Listed below are current postrgraduate projects that are being offered by different laboratories in the Institute. For more information, please contact the relevant research leader.
Cancer Biology | Immunology | Metabolic Medicine
Cancer Biology Research
The role of osteoclast loss in the development of life threatening lung metastasis in patients with osteosarcoma.
Osteosarcoma is the most common primary bone malignancy afflicting children. Unfortunately, 40% of patients with osteosarcoma will die as a consequence of pulmonary metastases. We have recently shown that the development of pulmonary metastases is preceded by the loss of osteoclasts at the site of the primary lesion in the bone. In fact, the loss of osteoclasts predicts with 90% accuracy whether a patient will develop pulmonary metastases. We are now conducting studies to see whether the loss of osteoclasts is responsible for the development of pulmonary metastases. In this regard, we have found that metastastic osteosarcoma cells are able to inhibit osteoclastogenesis and that osteoclasts are able to inhibit osteosarcoma cell migration. It is our aim to identify the factors responsible for osteoclast loss and to exploit this in the development of anti-metastases therapies.
Suitable for: PhD or Honours 
Cell Cycle control of entry into mitosis in normal and disease conditions; target for anti-cancer therapies.
Projects are available in each of the research areas of the laboratory. Please contact Associate Professor Gabrielli about more details.
Suitable for: PhD, Masters or Honours.
RNA Interference to treat cancer
This is a major focus of the lab and we have several areas of interest in which we have projects on offer.
Delivery of siRNA in vivo. A major problem is the lack of good in vivo delivery systems in which to deliver siRNA. We are looking to develop and test systems for delivery in the bloodstream, intra-vaginally, intra-nasally and intra-peritoneally. Along with our various collaborators we work on lipsomes, dendrimer nanoparticles, nano-needles and polymers. These projects would suit someone with an interest in drug delivery.
Suitable for: PhD, Masters or Honours.
Improving RNAi therapies. We have several projects on offer in the area of RNAi and cancer therapy. These include aspects of basic RNAi biology all the way to in vivo treatments and immunology. For example:
* Investigation of the fate of target RNAs following RNAi-based cleavage: Despite the established view that mRNA is immediately degraded upon RISC-mediated cleavage of mRNA there is little experimental evidence that this is actually so.
* Role of RNAi in modulating protein fate and translation: We have evidence that the 5’ end of mRNAs cleaved by RNAi can be translated. We need to understand the mechanism by which this occurs. RNAi and the immune system: RNAi can modulate the adaptive immune response (Gu et al. PNAS, 106(20):8314-19. 2009). We don’t understand the mechanism by which this is occurring.
* RNAi to treat melanoma: We are developing immune-enhancing RNAi and melanoma is the target.
Suitable for: PhD, Masters or Honours.
Chronic Leukaemia
In collaboration with the Oncology Dept at the Princess Alexandra Hospital we have been investigating the biology of chronic lymphocytic leukaemia. This cancer has no cure and current treatments only reduce the burden of disease. The projects would involve the role of micro-environmental chemokines and cytokines in leukaemia cell survival with the idea of developing novel therapies.
Cooperation between MYB amplification and BRCA1 inactivation in breast cancer
We have recently identified a critical role for the MYB transcription factor in oestrogen receptor-positive breast cancer. However, it is known that the MYB gene is also amplified in ~ 30% of breast cancers that are mutant for the breast cancer susceptibility gene BRCA1. This suggests that MYB gain and BRCA1 loss might functionally cooperate in causing breast cancer. Interestingly BRCA1 tumours – those with mutant BRCA1 or abnormally low expression of BRCA1 - are generally oestrogen receptor-negative, and represent an aggressive, difficult-to-treat subtype (‘basal’) of breast cancer. Showing that MYB overexpression and BRCA1 inactivation can functionally cooperate, and understanding the basis of this cooperation thus may provide important insights into this type of breast cancer.
Suitable for: PhD.
Targeting MYB in leukaemia and breast cancer
Because of the widespread involvement of MYB in major human cancers, including acute leukaemias, breast and colon cancers, therapies targeting MYB potentially have very broad applicability. We are taking several different approaches to development of such therapies:
i) Targeting the Myb protein itself. We have identified critical interactions between Myb and other transcriptional co-regulators, including the coactivator CBP/p300. We are now aiming to disrupt these interactions using small peptides, or potentially low-MW compounds, which may lead to the development of an anti-Myb drug.
ii) Because an anti-Myb drug is likely to be more effective clinically when used in combination with other agents, it is important to explore the ability of other anti-cancer agents to synergise with MYB inhibition in killing leukaemia and other cancer cells. We have some promising leads that suggest drug combinations that may be effective in killing breast cancer cells.
iii) It may also be possible to identify and target critical genes/proteins that act downstream of Myb, rather than blocking Myb itself.
iv) Finally, it may be possible to use targeted delivery of siRNA as an alternative approach to inhibiting MYB in specific cancer cell types.
Specific projects involving one or more of these approaches are likely to be available.
Suitable for: PhD
Application of high-throughput functional screening to cancer target discovery
The laboratory is heavily involved in developing and establishing high-throughput, gain- and loss-of-function cell-based screening. There is likely to be at least one project available that will use one of these technologies to identify potential therapeutic targets in breast cancer or leukaemia. Screens could involve identification of potential oncogenes, or “synthetic lethality” screens for targets which, when inhibited, might enhance the action of existing anti-cancer drugs.
Suitable for: PhD
Immunology Research
Interethnic studies of the genetics of rheumatoid arthritis.
Rheumatoid arthritis (RA) is a common form of arthritis in which genes determine most of the risk of developing the disease. Different genes are involved in the disease in different populations. We have established a unique, large cohort of Han Chinese RA cases and healthy controls to study. This cohort will be used to identify genes associated with RA, and to pinpoint key variants associated in genes which cause the disease. This project will involve cutting-edge SNP genotyping and next-generation sequencing technologies, and provide experience with a wide variety of laboratory and analysis methods. A successful outcome in this project such as the identification of a gene in this disease is likely to have high impact in terms of publications and contribution to our understanding of the causes of this common condition.
Suitable for: PhD.
Genetics of high bone mass.
Osteoporosis is a highly heritable condition associated with low bone mass and fragile bones. Identifying genes which cause the converse characteristics, high bone mass and strong bones, would be of value in identifying potential novel therapies for osteoporosis. This project will involve the study of cases with extreme high bone mass who have never fractured. Using next-generation sequencing technology, mutations in genes will be identified in these cases, then studied for their effect on bone development and metabolism.
Suitable for: PhD, Masters or Honours.
Genetics of Cervical Cancer
Working with Ian Frazer and other investigators in an international consortium, we are performing a genomewide association study in cervical cancer. This common disease is caused by persistent HPV infection, and the genes involved are likely to be related to the ability to clear HPV infection. This project will involve cutting edge genetics (genomewide associations approaches) and immunological approaches to determine how associated genes lead to disease.
Suitable for a PhD, Masters or Honours.
Students who expect to get a first class honours in a biomedical science subject and have a strong motivation to pursue a career in research in applied immunology are invited to contact Professor Ian Frazer to discuss possible PhD projects. The focus of the laboratory work is on understanding the effects of interactions between the innate and adaptive immune system on the effectiveness of immunotherapeutic responses induced by immunisation. Current projects include:
a) How one of two gene polymorphisms (EVER1, ERAP1) identified in GWAS as impacting on persistence of HPV infection actually achieve this (together with Professor Matt Brown)
b) How IFNg inhibits CD8 effector T cell function locally in skin
c) How the inflammasome contributes to effector T cell function in skin
d) How wnt signalling impacts on T cell function
e) NKT Cells as regulators of CD8 T cell function in skin
Factors predicting outcome in early RA
This project analyses predictors of inflammatory and radiological outcome after treatment of early RA with a strict protocol of combination DMARDs. We are using novel imaging techniques and laboratory measures, including PET-CT, NF-kappaB, microarray and serological markers to assess joint response, atherosclerotic disease and inflammatory and immunological control. Hypotheses generated from this clinical dataset are then tested in mouse models of RA, including novel interventions to prevent or attenuate disease.
Suitable for: PhD, Masters or Honours.
The molecular control of dendritic cell function in tolerance.
This project focuses on the function of the transcription factor RelB in the induction of tolerance by dendritic cells. Activity of the RelB subunit of NF-kappa B underlies the capacity of dendritic cells to stimulate T cells after microbial signalling. Inhibition of RelB expression or function in dendritic cells blocks their T cell stimulatory capacity. When antigen-exposed and adoptively transferred, these dendritic cells induce antigen-specific regulatory T cells which suppress inflammatory disease in recipient mice. This project examines the unique properties of RelBlo dendritic cells in migration, survival, interaction with effector cells, and generation of regulatory cells.
Suitable for: PhD, Masters or Honours.
Pathogenesis of rheumatoid arthritis.
A variety of proteins become citrullinated in diseased joints. Citrullination is a physiological process of arginine deimination that occurs during apoptosis and inflammation. This process results in post-translational modification of arginine-containing proteins, which can give rise to sets of neo-self antigens in individuals bearing HLA susceptibility alleles which put them at risk of RA. Citrullinated proteins have been demonstrated in inflamed tissues in RA, and at least two mouse models of inflammatory arthritis. Citrulline-specific autoantibodies are highly specific for RA and are associated with more severe joint damage and radiographic outcome. This project measures peripheral blood T cell responses to citrullinated or unmodified native peptides derived from RA-autoantigens based on their predicted binding to disease-associated HLA-DR molecules. It aims to clone the responding T cells so that crystallography can be carried out to compare interactions of the T cell receptor with native and citrullinated forms of autoantigen.
Suitable for: PhD, Masters or Honours.
Pathogenesis of inflammatory arthritis in skg mice.
Self-reactive T cells with a low signalling capacity through the T cell receptor have been observed in the SKG mouse model of rheumatoid arthritism, and have been linked to a spontaneous mutation in the ZAP-70 signal transduction molecule. This project examines the role that antigen presenting dendritic cells play in the development of arthritis in this model, and whether dendritic cell immunotherapy can be used to treat arthritic mice.
Suitable for: PhD, Masters or Honours.
Human type 1 diabetes.
We have developed a new diagnostic assay which identifies individuals with Type 1 diabetes (T1DM) and some of their relatives at risk of diabetes. Exposure of blood monocytes to the bacterial product lipopolysaccharide led to an abnormally low level of activation of the protein, RelB. We are now extending these studies to determine the value of the assay for predicting whether otherwise healthy siblings of children with T1DM will develop diabetes in the future. This would allow us to identify those at risk so that they could be treated earlier or encouraged to make preventative changes to their lifestyle. This project involves analysis of factors contributing to the abnormal RelB test, and researching ways in which RelB function can be restored in these dendritic cells, for new treatments.
Suitable for: PhD, Masters or Honours.
Type 1 diabetes in spontaneous mouse models.
We have several models of spontaneous autoimmune disease of the pancreatic islets including NOD mice and RelB-deficient mice. This project examines the interaction of two innate immune factors – interleukin-1 and NF-κB activity on the development of adaptive autoimmunity. It examines triggers for the excessive production of IL-1 in NOD mice, and how this production impacts on response to tolerising dendritic cell immunotherapy. It will particularly explore the impact of autoimmunity in NOD and RelB-deficient mice on regulatory T cell numbers and function.
Suitable for: PhD, Masters or Honours.
A randomised, controlled double blind study to evaluate the effects of simvastatin in reducing atherosclerosis in early rheumatoid arthritis.
The aims of this study are to examine the effectiveness of cholesterol lowering medicine in atherosclerotic disease progression in rheumatoid arthritis (RA). Patients with RA symptoms beginning within the past 12 months, and who have no history of cardiovascular or cerebrovascular disease are eligible. Sensitive ultrasound measures of the arteries and blood tests are taken before and after treatment to assess the progression of disease. Patients are randomly allocated to receive cholesterol-lowering therapy with either simvastatin or no active substance (placebo) for two years. Ultrasound and blood measurements are taken yearly to assess progression of arthritis and atherosclerosis. This project will focus on analysis of blood microarray profiles of patients from each group, before and after treatment.
Suitable for: PhD, Masters or Honours.
Cellular and molecular pathways of T-cell tolerance
Diseases of immune dysregulation such as autoimmunity and allergies develop because the normal mechanisms that control the immune system fail through either genetic or environmental causes. Induction of T-cell tolerance is seen as an attractive therapeutic for many of these diseases. We have developed several models that explore the concept of antigen-presenting cell-targeted gene expression for induction of peripheral tolerance in T cells as a means of restoring immune regulation. This project will define, using our established models of tolerance, key molecular pathways and cellular interactions that underlie the induction and maintenance of T-cell tolerance. Investigations using molecular, biochemical and cellular immunological approaches will be used to define the key ‘rules’ that control T-cell tolerance. Current themes include the role of regulatory T cells, NKT cells and inhibitory costimulatory molecules along with transcriptional profiling. Future themes include regulation of tolerance pathways in autoimmune-prone and -resistant T cells.
Suitable for: PhD, Masters, Honours.
Inactivation of memory T-cell responses
A current challenge for immunotherapy of autoimmune diseases is that once disease begins populations of activated and memory T-cells specific for the molecular targets of disease develop. To treat active autoimmune diseases, approaches need to be developed that can terminate the ongoing responses of activated and memory T cells. While it has traditionally been thought that activated and memory T cells were resistant to inactivation or tolerance induction, we have recently shown that steady-state peripheral dendritic cells expressing cognate antigen terminate CD8+ memory T cell responses (Blood. 111:2091-2100). This may be a useful approach to terminate ongoing autoimmune responses, and, in this project we aim to explore the crucial cellular and molecular interactions that inactivate memory T cells and to define methods to limit effector function that may be elicited during the process of tolerance induction.
Suitable for PhD, Masters, Honours.
Prevention and reversal of autoimmune diabetes
We have previously shown that autoimmune (type 1) diabetes in mice can be prevented by expression of key disease targets in dendritic cells as a means to interrupt disease development. We have available a diverse range of autoimmune diabetes models, both spontaneous and induced. This project will use these models to provide proof-of-principle studies that established diabetes-causing T-cell responses can be terminated. Studies will focus primarily on cellular immunology of the destructive T-cell responses and the role of dendritic cells in promoting or preventing those responses.
Suitable for PhD, Masters, Honours.
Blockade of established allergic T-cell responses
Allergies to environmental antigens are debilitating and respond poorly to conventional immunotherapeutic approaches. We propose that genetic targeting of antigen will prove a novel and effective approach to reverse established allergic immune responses. If successful, this approach could be used to prevent the risk of life-threatening allergic reaction and may also alleviate atopic asthma. This project will use established transgenic mouse models to test the capacity of antigen-targeting approaches to reverse allergic immune sensitisation and to prevent the pathogenesis of allergic airways hyper-responsiveness, an animal model mimicking many features of human asthma.
Suitable for PhD, Masters, Honours.
Novel methods of gene delivery for tolerance
We have developed substantial background expertise in the induction of antigen-specific tolerance in both naïve and memory T cells. Potential therapeutic applications of antigen-specific tolerance induction are being investigated in pre-clinical models of autoimmune and allergic diseases. However, currently available methods, for ethical and logistic reasons, limit the potential for clinical application of antigen-specific immunotherapeutic gene therapy. We are now seeking ways to develop a vaccine-like approach to facilitate gene-therapeutic induction of tolerance for application to autoimmune diseases. Projects are available which provide a mix of molecular, chemical and cellular biological approaches to explore and develop novel methods of in-vivo gene transfer to achieve immune tolerance.
Suitable for PhD, Masters, Honours.
Metabolic Medicine Research
Imaging the interaction of IMPDH with lipid droplets using a novel fluorescent protein fragment complementation approach.
This project will employ a new system to define the redistribution of inosine monophosphate dehydrogenase (IMPDH) to intracellular lipid droplets. Initially, the project will involve the generation of a series of chimeric proteins, each containing one part of a fluorescent reporter protein fused to the target protein(s). Following induction of expression of the chimeric proteins and treatment with an appropriate agent, such as insulin or fatty acid, when the two parts of the fluorescent protein are brought into close proximity they are able to interact, generating a fluorescent signal. The system will be used to probe the dynamics of IMPDH association with lipid droplets using real time video microscopy and may subsequently be employed to screen for novel interacting proteins using IMPDH and/or other target proteins of interest (IRS-1, Adiponectin, Adiponectin Receptors). Techniques will include a broad range of molecular biology and cell biology approaches.
Suitable for: Honours or PhD.
Molecular and functional characterisation of novel Adiponectin Receptor Interacting Proteins.
This project will involve the validation and functional characterisation of proteins recently identified by our group as Adiponectin Receptor Interacting Proteins (ARIPs). A range of approaches will be employed to determine:
i) the molecular details of the interactions (including the interacting domains) between AdipoR1/R2 and the ARIPs - using recombinant wild-type and mutant proteins produced in mammalian and bacterial expression systems;
ii) the functional and physiological significance of the interactions in the context of adiponectin signalling and adiponectin action - using overexpression, knockdown (shRNA), peptide antagonists and pharmacological interventions. Investigations will involve model cell systems and may progress to studies in vivo.
Suitable for: PhD.
Obesity and overweight pose major risks for development of serious chronic diseases, including type 2 diabetes, cardiovascular disease, hypertension and stroke, and certain forms of cancer. The health consequences range from increased risk of premature death to serious chronic conditions that reduce the overall quality of life. The Metabolism Group undertakes basic research into factors underpinning the relationship between obesity and metabolic disease, this includes analyses of factors regulating growth and metabolism of human adipose tissue and mechanisms involved in hormone metabolism, insulin signalling and glucose homeostasis in adipose tissue.
Obesity and FGF-1
We have identified FGF-1 as a potent stimulating growth factor for the growth of human fat cells. Our current work explores the therapeutic possibility of strategies to impair FGF-1 action to promote weight loss. Results to date indicate that pharmacological and gene knockdown approaches can reduce fat cell growth in vitro; and reduce adiposity in animal models of obesity.
Glucocorticoids and insulin resistance
Glucocorticoid hormones, which are increased in obesity; and glucocorticoid drugs, which are widely used in asthma and arthritis, cause impaired glucose tolerance and, in some individuals, diabetes. We are using human adipose cells to investigate the mechanisms behind this phenomenon. Information gained may allow us to develop ways to prevent the damaging side-effects of corticosteroids.
11betaHSD-1 and its relationship to metabolic dysfunction
11betaHSD-1 is an enzyme in adipose tissue that produces glucocorticoid hormones. We have demonstrated that the expression and activity of 11betaHSD-1 is increased in adipose tissue of obese individuals, suggesting that increased glucocorticoid may contribute to the metabolic dysfunction seen in obesity. We are currently investigating the efficacy of drugs that specifically block 11betaHSD-1 activity, as potential anti-diabetes strategies.
We currently have a number of projects available in each of the above research areas. These include:
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Identification of novel regulatory mechanisms in adipose tissue development
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Identification and characterisation of candidate molecules as potential anti-obesity targets
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Examination of Adipocytokine biology, particularly adiponectin
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Determination of corticosteroid effects on insulin action
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Examination of steroid interconversion and hormone metabolism in adipose tissue
These projects will utilise molecular, biochemical and genetic techniques in both in vitro and in vivo settings. For further information please contact Professor John Prins
(j.prins"at"uq.edu.au) or Dr Louise Hutley (l.hutley"at"uq.edu.au).
Cholesterol in prostate cancer
Elevated cholesterol is associated with aggressive prostate cancer while cholesterol reduction by statin therapy reduces the risk. We have recently shown that modulating the subcellular structure of caveolin, a protein on the cell surface that binds cholesterol, can reduce the aggressiveness of a metastasis-derived prostate cancer cell line. We will determine the mechanism linking cholesterol levels with prostate cancer progression. An Honours project is available to investigate the role of cholesterol in prostate cancer cell function. The techniques used will include cell culture, cell-based functional assays and cell signalling assays. A PhD project is available to perform proteomics and systems biology analysis on prostate cancer cells, and to determine the effect of statin treatment on prostate cancer metastasis using mouse models.
Tear biomarkers for diabetic neuropathy (in collaboration with Dr Anthony Russell and the Anterior Eye Laboratory at QUT).
Nerve damage affects up to 50% of patients with diabetes and diabetic peripheral neuropathy is a major cause of limb amputations and mortality. We have demonstrated that corneal nerve damage correlates with peripheral nerve damage. The accessibility of patient tears makes it an attractive source for discovery of biomarkers for early diagnosis of neuropathy. An Honours project is available to compare the proteome of tears obtained from patients with diabetic neuropathy and controls (collected by the Anterior Eye Laboratory, QUT). The techniques used will include 1D and 2D gel electrophoresis, in-gel tryptic digest and mass spectrometry. A PhD project is also available to compare differences in the sugar modifications of tear proteins in neuropathy, using our novel lectin array technique.
For more information, please contact Dr Michelle Hill (m.hill2"at"uq.edu.au) or Professor John Prins (j.prins"at"uq.edu.au).
To find out more about any of the projects listed above, please contact the relevant group leader. If you have a question about the Postgraduate Program in general, or would like more information about the Diamantina Institute, please contact our Postgraduate Administrative Officer on di.studentenquiries"at"uq.edu.au or phone 07 3240 5490.