaking pre-clinical trials of the cyclin F AAV-gene therapy – supported through a FightMND Drug Development Grant.

In December 2022, Macquarie University launched a spin-out company called Celosia Therapeutics, to take forwards the development of this gene therapy.

Research student supervision

We are always on the look out for enthusiastic researchers to join our program. At the moment, we are particularly interested in people with skills in molecular biology, synthetic biology, and computational biology/bioinformatics/AI (particularly non-coding RNA, and RNA-protein interactions).

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