In 2016, our RFA has provided funding to research projects in the following areas:
New molecular imaging agents for the early diagnosis of alzheimer’s disease
Chief investigator: Dr Peter Barnard
Co Investigators: Associate Professor Paul Donnelly
Alzheimer’s disease (AD) is a progressive neurodegenerative disease that leads to synaptic failure and neuronal death and it is the most common form of dementia. In recent years much progress has been made in terms of understanding the fundamental biology of AD and in the development of medicinal approaches for its treatment. This project seeks to develop the chemistry and radiochemistry associated with the preparation and evaluation of technetium-99m containing compounds for use as AD diagnostic imaging agents based on the cheap and widely available imaging technique: single photon emission computed tomography (SPECT).
Genes, behaviour and the gut-brain axis in mouse models of autism
Chief investigator: Professor Maarten van den Buuse
Co Investigators: Associate Professor Ashley Franks, Professor Cheryl Dissanayake
Autism is a highly prevalent neurodevelopmental disorder diagnosed by impairments in social communication and the presence of repetitive behaviours or restricted interests. Patients commonly experience a range of comorbid traits including gastrointestinal disorders and cognitive impairments but the interrelationship between these endophenotypes remains unclear. This project will investigate the relationship between genes, complex behaviour and disturbances in the gut-brain axis by correlating fecal microbiota samples and a range of behavioural phenotypes in two genetic mouse models of autism spectrum disorder
Investigating the presence of Alzheimer’s disease associated brain biomarkers in the blood
Chief investigator: Dr Lesley Cheng
Co Investigators: Dr Jacqueline Orian
Several blood-based tests have been explored to detect Alzheimer’s disease (AD) however, evidence is required to determine whether blood sampling is an appropriate specimen to diagnose brain diseases. Exosomes are extracellular vesicles secreted from cells and carry protein and genetic material which reflect the host cell. Exosomes can be isolated from blood hence, researchers are harnessing their contents for biomarkers. Our hypothesis is that exosomes secreted from brain tissue can migrate through the blood brain barrier into the blood whereby brain biomarkers are readily detected and reflective of disease occurring the brain, equivalent to a ‘liquid biopsy’ of the brain.
Novel approach to targeting Cancer and Alzheimer's disease: Identification of novel genes and small molecules that modulate γ-Secretase activity
Chief investigator: Associate Professor Prof Helena Richardson
Co Investigators: Professor Andrew Hill, Professor Sarah Russell, Dr Marta Portela
Cancer and Alzheimer's disease (AD) affect many Australians, and are huge burdens for the health system. This project focuses on γ-Secretase, a multisubunit enzyme involved in both cancer and AD. γ-Secretase is involved in cancer by acting as a positive regulator of Notch, which is the driving oncogene in T-cell leukaemia and solid tumours. Additionally, γ-Secretase cleaves the Amyloid Precursor Protein (APP) to produce the toxic Amyloid-beta (Aβ) fragments that are involved in the pathogenesis of AD. Here we will use the genetically amenable model, the vinegar fly, Drosophila, to identify new regulators of γ-Secretase, thereby targeting cancer and AD.
Defining the role of brain glutamate dysregulation in alcohol addiction
Chief investigator: Dr Elvan Djouma
Co Investigators: Dr Bradley Turner
Alcohol kills one person every 10 seconds worldwide but despite negative consequences, Australians continue to drink at alarming levels. Increasing evidence suggests that excessive glutamatergic drive in the reward circuits of the brain promotes drug-seeking in addiction disorders. Recently, expression of the key astrocytic glutamate transporter, EAAT2, which clears synaptic glutamate in the brain, was shown to be decreased by exposure to drugs of abuse in animal models. It is well established that EAAT2 is also downregulated in brains of amyotrophic lateral sclerosis (ALS) patients and rodent models expressing mutant superoxide dismutase 1 (SOD1) linked to ALS, leading to synaptic glutamate accumulation. This innovative and multidisciplinary project will, in a world first, screen the SOD1 rat for alcohol-seeking as a model of glutamate dysregulation to study addiction.
Mitochondrial function and cellular stress signalling in lymphoblasts from patients with ME/CFS
Chief investigator: Professor Paul Fisher
Co Investigators: Dr Sarah J. Annesley
This project is designed to investigate the role of mitochondrial dysfunction and cellular stress signalling in a little understood neurological disorder – Myalgic Encephalitis/Chronic Fatigue Syndrome (ME/CFS). Immortalized lymphocytes (lymphoblastoid cells, hereafter referred to as lymphoblasts) will be isolated from patient and control blood then assayed for a variety of parameters of mitochondrial function and cellular stress signalling. The results will test alternative models for altered mitochondrial function and elevated Reactive Oxygen Species in this enigmatic disease, one of which (mitochondrial hyperactivity) applies to Parkinson’s Disease and the other of which is hypothesized to involve impaired mitochondrial respiratory function in ME/CFS.
Randomised-controlled trial of very early intervention for infants showing early social-communication delays: Establishing a Melbourne-based site
Chief investigator: Dr Kristelle Hudry
Co Investigators: Dr Josephine Barbaro, Professor Teresa Iacono, Professor Cheryl Dissanayake, Dr Vicky Slonims, Professor Jonathan Green, Professor Andrew Whitehouse and the AICES Team
Social-communication delays affect many children in the first year of life and may lead to conditions such as developmental or language delays or autism in some cases. Leveraging off existing funding for a Perth-based site, support to LTU researchers from UD RFA in partnership with the Autism CRC will allow us to establish a Melbourne-based site for a randomised-controlled trial (RCT) of a promising very early intervention. This intervention recently attracted international attention when pilot RCT data were published in Lancet Psychiatry. The full-scale clinical trial proposed here will target infants who are showing early signs of social-communication delay and will reinforce LTU’s position as a premier centre of excellence in research on the early development of children at risk, and foster national partnerships with researchers in Western Australia and at the Autism CRC and with international groups in the United Kingdom.
The influence of oxytocin and early parenting on neurobiological mechanisms underlying human social behaviour
Importing the BDNF val68met knockin rat to establish a breeding colony at LARTF
Chief investigator: Professor Maarten van den Buuse
Co Investigators: Dr Emily Jaehne
Brain-derived neurotrophic factor (BDNF) is a protein involved in plasticity and development of the brain. Changes in BDNF signalling in the brain have been linked to aspects of schizophrenia, depression and other psychiatric illnesses. A common minor alteration in the BDNF gene (polymorphism), the val66met SNP, is associated with a range of psychological markers, such as aspects of cognition, stress resilience and brain neuroanatomy. Recently, a BDNF val68met ‘knockin’ rat model has become available and the funds from this grant are going to be used to import this novel animal model into Australia so that we can start using it in our studies.
Offloading practice in high-risk foot services
Chief investigator: Dr Anita Raspovic
Co Investigators: Mr Daniel Bonanno
Effective offloading of diabetes-related foot ulceration is essential to achieve good healing outcomes as adequate offloading reduces pressure and ongoing trauma to damaged tissues while they repair. The gold standard techniques for offloading, total contact casts or non-removable walkers, are effective however are often not tolerated well by patients. Conversely, alternative offloading options are accepted by patients however are not well researched. As a result, offloading in clinical practice is unstandardized, varied and often based on anecdotal evidence. This research aims to document current offloading practices in two Academic Research Network (ARN) high-risk foot services in Melbourne, one Northern site and one Southern site, to inform a larger future randomised controlled trial (RCT) comparing the effectiveness of offloading modalities commonly used clinically.
Effect of Mediterranean diet on visceral fat and inflammatory biomarkers
Chief investigator: Dr Jessica Radcliffe
Co Investigators: Professor Catherine Itsiopoulos, Dr Colleen Thomas, Associate Professor Audrey Tierney
Adherence to a traditional Mediterranean diet is recognised to prevent coronary artery disease (CAD), a major cause of global deaths, and reduce risks of secondary complications. Despite this, Mediterranean diet intervention trials have predominantly focused on primary prevention of CAD. Additionally, most trials have been conducted in Europe. This secondary prevention Mediterranean diet trial in the multi-ethnic Australian population aims to investigate whether participants who have survived their first acute myocardial infarct (AMI) and who adhere to a Mediterranean diet for 12 months post AMI reduce their risk of a secondary cardiac events compared to patients on standard treatment.
Enabling a program for the development of therapeutic anti-IL11 receptor antibodies
Chief investigator: Dr Ashwini Chand
Co Investigators: Professor Matthias Ernst, Dr Tracy Putoczki
Cancers of the gastrointestinal (GI) tract are a significant world-wide socioeconomic and healthcare burden. In 2010, more than 16,000 Australians were diagnosed with colorectal cancer and 2,100 with gastric cancer. Gastrointestinal cancers claim more than 5,200 lives in Australia; 5-year survival rates are 26-63%. Tumour growth is fuelled by factors produced by cells in the surrounding microenvironment. In two seminal research articles we previously identified and described signalling pathways that functionally link an inflammatory tumour microenvironment to GI tumour progression. The current funding will support pilot proteomic studies aiming to identify potential therapeutic targets for the treatment of gastric cancers.
Apoptosis-inducing drugs to treat schistosomiasis
Chief investigator: Dr Douglas Fairlie
Co Investigators: Professor Brian Smith, Dr Brad Sleebs
Schistosomiasis is one of the world's major diseases, affecting nearly 200 million people. Currently, schistosomiasis is treated with a single drug, however, its wide-spread has led to growing concern about the development of drug resistance. We have discovered a pathway that controls cell survival in the parasitic worms (schistosomes) that cause the disease. More recently we identified several small-molecule compounds that can bind to the key Bcl-2 pro-survival protein in schistosomes. In this project we will use structure-based design approaches to further develop these lead compounds by improving their target protein affinity and selectivity over related proteins in human hosts.
Planting new ideas for medicine: translational approach from plants to human diseases
Chief investigator: Dr Travis Beddoe
Co Investigators: Dr Anthony Gendall
New targets for the development of new anti-malarial’s include components of the Plasmodium falciparum translocon of exported proteins (PTEX) complex, a large protein-transporting complex that resides on the parasitophorous vacuole membrane that envelops the malaria parasite inside a red blood cell, and is essential for the blood-stage of malaria. We propose that the similarities in activities of the critical PTEX component HSP101 and plant HSP101-like proteins, combined with a specific collection of plant hsp101 mutants offers a novel platform for screening for specific, targeted HSP101-inhibitors in a biologically relevant context.
Determining the function of apoptotic cell disassembly in influenza A infection
Chief investigator: Dr Ivan Poon
Co Investigators: Professor Weisan Chen, Dr Mark Hulett
Programmed cell death (apoptosis) occurs in essentially all tissues as part of homeostasis, and in disease settings including cancer, neurological disorders and infection. Although apoptosis has been widely studied for many decades, we have recently discovered a novel mechanism that controls how dying cells disassemble into smaller fragments, a process that could aid the transfer of cellular contents between cells. The aim of this study is to define (i) the function of dying cell disassembly in influenza A infection, and (ii) whether pharmacological compounds shown to regulate cell disassembly can be used to modulate the progression of influenza A infection.
Deciphering the early innate immune response of the astrocyte
Chief investigator: Dr Karla Helbig
Co Investigators: Associate Professor Jason Mackenzie, Dr Ross O’Shea
The astrocyte is an important immune cell in the context of control of viral infections of the central nervous system, yet little is known about the mechanisms involved. This proposal utilises cutting edge CRISPR/cas technology to describe for the first time, factors influencing astrocyte control of viral infection; using viral mimics and the medically important flavivirus, West Nile Virus. An improved understanding of host cell factors involved in regulation of the anti-viral effectors, IFN- α and β, will better inform the tailoring of novel emerging treatments that artificially regulate these pathways to control viral infection.
Development of novel therapeutic agents for Enterococcus faecium and Streptococcus pyogenes
Chief investigator: Dr Steve Petrovski
Co Investigators: Dr Joseph Tucci, Dr Hiu Tat Mark Chan
Enterococcus faecium (formally known as group D Streptococcus) and Streptococcus pygenes (also known as group A Streptococcus) are important emerging nosocomial pathogens. Enterococcus and Streptococcus colonises patients and are part of their normal flora providing them with an avenue for successful dispersal. Both organisms can cause mild infections such as minor skin infections and strep throat respectively and in some instances can cause more serious infections such as urinary tract infections and life threatening bacteraemia. Antibiotic resistance among these organisms is on the rise and hence difficult to treat. This project aims to develop novel therapeutic products containing bacteriophages that specifically target these organisms.
A cell type specific host immune response to Zika virus
Chief investigator: Dr Karla Helbig
Co Investigators: Associate Professor Michael Beard, Associate Professor Jason Mackenzie
Zika virus (ZIKV) is an emerging viral disease, and is linked to catastrophic foetal abnormalities including microcephaly, spontaneous abortion and inter-uterine restriction due to placental insufficiency in infected pregnant mothers. This project seeks to understand the host control mechanisms against ZIKV at a cell type specific level of both neural origin and in the developing placenta, in an attempt to further future efforts to design novel therapeutic agents against this virus.
Defining and inhibiting the mechanisms of action for bacterial autotransporter virulence factors
Chief investigator: Dr Begoña Heras
Co Investigators: Dr Jason J Paxman, Professor Mark A. Schembri, Dr Salvatore Nocadello
Despite the prevalence and importance of autotransporter proteins in bacterial pathogenesis, they remain largely uncharacterised. We have determined the unique molecular structure of the autotransporter UpaB from uropathogenic E. coli (UPEC) which revealed two binding sites to the urinary tract epithelium that includes a new binding mode to fibronectin. Our molecular structures of the autotransporter adhesin/invasin TibA from enterotoxigenic E. coli have shown how post-translational modifications switch its mechanism of action. Finally, we are using an antibody-based drug discovery approach to develop inhibitors of the autotransporter Antigen43a from UPEC that block its ability to form bacterial aggregates and biofilms
Structural and functional characterisation of the innate immune modulator protein, viperin
Chief investigator: Dr Subir Sarker
Co Investigators: Dr Karla Helbig, Professor Jade Forwood
Viperin is a vital player in the host anti-viral innate response, and has over 80% homology between humans and lower order species such as the oyster, thereby implicating it to be a pivotal host protein. Recent work in our laboratory has identified a number of residues within viperin to be important in its ability to augment the early innate anti-viral response, and this project aims to decipher viperin’s protein structure in multiple human and non-mammalian viperin species in an attempt to provide structural information to inform downstream work to elucidate viperin’s mechanistic activities.
Unfolding the invasive mechanism in breast cancer with 3D nanoscopy
Chief investigator: Dr Shanshan Kou
Co Investigators: Dr Jiao Lin, Dr Belinda Parker, Associate Professor Brian Abbey
Stopping cell invasion is a critical event in the prevention/treatment of metastatic spread in human breast cancer. It is well known that myoepithelial cells play an important role in suppressing breast cancer invasion. Current available imaging techniques, however, are unable to reveal how these cells function to suppress cell invasion, particularly in the 3D environment. Using a novel 3D nanoscopy technique linked to unique 3D breast cancer cultures, we will tackle the problem and eventually unfold the key mechanism. The outcome of this project will offer significant implications into the clinical research of breast cancer.
Peptide-based therapies for the treatment of cancer
Chief investigator: Dr Douglas Fairlie
Co Investigators: Dr Erinna Lee, Professor Paul Watt, Dr Paula Cunningham
Peptides have long held promise as therapeutic agents, however, their application to intracellular targets is hampered by their inability to efficiently cross cellular membranes. Phylogica has developed a unique technology (“Phylomers”) that enables peptides to enter cells and engage with cytosolic protein targets. The Fairlie laboratory has developed BH3 domain-based peptides that potently and selectively disarm intracellular “BCL-2” proteins that maintain tumour cell survival. In preliminary studies, we applied cell-penetrating Phylomers to BH3 domains and showed mechanism-based cancer cell killing. We now aim to improve our current BH3 Phylomers and develop new reagents to kill cancer cells from the inside.
DCLK1: Elucidating the role of a novel driver gene of gastric cancer
Chief investigator: Dr Michael Buchert
Co Investigators: Dr Damien Zanker, Professor Matthias Ernst
Recent whole genome sequencing (WGS) studies have uncovered many new potential drivers of human cancers. One of them is the serine/threonine kinase doublecortin-like kinase 1 (DCLK1), which is among the 15 most mutated genes in human gastric cancer (GC), however how DCLK1 mutations promote tumourigenesis is currently unknown. Our project aims to better understand the biological role of DCLK1 expressing cells in gastric tumours and to identify the impact of the various DCLK1 missense mutations observed in human GC on tumour development using a combination of state-of-the art mouse genetics and in vitro analysis in human gastric cancer cell lines.
Induction of terminal differentiation as a novel treatment strategy for colorectal cancer
Chief investigator: Professor John Mariadason
Co Investigators: Associate Professor Niall Tebbutt
The objective of this study is to develop a new treatment paradigm for colorectal cancer (CRC) based on the induction of “terminal differentiation”. In preliminary studies we have demonstrated that combination treatment of CRC cells with a histone deacetylase inhibitor and a MAPK pathway inhibitor induces robust expression of differentiation markers and synergistically induces apoptosis. We will now extend these findings to in vivo models of CRC, and elucidate the mechanisms which underpin these events. Demonstration that this drug combination kills tumour cells by inducing “terminal differentiation” would represent a unique and novel treatment strategy for this disease.
Validating myoepithelial stefin A as a predictor of breast cancer relapse
Chief investigator: Dr Belinda Parker
Co Investigators: Professor Bruce Mann, Dr Marco Herold
Ductal carcinoma in situ (DCIS) is a pre-invasive stage of breast cancer, whereby the tumour cells remain restrained by the myoepithelial cells that surround breast ducts. It is very hard to predict which patients with DCIS will later develop secondary cancer, leading to over-treatment. We have discovered that the expression of the protease inhibitor stefin A in myoepithelial cells is important in blocking cancer invasion. This project aims to validate stefin A as a predictive marker of cancer relapse in a large patient cohort and to generate a stefin A knockout mouse to test its function in mouse models of cancer.
Study on Bok regulation of uridine metabolism and chemo-resistance
Chief investigator: Associate Professor Hamsa Puthalakath
Co Investigators: Dr Thomas Kaufmann, Associate Professor Matthew Perugini
Charles Heidelberger and colleagues discovered 5-Fluorouracil for treating cancer in 1957. Even today it is still commonly used in adjuvant therapies, but tumours often develop resistance. We discovered a new mechanism of chemo-resistance by a Bcl-2 family protein Bok. Bok interacts and activates UMPS (Uridine monophosphate synthetase), the enzyme responsible for chemosensitivity. Genetic ablation of Bok imparts chemo-resistance and colon cancer cell lines down regulate Bok to become chemo-resistant. We aim to understand the molecular basis and thermodynamics of this interaction with the hope of developing new therapies.
Loss of asymmetrical cell division promotes metastasis through alterations in the microenvironment
Chief investigator: Dr Nathan Godde
Co Investigators: Professor Patrick Humbert, Dr Belinda Parker
Polarity genes establish asymmetry within cells so cells can respond appropriately to developmental cues and build complex tissues. Disruption of cell polarity is a defining feature of cancer and we have recently identified a polarity gene, GPSM2 as a new tumour suppressor in breast cancer. GPSM2 polarises stem-like cells during cell divisions to maintain proportionate pools of stem-like cells within a tissue.
We are the first to show that GPSM2 is required for mammary stem cell maintenance and that GPSM2 depletion activates key cancer pathways, increases the numbers of Cancer Stem Cells (CSC), and enhances metastasis in experimental models of breast cancer.
We also made an unanticipated observation that GPSM2 loss in mammary stem cells led to transcriptional changes associated with microenvironmental remodelling including the increased expression of pro-invasive cytokines and ECM components. Tumor-microenvironment interactions are critical for tumour metastasis.
Development of an antibody for use in Herceptin resistant breast cancer
Chief investigator: Professor Andrew Scott
Co Investigators: Associate Professor Hui Gan, Dr Sagun Parakh, Professor James Whisstock, Dr Adam Parslow, Dr Camel Murone
Our laboratory has a long standing interest in the development of therapeutic antibodies to the epidermal growth factor receptor (EGFR or ErbB) family. We have successfully developed and licensed anti‐EGFR antibody mAb806 which is currently in global Phase II and Phase III trials in glioma patients.
More recently we have generated a novel ErbB2 antibody that shows preclinical promise in Herceptin resistant breast cancer. We propose to further characterise this antibody and generate data for inclusion in a NHMRC grant to allow further studies to understand the mechanism of action of the antibody and enhance its therapeutic effect.
Exosomes and their role in regulating embryo implantation
Chief investigator: Dr David Greening
Co Investigators: Professor Lois Salamonsen, Professor Richard Simpson
This project aims to determine the molecular mechanisms implicated in intercellular communication and implantation. This multidisciplinary proposal will advance our understanding of the complex mechanisms that interconnect maternal-embryo crosstalk to reveal extracellular modulators regulating implantation. Given the fundamental importance to cellular processes, the current lack of understanding of the dynamics underlying implantation is surprising. The results will have significant importance and strong implications to human biology by understanding mechanisms of cell communication and signaling, intercellular transfer, implantation, and developmental regulation, and inform future development strategies enhancing pregnancy outcomes.
Development of a microfluidics platform for single particle tomography at the nanoscale via FIB-SEM
Chief investigator: Associate Professor Brian Abbey
Co Investigators: Dr Daniel Langley, Dr Eugeniu Balaur, Dr Ivan Poon, Associate Professor Alex de Marco
The overarching aim of this project is to use microfluidics in combination with FIB-SEM (Focused Ion Beam - Scanning Electron Microscopy) to reproducibly obtain with nanometre resolution the 3D structure and distribution of the internal components of cells.
If successful this project, which partners La Trobe with Monash University and Leica could have significant research and commercial outcomes. In addition to the potential industrial linkages the development of new microfluidics technology for FIB-SEM will provide a new platform for La Trobe researchers to be able to use electron microscopy to image sub-cellular features in 3D at the nanoscale.
A new class of peptide ligases as tools in protein engineering
Chief investigator: Professor Marilyn Anderson
Co Investigators: Dr Karen Harris, Dr Simon Poon, Dr Thomas Shafee, Professor David Craik
Asparaginyl endopeptidases (AEPs) are a new class of peptide ligases that are highly promiscuous, outside of short recognition sequences. AEP-mediated ligation can result in peptide circularisation (intra-molecular ligation) or the creation new linear peptides (inter-molecular ligation). These modifications can confer peptides with favourable properties, such as increased stability, or introduce functional groups. This project will explore the application of AEPs to the development of new anti-microbial peptides and investigate the relationship between substrate length and enzyme efficiency. Furthermore, using a newly developed bioinformatics tool, sequence characteristics that result in some AEPs preferentially functioning as a ligase will be described.
Charting molecular pathways for cellular copper homeostasis
Chief investigator: Dr Megan J Maher
Co Investigators: Dr Ann Kwan, Dr Sharon La Fontaine, Dr Blaine Roberts
This project aims to define the molecular pathways by which copper is trafficked within human cells. Copper (Cu) is an essential requirement for optimal nutrition, where it is a crucial component of enzyme systems such as those which act to fuel cellular energy demands. In humans, copper is carefully managed by metalloregulatory systems that ensure that the essential requirement for this metal is met, while avoiding potential toxicity. This project will examine the pathways by which Cu is managed within human cells by focusing on the proteins and their interactions, which balance this system.