Our researchers seek to understand the structure, functionality, and behaviour of biologically important molecules from the atomic to the macro-molecular scale. By combining cutting-edge techniques such as electron microscopy, mass spectrometry, and single-molecule imaging with computational and biochemical approaches, we aim to unravel the structure and behaviours of proteins to better understand their function.
Our research integrates technologies in human pluripotent stem cell (hPSC) biology, neuroscience, and bioengineering to create cellular models of the human nervous system. Specifically, we work on establishing new techniques for differentiating hPSCs into various neural lineages, such as dorsal root ganglia sensory neurons, cortical neurons and auditory neurons. Our work plays a pivotal role in advancing our understanding of human neurodevelopment and has impact on regenerative medicine applications for neurological disorders, specifically Friedreich's ataxia (FA) and hearing loss.
Our laboratory has also developed valuable tools for collaborative research in modelling neurodegenerative conditions. This includes generation of NGN2 transgenic hPSC lines, which allows for rapid conversion of neurons in vitro (following the protocol of Fernandopulle et al.). Our transgenic hPSC lines includes FA induced pluripotent stem cell lines (iPSC) and their corresponding isogenic control iPSC lines, that were developed by Dr Marek Napierala (owned by University of Alabama, USA). The transgenic cell lines have been applied to study disease mechanisms underlying FA and to test potential therapeutic interventions, including candidate pharmaceutical compounds and gene therapy.
The Dowton group is directed at understanding how DNA molecules evolve with particular interest in the mitoochondrial genome, which has remarkably little non-coding DNA. For example, protein-coding regions account for 70% of the mitochondrial genome in humans, but only 1% of the nuclear genome. Genes are sandwiched together, often with only a few non-coding nucleotides between them. This has resulted in remarkable stability in the arrangement of genes, as any gene movement is likely to disrupt the function of a neighbouring gene; many genes are in precisely the same position that they were in hundreds of millions of years ago. Our research has focussed on one lineage of animals that have broken this trend. The Hymenoptera (ants, bees and wasps) have mitochondrial genomes whose genes change positions relatively frequently. By sequencing related hymenopteran mitochondrial genomes, we can identify the sorts of changes that have occurred, and better understand the fundamental mechanism of mitochondrial gene rearrangement.
View Professor Mark Dowton's Scholars page
Contact mdowton@uow.edu.au for more information.
The Ecroyd research focus is in the field of protein homeostasis (proteostasis), an important area of research as disturbances in proteostasis can lead to protein aggregation (i.e. the clumping of proteins into large deposits), a pathological hallmark of many human diseases, including Alzheimer’s disease, Parkinson’s disease and Motor Neurone Disease (MND). Research in the Ecroyd lab focuses on the role of molecular chaperone proteins in proteostasis. This is because these are the body’s front-line defenders against protein aggregation. By identifying innovative approaches to activate molecular chaperones, the group aims to develop new drugs to treat, and ultimately prevent, neurodegenerative diseases such as MND.
Work currently being undertaken in this laboratory extends from molecular biology-based techniques to recombinant protein expression and purification, in vitro biochemical assays of chaperone protein activity, to mammalian cell culture and the study of protein expression and modification in animal tissues. Of late, my group has been involved in developing novel techniques to study heat-shock chaperone function in cells and a flow cytometry-based method to count and physically isolate protein inclusions from cells. The group are also developing new single-molecule approaches so that, for the first time, we can see and characterise the interactions between heat-shock proteins and aggregation-prone proteins.
The small heat shock protein Hsp27 (HSPB1) bound to the surface of an a-synuclein amyloid fibril. This image was obtained using Total Internal Reflection Fluoresence (TIRF) microscopy. We think, by binding to amyloid fibrils, these molecular chaperones protect the cell from their toxic effects.
View Professor Heath Ecroyd's Scholars page
Contact heathe@uow.edu.au for more information.
The development and application of high-resolution mass spectrometry imaging methods to study localized chemical processes occurring within complex surfaces such as biological tissue and cells. MSI developments focus on are (i) improving spatial resolution; (ii) the types of molecules that can be detected using MALDI-based approaches; and (iii) techniques to unambiguously identify the detected molecules. Key application areas include visualizing and understanding alterations in lipid biochemistry occurring throughout heterogeneous tissues, and more generally, disease-induced bimolecular alterations that occurring within diseased tissues.
Contact sellis@uow.edu.au for information.
Humans are experiencing stress at higher levels than ever before. In the developed world, this appears to be a product of our way of life, where we are busier than ever yet more isolated from our natural environments and communities. In other places, war, conflict, climate change and environmental disasters are displacing people from their homes and countries at unprecedented rates.
Stress is not always bad for us. It’s what gets us out of bed and gives us laser focus. Yet stress that is stronger than an individual’s ability to adapt and cope is one of the leading risk factors for developing severe mental illnesses including depression, bipolar disorder, schizophrenia, post-traumatic stress disorder, and anxiety. In fact, the World Health Organisation predicts that by 2030, one third of all disease burden in the world will be caused by stress.
We are therefore at a crossroad. We urgently need an improved understanding of the detailed and widespread effects of stress on human biology, so that we can identify people who are vulnerable to the effects of stress and improve their resilience. To do this, we must first understand what are the biological effects of stress and how does stress raise risk to mental illness.
An inverse Colgi-cox stained image of the human brain cortex by Dominical Kaul
Our goal
The Matosin Lab broadly aims to understand how stress contributes to the development of mental illness. The lab has two main streams:
Our values in and out of the lab
Scientific excellence, impactful research, collaboration, openness and authenticity, training and connecting the next generation of scientists with world leaders, enthusiasm, creating an environment that is positive and encourages teamwork and generosity.
View Dr Natalie Matosin's Scholars page
Contact nmatosin@uow.edu.au for more information.
Life is driven by chemistry. Digesting food, contracting muscle, eyesight, and all of the other processes that keep us alive are driven by it. Physicist Richard Feynman said “it is very easy to answer many of these fundamental biological questions; you just look at the thing!” Knowing the three-dimensional shapes of important biological molecules can help us understand how they work. Knowing their structure can inform the discovery of therapeutic agents. So how do we “see” the structures of biological molecules? We use a technique called X-ray diffraction and computational techniques to study the structure and dynamics of two important classes biological molecules: proteins and nucleic acids.
Our research is exemplified by the following projects:
View Associate Professor Aaron Oakley's Scholars page
Contact aarono@uow.edu.au for more information.
The Immunology and Cell Signalling Group focuses on extracellular signalling pathways between immune cells in the context of health and disease in humans and companion animals. A key focus of the group is the study of signalling pathways mediated by extracellular ATP and purinergic receptors (mainly P2X7, P2X4, P2Y12 and A2A), as well ecto-enzymes (mainly CD39 and CD73), which regulate the availability of extracellular nucleotides and nucleosides (see Figure). These pathways are currently being investigated in the context of immunity, inflammation and blood clotting, as well as diseases such as cancer, graft-versus-host disease, psoriasis, inflammatory pain and motor neuron disease.
To better understand the above, the group utilises a number of technologies and approaches including flow cytometry, mass cytometry, cation flux assays, recombinant DNA techniques, mouse models including humanised mice, and blood samples from people, cats and dogs.
Purinergic signaling pathways amongst immune cells. ATP released from damage, infected or malignant cells can activate P2X7 (and P2X4, not shown) on leukocytes to promote inflammation and immunity. Extracellular ATP can be sequentially degraded by the ecto-enzymes CD39 and CD73 to adenosine, which can activate A2A on leukocytes to suppress inflammation and immunity. ADP released from cells or resulting from ATP degradation can activate P2Y12 on platelets to promote coagulation.
View Associate Professor Ronald Sluyters Scholar page
Contact rsluyter@uow.edu.au for more information.
The Tolun group studies the bio-nano-machines carrying out processes involving nucleic acids such as DNA recombination, replication, repair and RNA transcription. We use molecular imaging (electron microscopy), structural biology (Cryo-EM), biochemistry and molecular biology.
The main technique utilised in my group is electron microscopy (EM). In addition to the state-of-the-art cryo-EM, we also use the classical EM techniques such as shadow-casting (i.e., metal shadowing) and negative staining. Shadow-casting is a technique ideally suited for visualising DNA and DNA-protein complexes at the single-molecule level.
DNA Recombination
Single strand annealing homologous DNA recombination (SSA) is a process found in virtually all life. It is particularly important in the double-strand DNA (dsDNA) viruses, such as the oncogenic viruses Epstein-Barr Virus (EBV) Kaposi's sarcoma-associated herpesvirus (KSHV), and Herpes Simplex Virus 1 (HSV-1). SSA is catalysed by a protein complex called a two-component recombinase (TCR), composed of an exonuclease and an annealase. The exonuclease generates a single-strand DNA (ssDNA) overhang, and the annealase binds to this nascent ssDNA and anneals it to a homologous ssDNA strand.
My research group is using a multi-disciplinary approach to better understand how this machinery works, with a focus on cryo-EM. We are interested in determining the structures of proteins and protein complexes involved in SSA, using cryo-EM.
DNA Replication
In collaboration with the research groups of Nick Dixon, Antoine van Oijen, and Aaron Oakley, we are studying DNA replication to better understand the molecular mechanistic details of this process.
Collaborations
We are a very collaborative group, and in addition to our main interests above, we also work on many collaboration projects to determine the cryo-EM structures of proteins or complexes from other systems. Some of the topics we are working on with our collaborators include transcription, snake venom toxins and chaperons.
View Dr Gökhan Tolun's Scholars page
Contact gokhan_tolun@uow.edu.au for more information
Our lab investigates therapeutic strategies to prevent the development of graft-versus-host disease. Donor stem cell transplantation can be a curative therapy for people with blood cancer. However, in 50% of recipients receiving a donor stem cell transplant, the immune cells in the transplant (graft) attack the patient (host) leading to graft-versus-host disease. The donor immune cells are activated damaging the liver, gut and skin and other organs in the recipient and this leads to a debilitating and painful disease with a 15% mortality rate. Current therapies are limited, using broad range immunosuppression, which leads to cancer relapse and infection.
In our research laboratory, we use strategies that specifically deplete the donor immune cells that attack the organs to prevent graft-versus-disease, while retaining the immune cells that respond to cancer and infection. Further, we target the purine signalling pathway, including the P2X7 receptor, known to play a role in graft-versus-host disease development, and we examine combined therapies to prevent disease in preclinical models.
View Dr Debbie Watson’s Scholars page
Contact dwatson@uow.edu.au for more information.
The Wilson research group is focussed on both basic and applied science relating to chaperones and protein folding, with a special emphasis on a novel group of (normally secreted) extracellular chaperones discovered by us. We reported the first known extracellular chaperone in mammals (clusterin) and have continued to discover new examples of this small but growing family of important molecules. Our studies include in vitro structure-function studies of extracellular chaperones, and also encompass work in small animal models (Drosophila, zebrafish and C. elegans) addressing basic science questions and specific disease scenarios. We have also developed new fluorescence-based technology platforms, including a high-throughput flow cytometry system currently being applied in a search for novel drugs to treat motor neurone disease.
A 3-colour image of a stressed cell: nucleus (blue), endoplasmic reticulum (red) and a chaperone (BiP; green)
View Senior Professor Mark Wilson's Scholars page
Contact mrw@uow.edu.au for more information.
The Yerbury lab is dedicated to understanding the molecular mechanisms underpinning Motor Neurone Disease (MND), with a particular focus on protein misfolding and protein aggregation. Utilising a broad array of methods ranging from the fields of biophysics, biochemistry, and cell and molecular biology, we study the basic biological processes that lead to protein aggregation, with the aim of identifying and developing novel therapeutic strategies for the treatment of MND.
Currently, we are developing a powerful high-throughput microscopy method to screen novel and clinically-approved compounds for their protective properties against MND-related protein aggregation in cultured cells. Utilising this approach, we are able to identify clinically-translatable compounds and assess their therapeutic potential in preclinical models, in an effort to uncover novel treatment avenues for MND.
Motor neurons in culture captured using confocal microscopy (Christen Chisholm, PhD candidate)
View Professor Justin Yerbury's Scholars page
Contact jjyerbury@googlemail.com for more information.
Our research efforts focus on developing and applying theoretical and computational tools to understand the structure-dynamics-function relationship in the complex (bio)molecular and nanoscale systems. Complementary to experimental investigations, such studies can gain new insights at the atomic level into the underlying mechanism and provide necessary knowledge for molecular engineering and discovery of novel therapeutics. Current research projects include computational studies of protein-ligand interactions, mechanistic studies of enzymatic reactions, and computer-aided enzyme design.
View Associate Professor Haibo Yu’s Scholar page
Please contact hyu@uow.edu.au for more information.