In 2017, our RFA has provided funding to research projects in the following areas:
Young in mind - What is 'embryonic' PLAG1 doing in the adult brain?
Chief investigator: Dr Bert De Groef
Co Investigators: Dr Sylvia Grommen and Prof Maarten van den Buuse
Mostly known for its tumourigenic role in various types of human cancers, the transcription factor PLAG1 is also crucial for normal development, growth and reproduction. Recent preliminary data from our group, however, showed that PLAG1 is also widely expressed in the adult brain and PLAG1 deficiency causes changes in brain cell proliferation and morphology of cerebral blood vessels. Moreover, knock-out animals showed increased anxiety-like behaviour (females) and altered sleeping behaviour. This project aims to further elucidate this role of PLAG1 in brain by studying the effect of Plag1 knock-out on adult neuroanatomy, cognition and social behaviour.
Can protecting the endothelium protect the brain after stroke?
Chief investigator: Dr Michael De Silva
Co Investigators: Prof Christopher Sobey
Stroke is a devastating disease that leads to permanent brain damage and is a leading cause of death and disability in Australia. At present, we have limited therapeutic options for patients who have had a stroke. Therefore, the development of new therapies that protect tissue from stroke damage is desperately needed. Peroxisome Proliferator-Activated Receptor gamma (PPARγ) is a transcription factor that has been shown to have protective effects, including in blood vessels. Previous studies have shown that endothelial PPARγ is protective in cardiovascular disease, such as hypertension. It is not known whether this extends to protection during stroke.
Development of novel inhibitors of DNA-dependent protein kinase (DNA-PK) for cancer co-therapy
Chief investigator: Dr Jasim Al-Rawi
Co Investigators: A/Prof Philip Thompson and A/Prof Jake Shortt
DNA repair by cancer cells represents a major obstacle to effective anti-cancer treatments by radiotherapy or pharmaceuticals. DNA-PK is an enzyme required for DNA repair and so inhibitors of the enzyme are potential therapeutic agents to potentiate the anti-cancer activity of treatments that target DNA cleavage. The CI has developed a compound, LTU-MS 051 that is more potent and selective than any DNA-PK inhibitor yet reported. This research will characterise the activity of this compound, evaluate its pharmaceutical properties and set the groundwork for in vivo profiling in animal models of cancer.
Regulators of BRAF oncogene-driven gene expression in colorectal cancer
Chief investigator: Dr Amardeep Dhillon
Co Investigators: A/Prof David Williams and Dr Fiona Chionh
About 20% of cancers express mutant BRAF proteins, which drive cell proliferation and tumour growth by activating the MEK-ERK signalling pathway. While drugs that target mutant BRAF proteins have been developed, their clinical activity is inconsistent across different BRAF mutant cancers and lacks durability. We have identified a protein (FRA1) that appears critical for mutant BRAF protein to activate pro-malignant genes in colorectal cancer cells, underscoring its potential as a novel therapeutic target. This project will investigate if FRA1 drives BRAF inhibitor resistance and establish mouse models to define the role of FRA1 in mutant BRAF-driven colorectal cancer in vivo.
Monitoring breast cancer using circulating tumour DNA
Chief investigator: A/Prof Alexander Dobrovic
Co Investigators: Dr Belinda Yeo
Exciting changes are emerging in the surveillance of breast cancer patients. Analysis of circulating tumour DNA (ctDNA) marks a new frontier in cancer diagnostics that enables monitoring the response to therapy in a non-invasive manner with significant advantages over CT scanning to which ctDNA represents a complementary technology. This study aims to validate DNA methylation at specific loci as tumour-specific biomarkers for the detection of breast cancer ctDNA using the droplet digital PCR methodology. We consider that a panel of DNA methylation assays (unlike mutation-based assays) can give robust markers that can be used to monitor every breast cancer patient.
Identification and characterisation of novel driver genes for inflammation-associated gastric cancer
Chief investigator: Dr Moritz Eissmann
Co Investigators: Dr Jian Zhong Tang, Prof Phoebe Chen and Dr Merridee Wouters
Whole genome sequencing led to comprehensive identification of the gastric cancer mutation spectrum. However, for many of these mutations it remains unclear whether they serve as “drivers”, promoting cancer growth or constitute non‐phenotypic “bystanders”. We established and initiated a unique stomach specific functional genetic screen utilising Sleeping Beauty transposase‐transposon mutagenesis. Here, we aim to identify putative cancer driver genes and mutations, which caused Sleeping Beauty‐mediated tumour growth in our mutagenesis mouse model. In vitro and in vivo validation studies will verify the potential of selected candidate cancer genes as novel targets for gastric cancer therapy.
Disarming the critical drivers of aggressive and untreatable breast cancer
Chief investigator: Dr Erinna Lee
Co Investigators: Dr Douglas Fairlie
Unlike most breast cancer subtypes, there are no targeted therapies for triple negative basal breast cancers. Hence, chemotherapy is the only treatment option. A feature of many of these cancers is deregulated Myc expression, and deregulated apoptosis is a hallmark of most, if not, all cancers. Our preliminary studies have shown that in some cancers, highly synergistic cell-killing responses occur when Myc and Bcl-2 proteins are targeted simultaneously. In this project we will use novel direct Myc inhibitors together with the latest Bcl-2 antagonists to establish if such synergy is also observed in highly aggressive, difficult to treat, breast cancers.
Identification of mechanisms of breast cancer resistance to anti-HER2 and CDK4/6 therapy
Chief investigator: Dr Jian Zhong Tang
Co Investigators: Dr David Goode and Prof Robin Anderson
Approximately 1 in 4 breast cancers are diagnosed as high-risks Her2-enhanced subtype (HEBC) with inferior outcome. While the use of HER2 blockade has transformed patient outcome, HEBC becomes harder to treat when resistance develops. Targeted inhibition of both HER2 and CDK4/6 has shown improved preclinical efficacy, leading to the first clinical trial of this new therapeutic combination. However, acquired resistance to this combination is expected to restrict its clinical effectiveness. We will apply a state-of-the-art transposon mutagenesis screen to uncover novel resistance mechanisms to HER2 and CDK4/6 combination therapy, which will further improve management of HEBC patients.
Clonal evolution of T-cell receptor repertoire in Diffuse Large B-cell Lymphoma
Chief investigator: Dr Eliza Hawkes
Co Investigators: Dr Joel Wight, A/Prof Alexander Dobrovic, Dr Thomas Mikeska and Dr Hongdo Do
Diffuse large B-cell Lymphoma (DLBCL) is the most common lymphoma. Most patients are cured with combination chemotherapy, however ~30% relapse and die from their disease. Tumour growth and response to therapy is intimately related to the tumour microenvironment. The T-cell receptor (TCR) repertoire of DLBCL Tumour-infiltrating lymphocytes at diagnosis is prognostic, and is potentially therapeutically relevant with the advent of novel immunotherapy agents. It is not known whether TCR repertoire changes over time. This project will assess, for the first time, whether TCR repertoire evolves in patients who relapse by analysing matched samples at diagnosis and relapse.
Development of mTOR radiotracers to improve treatment selection for breast cancer patients
Chief investigator: Dr Adam Parslow
Co Investigators: Prof Andrew Scott and A/Prof Uwe Ackermann
Our project aims to develop a non-invasive molecular imaging probe to predict breast cancer patient resistance to treatment. Cancer therapeutics targeting proteins on the cell surface have dramatically improved outcomes for patients. However, inevitably, some patients develop resistance to these agents and their treatments no longer work. We are developing an imaging agent which labels a specific cellular pathway important for the development of resistance to breast cancer therapies. Several inhibitors of this pathway are under clinical investigation. Monitoring the development of resistance with our agent can improve a patient’s outcome through enhancing the selection of the most appropriate treatment.
Defining CD8 T cell responses in murine triple negative breast cancer
Chief investigator: Dr Damien Zanker
Co Investigators: Dr Belinda Parker and Prof Weisan Chen
Human and murine models of triple negative breast cancer (TNBC) are poorly understood in regards to both causative protein mutations and the adaptive immune response targeted against them, making assessment of therapeutic efficacy difficult. CD8 T cells are known to eliminate cancer cells. We have identified CD8 T cell responses against murine TNBC models and aim to identify the exact mutated sequences they are targeted against. This project will generate currently lacking tools to track the efficacy of TNBC treatment regimes, generate novel vaccination targets and give important insight into mutated proteins that can be further assessed in human samples.
Molecular dissection of a metastatic long non-coding RNA, MALAT-1
Chief investigator: Dr Mihwa Lee
Co Investigators: A/Prof Hamsa Puthalakath and Dr Andrew Whitten
Dynamic interactions between proteins and nucleic acids are fundamental process in gene regulation, where aberrant regulation leads to lethality or various diseases. This project aims to elucidate the underlying mechanisms of a long non-coding RNA, MALAT-1 in tumorigenesis and metastasis at the molecular level by characterising the interaction between MALAT-1 and SFPQ, a multifunctional nuclear protein. The results will provide a fundamental understanding of the molecular mechanisms of the interaction between MALAT-1 and SFPQ and its consequences in gene regulation. The result will also provide the first structure on a complex of a long non-coding RNA and a nuclear protein.
Australian regional genetic diversity in the honey bee pathogen Ascosphaera apis
Chief investigator: A/Prof Joseph Tucci
Co Investigators: A/Prof Michael Angove
The fungus Ascosphaera apis is a major pathogen of the larvae of the honey bee (Apis mellifera). After infection, there’s penetration of the gut wall by fungal hyphae and eventual larval death. A better understanding of the competitive interaction between the fungus and the bee hosts may aid disease control. Studies overseas have focussed on several polymorphic intergenic loci of A. apis in order to determine whether the degree of pathogenicity could be linked to certain haplotypes. We plan to carry out similar studies on 120 A. apis strains gathered from a range of diverse Australian environments.
Understanding how viruses change gene expression at single cell resolution
Chief investigator: Dr Mathew G Lewsey
Co Investigators: Dr Quentin Gouil and Prof Ryan Lister
I propose to investigate virus-responsive gene expression at single cell resolution in the cells of an infection site. A viral lesion comprises of hundreds of infected host cells, with each cell at a different stage of infection. Moreover, each individual cell experiences a subtly different set of internal and external stimuli. These factors combined lead to unique patterns of gene expression in every cell. However, we know little of gene expression within single cells because it has been impossible technically to measure this until very recently. We will employ cutting edge microfluidic technology that enables single cell gene expression measurement.
The Eyes Have It: Integrated ‘Omics’ and Ionic Micro Analysis in Myopia Aetiology
Chief investigator: Prof Sheila Crewther
Co Investigators: Prof Alan Marshall, Ms Nina Riddell, Prof DP Crewther and Dr Melanie Murphy
Myopia prevalence is increasing dramatically worldwide, affecting >1.75B of whom ~20% will develop secondary blindness. Our study will integrate multi-omics and ion localization measures in the chick defocus model of myopia to elucidate the biological cascades underlying the early initiation of structural and refractive changes, and then the later progression to neurodegeneration and secondary pathologies. Funding will provide both a translational perspective on which particular ions, genes, proteins, and metabolites predict changes in eye structure and health, and theoretical information regarding the temporal trajectory of interactions between these molecules (such multi-omic data are a world first in retina).
Pathogenesis and immunogenicity of bacterial membrane vesicles
Chief investigator: Dr Maria Liaskos
Co Investigators: Professor Tim Stinear
This proposal will facilitate the development of nano-sized bacterial membrane vesicles, or blebs, as innovative, multi-use vaccine technology. We will perform fundamental biological studies to understand the mechanisms whereby these bacterial blebs function in disease, their composition and their development as a novel vaccine delivery system.
Identification of novel regulators of lung macrophage memory formation
Chief investigator: Dr Erika Duan
Co Investigators: Prof Weisan Chen, Dr Jasmine Li, Prof Steven Turner and Prof Alistair Stewart
Lung macrophages are a group of immune cells responsible for maintaining lung health and efficient pathogen detection and clearance. Macrophages have been traditionally viewed as rapidly responsive immune cells, which broadly respond to environment cues. Recent studies, however, indicate that macrophages are also capable of immune cell memory (a specialised ability to recognise and more effectively respond to previous pathogen infections). Our study will identify novel transcriptional and epigenetic pathways driving lung macrophage memory formation, and define how influenza infection enhances chronic lung disease susceptibility through the development of lung macrophage memory.
Defining the interaction between engulfment receptor BAI1 and phosphatidylserine on apoptotic cells
Chief investigator: Dr Ivan Poon
Co Investigators: A/Prof Marc Kvansakul, Dr Mark Hulett and Amy Baxter
In humans, billions of cells will die daily as part of normal turnover in various organs. It is vital that dying cells are rapidly removed as their accumulation has been linked to autoimmunity and inflammation. To aid efficient removal of dead cells, dying cells expose ‘eat-me’ signals such as phosphatidylserine, which can be recognized by engulfment receptors on neighbouring cells to trigger their removal. The aim of this study is to define (i) the molecular interaction between BAI1 (an engulfment receptor) and phosphatidylserine on apoptotic cells, and (ii) the importance of this interaction in dying cell clearance.
Dynamic T cell-APC interactions in the vasculature during hypertension
Chief investigator: Dr Antony Vinh
Co Investigators: Prof Grant Drummond, Prof Michael Hickey, Dr Travice De Silva, Prof Tomasz Guzik and Prof Anthony Purcell
High blood pressure (hypertension) remains the leading risk factor for cardiovascular diseases. Alarmingly, 20-30% of patients are resistant to anti-hypertensive treatments. We believe that a major cause of resistant hypertension is immune cell activation and chronic inflammation; mechanisms that are not targeted by current drugs. We have identified that immune cells accumulate in the blood vessels and kidneys during hypertension where they promote inflammation and damage, leading to elevated blood pressure and downstream consequences such as hardening of the arteries and kidney disease. We aim to determine how immune cells are recruited and activated during hypertension with a view to identifying novel therapies to control inflammation in hypertensive patients.
Synthesis and Evaluation of Dihydroquinolinones as Neuroprotective Agents in Motor Neurone Disease
Chief investigator: Dr Belinda Abbott
Co Investigators: A/Prof Julie Atkin
Motor neurone disease (MND) is a progressive and fatal neurodegenerative disorder with no cure. Therapies which can prevent motor neurone death are urgently needed, and are most likely to be successful if targeting early disease stages. One common and early pathology in MND is the disruption of protein transport, causing cell stress and death. We have recently identified a class of small drug-like molecules which have excellent protective effects in cellular models of MND. We aim to synthesise a large family of chemical analogues in order to understand their action and obtain the best compound for study against MND.
Identifying causes of filariasis hotspots and potential transmission re-emergence in American Samoa
Chief investigator: Dr Shannon Hedtke
Co Investigators: Dr Warwick Grant, Dr Colleen Lau, Dr Karen McCulloch, Dr James McCaw and Dr Patricia Graves
Over 175 million people are infected by parasitic nematodes that cause diseases such as lymphatic filariasis and onchocerciasis. Mass drug administration (MDA) attempts to eliminate these diseases by providing chemotherapy to entire communities until monitoring indicates that infection rates are below target prevalence thresholds. We use DNA sequences of LF parasites to explore transmission dynamics in a region experiencing resurgence of LF post-MDA, particularly the role of parasite reintroduction by travellers moving from areas with high to low prevalence. Results will be incorporated into epidemiological models to inform decisions for post-MDA surveillance for the Global Programme to Eliminate Lymphatic Filariasis.
Structural characterisation of bacterial zinc resistance efflux pathways
Chief investigator: Dr Megan Maher
Co Investigators: Dr Christopher McDevitt, Prof So Iwata and Dr Jennie Sjöhamn
Streptococcus pneumoniae is the world’s foremost bacterial pathogen. It is responsible for more than one million deaths worldwide annually and kills more children than AIDS, malaria and tuberculosis combined. The trace element zinc has a major role in immune function, while its deficiency is associated with markedly increased susceptibility to infection. Despite this, the way in which zinc protects against bacterial infections remains poorly understood. This project aims to define the structure of the protein CzcD from Streptococcus pneumoniae, which is the major Zn-resistance efflux protein. This work will scaffold the design of inhibitors that attenuate zinc resistance in this organism, with an ultimate view to novel antibacterial design.
Metformin use during pregnancy in overweight females; consequences for long term health
Chief investigator: Dr Tania Romano
Co Investigators: Prof Mary Wlodek, Dr Jessica Griffith, Dr Regina Belski, Prof Grant Drummond and Dr Seb Dworkin
Obesity is the world’s greatest public health challenge. 45-50% of Australian pregnant women are overweight/obese, which is strongly associated with development of gestational diabetes and hypertension. Recent reports highlight that offspring from obese/overweight mothers develop obesity, cardiovascular, metabolic and skeletal disorders later in life. Many obese/overweight women don’t adopt healthy lifestyles during pregnancy. Metformin is a drug safely used to treat gestational diabetes and excess weight gain, but the effects on offspring are unknown. We will examine the effects of Metformin on the mother’s health during pregnancy, as well as that of her offspring in the long term.
Maternal obesity causes hypertension in offspring: Role of brain neurotrophic factors
Chief investigator: Dr Joon Lim
Co Investigators: Prof Grant Drummond, Prof Geoff Head and Dr Colleen Thomas
Most new cases of hypertension (high blood pressure) are related to being overweight or obese. Compelling epidemiological and experimental evidence shows early life environment also contributes to the progression of this disease. We recently found that maternal obesity can directly influence the offspring by activation of the nerves to the kidney, which is a major mechanism for hypertension, and that this involves subtle changes to a region of the brain that controls the appetite. We will investigate how the signalling molecules in this region change with a high fat diet to uncover the cause of obesity-related hypertension.
Telehealth for enhanced gestational diabetes mellitus management in rural setting
Chief investigator: A/Prof Irene Blackberry
Co Investigators: A/Prof John Furler, A/Prof Kwang Lim, Mr Tshepo Rasekaba and Dr Jessica Triay
Gestational diabetes mellitus (GDM) affects 1 in 7 pregnant women. Optimum blood glucose levels (BGL) produces better maternal and foetal outcomes. Our trial in the urban setting showed telehealth significantly reduced time to achieve glycaemic target without compromising the quality and safety of care. We propose to examine telehealth in rural areas where access to diabetes care is limited. We will undertake preliminary work to establish (1) feasibility and acceptability of telehealth for GDM by exploring patient and health providers’ perspective on telehealth, and (2) how telehealth can be embedded as part of routine care in rural setting.
Microbial colonisation of the gastrointestinal tract and immune response before birth
Chief investigator: A/Prof Ashley Franks
Co Investigators: Dr Elisa Hill, Dr Bert De Groef and Dr Cesar Guzman
The establishment of a functioning microbiome in the gastrointestinal tract is the foundation of the host’s metabolic performance, immune system priming, protection against pathogens, digestive function, and behaviour. With the knowledge that the foetal microbiome is active at 5 months of gestation, contrary to the paradigm of the sterile foetus, this research will focus on understanding the mechanisms and interactions between microbiome and the foetal host at the level of gene expression, biochemistry and immune response. This has the potential to initiate therapeutics that target diseases such as allergies, obesity, diabetes, asthma, and inflammatory bowel diseases.
The effect of high-polyphenol olive oil on markers of cardiovascular disease risk
Chief investigator: Dr Wolfgang Marx
Co Investigators: Ms Elena George, Dr Colleen Thomas, Prof Catherine Itsiopoulos and Dr Audrey Tierney
Extra virgin olive oil, a key ingredient of the cardioprotective Mediterranean diet, is considered a healthy source of dietary fat due to its high content of monounsaturated fatty acids and antioxidant polyphenols. However, while consistent, promising evidence exists, the unique contribution of polyphenols to the cardioprotective effect of olive oil is not fully established. This study will examine the effect of high-polyphenol extra virgin olive oil versus low-polyphenol olive oil on markers of cardiovascular disease risk that are related to cholesterol metabolism and total antioxidant capacity.