Student Projects 2008

Cancer & Cell Biology

• Membrane Transport
• Radiation Signaling and Disease
• Ataxia-telangiectasia and ATM kinase activation
• Cloning of Novel Snake Venom Proteins
• Ataxia with oculomotor apraxia in DNA damage response and RNA metabolism
• Signaling in Cancer cells
• Genetic Changes in Colon Cancer and Colorectal Cancer
• anti-Cancer Drugs from the Rainforest

Infectious Diseases

• Helminth Biology
• Immune events in Malaria and Leishmaniasis
• Bacterial Pathogenesis
• Receptors and potential drug targets of Malaria Infection
• Studies on malaria enzymes involved in gene regulation
• Group A Streptococcus vaccines
• Mosquito Control

Genetics and Population Health

• Cancer predisposition genes in Endometrial cancer
• Predisposition to Endometrial; Ovarian and Oesophageal cancer
• Functional Analysis of BRCA1/2 Sequence Variants of Unclassified Clinical Significance
• Epigenetics
• Familial Cancer

Immunology

• Clinical Immunohaematology

---

How to apply:
Contact the Laboratory Head related to the project area of interest (see below).   Application and admission details in "Becoming a Student".

Legend:
P   = PhD, MPhil project
H   = Honours project
TU = Top-Up available

Cancer and Cell Biology Division

Membrane Transport Laboratory
Dr Nathan Subramaniam
07-3362 0179
Email nathanS@qimr.edu.au
[ P, H]

Membrane Transport

In recent years it has become very evident that a large number of human disorders can be attributed to defects in the trafficking and localisation of molecules, predominantly membrane proteins. By studying how mammalian cells regulate the synthesis, assembly, trafficking and localisation of membrane proteins implicated in these human disorders we hope to advance our understanding of these disorders with the prospect of a better therapeutic intervention.

HFE, transferrin receptor 2, ferroportin1 and hepcidin are four proteins which have been implicated in iron metabolism. Mutations in these four proteins have been shown to cause iron overload in humans.

A number of exciting projects are available in the laboratory. These include:

1. Molecular and cellular analysis of hepcidin and hemojuvelin
   Hepcidin and hemojuvelin are genes found to be mutated in juvenile haemochromatosis. The role of hemojuvelin in iron regulation is still unknown. Using a variety of molecular and cellular biology tools we will study the synthesis, assembly, trafficking and regulation of hemojuvelin and hepcidin. Using proteomics we will identify molecules which interact with hemojuvelin with the ultimate aim of understanding the role of hemojuvelin and these proteins in regulating iron absorption and transport.
2. Studying the mechanism by which SNAREs influence trafficking of membrane proteins.
   Receptors on both exocytic and endocytic vesicles, termed SNAREs, and a number of adaptor molecules have been shown to influence the trafficking and localisation of membrane proteins. We are studying the role of these proteins in the trafficking of HFE and transferrin receptor 2. Both these proteins are expressed on the cell surface. Studies are aimed at studying the regulation and internalization of these molecules.
3. Molecular and functional characterisation of a novel ubiquitin-like protein.
   We have recently identified a novel ubiquitin-like protein with homology to yeast proteins involved in protein degradation and DNA-damage repair. We have also identified a related homolog. Studies have been initiated at understanding the role of these mammalian proteins in these processes. This project would analyse the expression and distribution of these proteins using real-time RT-PCR in various tissues and cell lines. Proteomics will be used to identify interacting molecules. These molecules will then be cloned and characterized. Using the yeast protein as a model the interaction of candidate proteins will be studied.

Back to Top

Radiation Biology and Oncology Laboratory
Prof Martin Lavin
07-3362 0341
Email martinL@qimr.edu.au
[H, P]

Radiation Signaling and Disease

The major emphasis of our research is the recognition of damage in DNA using human and animal models to investigate genome instability, cancer predisposition and neurodegeneration.
Research is also directed to isolating novel therapeutic compounds from snake venom, early detection of prostate cancer and identification of genes in development.

Much of our work focuses on the gene defective in the human genetic disorder ataxia-telangiectasia (A-T), ATM, that plays a central role in recognising double-strand breaks in DNA, and signalling of these breaks to slow the passage of cells through the cell cycle so that the DNA damage can be repaired. Failure to recognise and repair this damage in A-T patients results in increased frequency of cancer and a progressive neurodegeneration. Being able to slow or halt the progress of this neurodegeneration would be of great benefit to A-T patients.

More recently we have extended this work to include investigations on other ataxia syndromes where a defect in DNA repair is also implicated in the phenotype.

Student projects:

• Mouse models for cancer predisposition
• Mouse models for neurodegenerative human syndromes
• Use of antioxidants to protect against neurodegeneration
• Mechanism of action of aprataxin mutated in ataxia oculomotor apraxia type 1
• Characterization of senataxin mutated in ataxia oculomotor apraxia type 2
• Role of the hSMG-1 protein kinase in stress granule formation
• Identification of novel proteins in snake venom with potential therapeutic activity
• Early detection of prostate cancer
• Dna damage and aging

Back to Top

Radiation Biology and Oncology Laboratory
Dr Sergei Koslov
Prof Martin Lavin
07-3362 0344
Email sergeiK@qimr.edu.au
Email martinL@qimr.edu.au
[H, P]

Ataxia-telangiectasia and ATM kinase activation

A-T is a prominent example of a genetic disease which over the years stimulated fundamental research into an understanding of major cellular processes. ATM (ataxia-telangiectasia, mutated) protein mutated in the disease, is involved in multiple aspects of cellular metabolism, such as response to DNA damage, cell cycle and genetic stability.

ATM belongs to superfamily of phosphatidylinositol (PI) 3-kinase related proteins and was found to be a protein kinase which is rapidly activated in the presence of DNA double strand breaks but the mechanism of ATM kinase activation remains poorly understood.

The importance of autophosphorylation in regulation of ATM kinase activity was suggested (Kozlov et al 2003, J Biol Chem, v.278:9309), followed by identification of S1981 as a major autophosphorylation site of ATM in vivo (Bakkenist and Kastan, 2003 Nature, v.421:499).

It was speculated that ATM can "sense" unknown changes in the higher order chromatin structure caused by DNA double-strand breaks (DSB) away from the actual site of the break. Protein phosphatases PP5, PP2A and PP2C phosphatase Wip1 (Ali et al 2004 Genes Dev. v.18:249; Goodarzi et al, 2004, EMBO J. v.23:4451; Shreeram et al, 2006, Mol Cell. v.23:757) have also been implicated in the regulation of ATM kinase activity.

Regulation of ATM kinase activity by acetylation via interaction with acetyltransferases Tip60 and hMOF1 was also observed (Sun et al 2005, Proc Natl Acad Sci U S A. v.102:13182; Gupta et al 2005, Mol Cell Biol., v.25:5292). Mre11/Rad50/Nbs1 (MRN) complex was found to be necessary for the optimal activation of ATM kinase (Uziel et al 2003, EMBO J., v. 22:5612; Lee and Paull 2004, Science, v.304:93; Costanzo et al 2004 PLoS Biol; v.2:E110; Lee and Paull 2005, Science, v.308:551).

We have recently completed a study of the human ATM kinase autophosphorylation sites (Kozlov et al, 2006 EMBO J, v.25:3504). Our current work is based on a hypothesis that ATM kinase activation is a multi-step process of sensing of alterations in global chromatin and nuclear structure and involves multiple post-translational modifications.

PhD projects are available to investigate the role of ATM kinase as a "chromatin status" sensor and establish an essential role of post-translational modifications in the ATM kinase activation.

Back to Top

Radiation Biology and Oncology Laboratory
Dr Geoff Birrell
Prof Martin Lavin
07-3362 0337
Email Geoff.Birrell@qimr.edu.au
Email Martin.Lavin@qimr.edu.au
[H, P]

Cloning of Novel Snake Venom Proteins

Our lab has identified over 725 proteins in venoms from 20 Australian snakes (Birrell et al, Mol Cell Proteomics. 2007 (6):973-86.

We also have obtained the cDNA sequence for many of these. A Summer Vacation project exists to PCR amplify and sequence several novel genes from snake venom gland cDNA. The sequences will be aligned and compared with those from other snakes.

This will increase both our understanding of phylogenetic relationships between snakes and the potential for novel venom proteins as human therapeutics.

Back to Top

Radiation Biology and Oncology Laboratory
Dr Olivier Becherel
Prof Martin Lavin
07-3362 0341
Email Olivier.Becherel@qimr.edu.au
Email Martin.Lavin@qimr.edu.au
[H]

Ataxia with oculomotor apraxia in DNA damage response and RNA metabolism

Ataxia oculomotor apraxia (AOA) is a common phenotype found in several degenerative disorders of the nervous system. Ataxia refers to lack of coordination and oculomotor apraxia describes the difficulty in moving the eyes. These debilitating diseases include ataxia-telangiectasia (A-T), A-T like disorder (A-TLD), both of which are characterized by a defective response to DNA damage and cancer predisposition, and ataxia oculomotor apraxia type 1 (AOA1) and type 2 (AOA2).

The gene mutated in AOA1, APTX, was identified in 2001 and encodes for aprataxin, a novel protein involved in DNA repair/DNA damage processing. In the case of AOA2, the gene mutated, SETX, was recently discovered and encodes for senataxin, a novel protein predicted to contain a seven-motif domain at its C-terminus, typical of the superfamily I of DNA/RNA helicases. Preliminary results on senataxin and recent data on aprataxin suggest a potential role of these two proteins in the repair/processing of DNA breaks and RNA metabolism.

To gain further insight and ultimately pinpoint their cellular roles during the response to DNA damage and in RNA metabolism, several studies are under way, such as:

1. Role of senataxin in DNA transcription and mRNA splicing (localisation, dynamics and splicing efficiency
2. Down-regulation of genes mutated in recessive spinocerebellar ataxias by stable small interfering RNA
3. Cloning and expression of GST-fusion proteins for protein-protein interaction studies

A panel of methods are used in the various aspects of the study and include classical molecular biology techniques (e.g: cloning, PCR), biochemistry (e.g: protein expression and purification, analysis of protein-protein interactions), cell culture, and cell biology (e.g: microscopy, immunofluorescence).

Back to Top

Signal Transduction Laboratory
Dr Kumkum Khanna
07-3362 0338
Email Kumkum.Khanna@qimr.edu.au
[ H, P]

Signaling in Cancer cells

Work within the Signal Transduction Laboratory centres on how a cell responds to chromosomal DNA damage. In any organism, the capacity to sense and respond to DNA damage is vital for maintaining healthy functioning cells. DNA damage response encompasses an intricate network of molecular pathways controlling passage through the cell division cycle, repair of damage to DNA, and initiating cell suicide programme when the fate of cell is grim. ATM is a key regulator of cellular response to double strand DNA breaks and genes that lie downstream of ATM, including p53, BRCA1 and Chk2, are associated with familial predisposition to breast cancer or with one or other forms of cancer.

Our current area of research include:

1. To understand the normal functions of these tumor suppressors in normal mammary epithelial cells
2. Characterize proteins that bind to these tumor suppressors to understand how these tumor suppressors work together with other proteins to perform multiple functions
3. Characterization of novel factors involved in protecting cells from DNA damage and to study their mechanism of action and link with cancer susceptibility.

Back to Top

Gasteroenterology Laboratory
Dr Vicki Whitehall
Dr Kevin Spring
Prof Barbara Leggett
07-3362 0170;  07-3636 3110
Email Barbara_Leggett@health.qld.gov.au;
[ H, P ]

Genetic Changes in Colon and Colorectal Cancer

Characterisation of the genetic changes underlying the progression of a pre-cancerous colonic polyp to colon cancer will increase our understanding of this disease and improve treatment options

We are studying both polyps and cancers in an effort to identify genetic markers for progression, prognosis and response to therapy.

Colorectal cancer continues to be one of the most common internal malignancies occurring in the Australian population. One in twenty-three of our population will develop it during their lifetimes and half of these cases will not survive beyond five years. However, colorectal cancer has a great potential for prevention as most of these malignancies develop within pre-cancerous growths called polyps which can be removed at colonoscopy.

Colorectal cancer is a somewhat heterogeneous disorder. Across the spectrum of colorectal cancer types, there is a gradient of genetic causation tempered by the effects of environment such as smoking, diet and the use of anti-inflammatory drugs.

Over the last decade our laboratory has contributed to the growing understanding that these different influences result in a number of distinct subtypes of colorectal cancer. These develop along different molecular genetic pathways and have characteristic somatic changes.

This work has important implications for improving prevention and therapy of the disease.

Honours project

Potential honours projects will examine candidate genes for a role in the development of colorectal cancer. Putative tumour suppressor genes can be evaluted by a number of techniques to examine expression changes, altered methylation, mutation and gene deletion. This would then be compared with important molecular events characteristic of specific colon cancer subgroups. Gene candidates can then be expressed in cell lines for functional analysis. Finally, we have detailed patient records for further comparison of genetic alterations with tumour pathology and clinical outcome.

PhD project

Potential PhD projects will examine candidate genes for a role in the development of colorectal cancer. Such genes will be selected either by a traditional candidate gene approach, or as a result of expression or methylation profiling experiments. Putative tumour suppressor genes can be evaluted by a number of techniques to examine expression changes, altered methylation, mutation and gene deletion.
This would then be compared with important molecular events characteristic of specific colon cancer subgroups. Gene candidates can then be expressed in cell lines for functional analysis. Correlation can then be sought between the observed genetic alterations, tumour pathology and clinical outcomes based on our detailed patient records.

Back to Top

Drug Discovery Laboratory
Prof Peter Parsons
07-3362 0316
Email Peter.Parsons@qimr.edu.au
[ H, P]

Anti-Cancer Drugs from the Rainforest

Australian Rainforest Foundation Honours Scholarship: click here

This scholarship is offered for study primarily in the Drug Discovery Group at QIMR. As part of a collaborative project, this group has identified a family of bioactive compounds that occur in related plant species of the North Queensland rainforest. The compounds are active in cell signalling pathways relevant to controlling cancer, and are likely to influence the ecology of their source plants in their natural setting, particular in providing protection against herbivores. Much remains to be learnt about all aspects.

The Scholar will focus on one or more of the following: (1) the structures of a family of bioactive compounds from the rainforest and their distribution in related species, (2) structure/bioactivity relationships in relation to their anticancer activity, or (3) the ecological implications in terms of defence.

A wide range of supervisory experience will be provided for the particular project path chosen, along with mentoring to help achieve a high quality Honours report. Training will be given in a range of techniques including HPLC, MS, cell culture, flow cytometry and gene expression.

Applicants should have a sound undergraduate record in the particular area of interest selected for study, and must be acceptable for enrolment in the relevant department of a university in Queensland. The stipend will be $5000 and is expected to be tax-free.

Enquiries, and applications including CV, copy of academic record, names and contact details of two professional referees and covering letter should be emailed to

Prof. Peter Parsons
Drug Discovery Group
Queensland Institute of Medical Research
Herston , Qld 4029

Closing date: 31 October, 2007

Back to Top

Infectious Diseases

Helminth Biology
Dr Alex Loukas
Ph: 07-3845 3702
Email Alex.Loukas@qimr.edu.au
[ H,P]

Vaccines against blood-feeding parasites

The Helminth Biology laboratory is interested in parasitic helminths (worms) that parasitize humans. These large parasites are long-lived and have developed incredibly sophisticated mechanisms to allow them to survive and proliferate within almost hlaf the world's population.

Much of the success of these worms can be attributed to the proteins they secrete into host tissues. These proteins are involved in migration, feeding and evasion/manipulation of the host's immune response.

Our lab explores the nature and functions of these parasite excretory/secretory (ES) proteins using various molecular and immnological techniques. We have exploited our knowledge of these parasite proteins and used them to develop vaccines that interrupt key physiological processes that are essential for parasite survival. By harnessing the potent immunomodulatory properties of helminths, we are also exploring the potential of helminth ES proteins as therapies for autoimmune disorders, particularly inflammatory bowel diseases.

Major PhD projects in the lab include:

1. Understanding the molecular biology of blood-feeding in hookworm parasites
2. Developmental molecular biology of hookworm larvae
3. Using surface tetraspanins as recombinant vaccines for schistosomiasis
4. Using intestinal proteases as anti-blood-feeding recombinant vaccines for hookworm disease
5. Hookworm ES proteins as therapies for auto-immune disorders
6. Understanding how the liver fluke, Opisthorchis viverrini, causes liver cancer in SE Asia

For examples of some of our recent work, see the following papers.

• Tran et al. (2006) Tetraspanins on the surface of Schistosoma mansoni are protective antigens against schistosomiasis. Nature Med. 12(7):835-40
• Loukas et al. (2005) Vaccination with recombinant aspartic hemoglobinase reduces parasite load and blood loss after hookworm infection in dogs PLoS Med. 2(10):e295.
• Loukas et al. (2006) Hookworm vaccines: past, present, and future Lancet Infect Dis. 6(11):733-41.
• Sripa et al. (2007) Liver fluke induces cholangiocarcinoma. PLoS Med. 4(7):e201

Scholarship top-ups are available. For more information, contact Dr Alex Loukas.

Back to Top

Immunology and Infection
Dr Christian Engwerda
Ph: 07-3362 0428
Email Christian.Engwerda@qimr.edu.au
[ H,P]

Immune events in malaria and leishmaniasis

Cerebral malaria (CM) and visceral leishmaniasis (VL) are significant parasitic diseases in the developing world. We work with experimental models of CM caused by Plasmodium berghei and VL caused by Leishmania donovani. Both protozoan parasites induce strong inflammatory immune responses by their hosts that contribute to the development of tissue pathology.

One of the major aims of the Immunology and Infection laboratory is to understand how these inflammatory responses are initiated, identify the immune cells that cause pathology and to devise strategies to protect the host from disease, without impeding the development of protective immunity. We focus on two stages of infection. First, the priming of parasite-specific T cells that produce inflammatory mediators, and second, the migration of activated T cells to sites of infection and their interaction in local tissue micro-environments.

Many of our studies are performed in situ with infected tissue so that we avoid changes to cell behaviour once they have been removed from local tissue micro-environments. Therefore, these studies require the use of unique reagents and specialised techniques such as immunohistochemistry, confocal microscopy, laser micro-dissection and whole-tissue imaging.

Students in our laboratory would become familiar with all of these techniques. There will also be opportunities for successful Honours students to enrol for PhD studies and continue work in the Immunology and Infection laboratory.

Project 1  Defining early immune events following Plasmodium berghei infection

The activation of parasite-specific T cell responses is a key event in the pathogenesis of cerebral malaria (CM) in mice caused by Plasmodium berghei. Dendritic cells (DCs) play an important role in the activation of T cells by presenting parasite antigens, providing co-stimulatory signals and producing pro- and anti-inflammatory cytokines that influence the phenotype of activated T cells. We will isolate splenic DC's from mice at various times after infection with P. berghei to determine the co-stimulatory molecules and cytokines being expressed by these cells.

Initially, we will study the important co-stimulatory molecules CD80, CD86 and CD40, as well as the pro-inflammatory cytokine IL-12 and anti-inflammatory cytokine IL-10. Blocking antibodies raised against these molecules will be administered to mice prior to infection and the effects of DC function and T cell activation will be analysed, as well as effects on the development of CM. This work will be the first step in identifying the key molecules that activate T cells involved in the development of pathology during CM. Once identified, strategies to modulate their expression can be devised with the aim of preventing the development of cerebral malaria in humans.

Techniques used in this project will include cell biology, molecular biology, histology, microscopy and analysis of blood parasite levels. Resources are available to continue this work as a PhD project.

Reference: Good M. F., H. Xu, M. Wykes and C. R. Engwerda. 2005. Ann Rev Immunol 23:69.

Back to Top

Bacterial Pathogenesis Laboratory
Assoc Prof Sri Sriprakash
Dr David McMillan
07-3845 3712
Email daveM@qimr.edu.au
[ H,P]

Bacterial Pathogenesis

The Bacterial Pathogenesis Laboratory conducts research into beta-hemolytic streptococci, a group of bacteria that cause a wide range of diseases in humans. We currently have two projects available that would suit enthusiastic Honours students. Smaller aspects of these projects are also available to Summer students who would like to gain experience in a research laboratory.

Multi-locus sequence typing of group G streptococcus (GGS)

Normally considered a commensal organism or opportunistic pathogen, several studies have now demonstrated that GGS is able to cause a range of diseases in humans. The virulence factors that enable GGS to cause these diseases are unknown. It is also unknown whether GGS strains capable of causing disease comprise a distinct evolutionary lineage from those strains incapable of causing disease.

In this project Multi Locus Sequence Typing (MLST) will be used to determine the evolutionary relationships between multiple GGS isolates. An MLST profile for an individual strain is created by nucleotide sequencing seven conserved house-keeping genes, that are not be the subject of evolutionary pressure. Our laboratory has a collection of clinically defined GGS isolates collected from patients presenting with invasive disease. We also have a collection of non-disease associated GGS isolates. MLST will be used to investigate the evolutionary relationships between the GGS isolates in these two collections.

Expression and characterisation of exofoliative toxin in Group A streptococcus

Group A streptococcus is a Gram-positive organism that is associated with a wide range of diseases in humans. These include pharyngitis, skin diseases and the post-infectious sequelae rheumatic fever and rheumatic heart disease. A wide number of virulence factors have been characterized in GAS. These include adhesins, factors that help the bacteria avoid host immune defenses and toxins.

Exfoliative Toxin (ET) is an important virulence factor in Staphylococcus that contributes to skin disease and bacterial dissemination. Our own studies have determined a gene encoding an ET homologue to be present in all GAS isolates. In this project we will characterize ET in GAS. The ET gene will be cloned into an expression vector for purification of ET and anti-ET antibodies produced in mice. These antibodies will be used in Western blots to investigate the expression of ET by multiple GAS isolates. Sequencing of the ET gene in these isolates will be undertaken to investigate the allelic diversity of the gene. Through homologous recombination we will also generate an ET deficient GAS strain. This strain will be compared to the parental host strain in a mouse infection model.

For further enquires please contact Dr David McMillan.

Back to Top

Malaria Biology Laboratory
Dr Katharine Trenholme
Dr Tina Skinner-Adams
Dr Don Gardiner
07-3362 0432
Email Katharine.Trenholme@qimr.edu.au
[ H,  P]

Receptors for Malaria Infection

General Information
There are an estimated 300-500 million clinical cases of malaria each year, resulting in between 1.5 and 2.7 million deaths annually. These are mainly caused by infection with the malaria parasite Plasmodium falciparum. The Malaria Biology Laboratory group at QIMR is involved in a number of projects that are designed to provide us with important information about Plasmodium falciparum and the way this organism functions. Many of the projects in our laboratory have both molecular and cellular components and involve determining the function of genes.

The molecular approaches often rely on transfection, a process that allows us to introduce foreign DNA into parasites so that we can determine function. We can alter genes, "knock" them out, tag them or simply permit them to be expressed in an environment where they may not have been previously expressed. We are also involved in assessing the ability of particular parasite proteins to protect the host from infection and recently we have become interested in assessing the activity of some novel anti-malarial agents as well as extending our molecular experience into the drug action and drug resistance arena.

Hons, Masters/PhD Projects are available in the following subject areas:

Gametocytogenesis
Gametocytogenesis is a poorly understood stage of the parasite lifecycle that is essential for transmission of the parasite from the human to the mosquito host. We are exploring this stage as a potential focus for intervention strategies.

Identification of red cell receptors for P. falciparum
Identification of red cell receptors for P. falciparum including identification of genes associated with carbohydrate-binding lectin(s) on the surface of P. falciparum merozoites as there is increasing interest in the use of lectins as targets of specifically tailored drugs.

Evaluation of aminopeptidases as potential drug targets
There are 4 aminopeptidases involved in haemoglobin degradation and each enzyme represents a potential target at which novel antimalarial drugs that disrupt parasite protein turnover and synthesis could be developed Katharine.Trenholme@qimr.edu.au

Back to Top

Clinical Tropical Medicine Laboratory
Dr Kathy Andrews
Dr James McCarthy
07-3845 3725
Email Kathy.Andrews@qimr.edu.au
[H]

Studies on malaria enzymes involved in gene regulation

Malaria is responsible for over 2 million deaths annually, making it the most lethal parasite-mediated infectious disease. Most deaths are caused by P. falciparum. No vaccine is currently available for this disease and resistance to antimalarial drugs is a global problem. New anti-malarial agents that act against novel parasite targets are a high priority to combat multi-drug resistant parasites.

Enzymes involved in gene regulation and cell cycle progression have yet to be exploited as potential new antimalarial targets. Our work focuses on these pathways, in particular enzymes involved in histone modification (P. falciparum histone deacetylases (PfHDACs). Understanding the role of these enzymes on parasite gene regulation and development will allow us to more rationally target these, and interacting proteins for, development of new antimalarial therapies.

This project may involve investigating the role of PfHDACs on parasite development, identifying new inhibitors of PfHDACs, generating transgenic parasites, or studying the basic biology of PfHDACs.
For further information contact Dr Kathy Andrews
References:

1. Pasvol, G., Weatherall, D.J., Wilson, R.J., Smith, D.H. & Gilles, H.M. Fetal haemoglobin and malaria. Lancet 1, 1269-72 (1976)
2. Pasvol, G., Weatherall, D.J. & Wilson, R.J. Effects of foetal haemoglobin on susceptibility of red cells to Plasmodium falciparum. Nature 270, 171-3 (1977)
3. Shear, H.L. et al. Transgenic mice expressing human fetal globin are protected from malaria by a novel mechanism. Blood 92, 2520-6 (1998)
4. Witt, O. et al. Induction of fetal hemoglobin expression by the histone deacetylase inhibitor apicidin. Blood 101, 2001-7 (2003)
5. Andrews, K.T. et al. Anti-malarial effect of histone deacetylation inhibitors and mammalian tumour cytodifferentiating agents. Int J Parasitol 30, 761-8 (2000)
6. Glenn, M.P. et al. Antiproliferative and phenotype-transforming antitumor agents derived from cysteine. J Med Chem 47, 2984-94 (2004)

Back to Top

Malaria Immunology Laboratory
Dr Colleen Olive
07-3362 0431
Email Colleen.Olive@qimr.edu.au
[H, P]

Group A Streptococcus vaccines

Infection with group A streptococcus (GAS) is responsible for causing many clinical manifestations including pharyngitis, impetigo, scarlet fever, invasive infections such as toxic shock syndrome and necrotizing fasciitis, as well as the post-infectious sequelae - rheumatic fever (RF) and rheumatic heart disease (RHD). The latter are a major problem in developing countries and indigenous populations worldwide, particularly in Australian Aboriginals who have the highest reported disease incidence rates.

RF is a multi-organ disease which usually follows 2-6 weeks after an untreated acute GAS throat infection with symptoms of polyarthritis, carditis and chorea. It has been reported that up to 3% of untreated GAS throat infections lead to RF. Acute RF can result in RHD, which is a major cardiovascular condition in Australian Aboriginals contributing to high morbidity and mortality in young adults and a mean life expectancy of 33 years.

Current control strategies to prevent streptococcal infection, which would prevent RHD and other GAS-associated diseases, are proving ineffective and it is believed that the development of a vaccine represents the best primary prevention solution. Furthermore, in the absence of an effective primary prevention vaccine strategy, GAS infections continue to be a significant burden on human health worldwide.

Research is focused on the development of a novel mucosal GAS vaccine using multiple vaccine candidates, and investigation of LCP as a platform delivery technology gainst other human pathogens.

Projects are available for Honours and PhD scholars in 2008.

The development of a peptide-based group A streptococcal vaccine

Project: Mucosal delivery of GAS vaccine antigens
My research over the last seven years has focused on the development of a synthetic multiepitope mucosal GAS prophylactic vaccine based on the Lipid-Core Peptide (LCP) system. I have published more than 15 research papers and six review articles on this area. My research has progressed to the design of dual antigen (M protein and SfbI)-containing vaccines designed to provide superior protective immunity, when compared to single antigen vaccines, against GAS and which can be delivered nasally.

A research project is available which involves the investigation of the protective potential of GAS vaccine candidates delivered mucosally to mice. Vaccine candidates will be synthesised using lipid core peptide technology incorporating protein antigens important in bacterial virulence. Two such antigens to be targeted are the bacterial surface proteins - M protein (anti-phagocytic molecule) and fibronectin-binding protein (epithelial cell adhesion molecule). A substantial component of the research will involve animal handling, in addition to laboratory procedures for the assessment of the induction of protective immune responses as reflected by antibody production, and the ability of antibodies to kill bacteria in vitro.

Project: T-cells and LCP-based GAS vaccines
A project is available to investigate cellular immune responses induced following immunisation of mice with LCP-based vaccines. The methods used will involve the isolation of T-cells from spleen and lymph nodes, measurement of proliferation to immunogens, measurement of cytotoxic potential to target cells, FACS staining for the determination of CD4 and CD8 T-cell populations and markers of T-cell activation, and the assessment of cytokine production.

Lipid-core peptide vaccine delivery as a platform technology
These projects will investigate the potential of lipid-core peptide vaccine delivery to protect against infection with 1) Helicobacter pylori, a bacterial agent which causes gastric ulcer and gastric adenocarcinoma; and 2) Papillomavirus infection, which causes cervical cancer. In addition, the improvement of peptide vaccine efficacy by combined targeting and signaling, will be investigated. Studies will use mouse animal models. In preliminary experiments, we have shown that an LCP formulation containing a protective CTL epitope from human papillomavirus induced anti-tumour immunity and protection from tumour development. This has the potential as an immunotherapeutic approach against HPV-associated cervical cancer. Further studies will also investigate the inclusion of receptor ligands into vaccine formulations to target antigen uptake by dendritic cells as well as investigating the mechanisms of vaccine-induced immunity.

Project: Investigation of mannosylated LCP-based vaccines as potential immunotherapeutic anti-cancer vaccines.
Cervical cancer represents the second most common cancer worldwide, with 500, 000 new cases diagnosed each year, resulting in 270, 000 deaths. Cervical cancer has been identified as near 100% attributable to human papillomavirus (HPV) infection of the cervix, with HPV types 16 and 18 responsible for approximately 50 and 20% of cancers, respectively. The ability to create prophylactic vaccines targeting these strains would therefore offer the capacity to prevent up to 70% of cervical cancers. A large proportion of the global population, however, is already infected, and many women will continue to become infected with cervical cancer-associated HPV strains until global vaccine coverage is achieved. The development of therapeutic vaccines, capable of eliminating HPV infected cells and clearing established HPV-associated tumours, would therefore be beneficial. Together, the application of prophylactic and therapeutic HPV vaccines offers the best approach to achieve HPV eradication.

Data from my lab using a HPV tumour mouse model have recently reported that experimental mannosylated HPV vaccines synthesised using the LCP system, can prevent the development of tumours (J Med Chem in press). I plan to extend these studies using a therapeutic tumour mouse model to investigate the ability of our mannosylated LCP-HPV vaccines to induce immune responses capable of eradicating established HPV-16 associated tumours.

Project: Comparison of Virus-Like Particle (VLP) vs LCP vaccine delivery approach to prevent Helicobacter pylori infection in a mouse model.
We have explored the potential for dual vaccination against Hepatitis B virus and H. pylori using a recombinant VLP. We inserted overlapping sequences from the carboxy terminus of the H. pylori katA gene into the hydrophilic 'a' determinant region of the small envelope protein, HBsAg-S, to create a vector with a surface orientation of the inserted peptide sequence. HBsAg-S molecules self polymerise to form VLPs that are immunogenic at the B and T cell level. VLPs containing KatA epitopes were produced and were able to induce KatA specific antibodies in vaccinated mice. Recombinant VLPs expressing KatA epitopes were tested in a mouse challenge model, of which three constructs induced a significant reduction in H. pylori bacterial load, as demonstrated by culture and histological examination of the gastric mucosa.

We have described a novel delivery system, which is also the first report of recombinant VLPs stimulating protective immune responses to bacterial peptides (manuscript in preparation). We are currently performing immunogenicity and protection studies in mice involving the LCP system for intranasal delivery of the KatA epitopes.

Project: Investigation of multiple Toll-like receptor agonists and targeting moieties to enhance performance and improve the immunological potency and protective efficacy of peptide-based vaccines.
It is widely believed that new approaches are required for the development of effective vaccines against infectious diseases such as tuberculosis, malaria and AIDS, and malignancies, and that these will need to induce potent, long-lasting antibody and T-cell responses. Targeting to professional antigen-presenting cells, primarily dendritic cells, to induce optimal cellular and humoral immune responses following vaccination, is also a strategy being used to enhance vaccine efficacy. It is becoming increasing clear that to elicit sustained immunity, targeted vaccines are likely to be most efficacious when combined with adjuvants that elicit activation signals.

We plan to carry out a systematic comparison of various vaccine constructs in three established mouse models (bacterial, viral and cancer) to validate our approach and determine the optimal requirements for each vaccine's efficacy.

Back to Top

Mosquito Control Laboratory
Dr Peter Ryan
07-3362 0351
Email Peter.Ryan@qimr.edu.au
[ P]

Mosquito Control

PhD student top up Scholarships and APA Top Up Scholarships available for 2008

The School of Integrative Biology, The University of Queensland
Laboratories of Professor Scott O'Neill and Dr Elizabeth McGraw
The Queensland Institute of Medical Research

Dr Peter Ryan and Prof Brian Kay, Mosquito Control Laboratory and the Australian Centre for International and Tropical Health and Nutrition The UQ/QIMR team is internationally recognised for its contribution to the fields of Wolbachia endosymbionts and host interaction, medical entomology including biological control of medically important vectors, and translation of research into practical public health interventions. Based on this track record, we have been funded by the NHMRC to develop new methodologies for the management of emerging vector-borne disease threats in Australia.

The project involves the infection of mosquito vectors with an endosymbiotic bacterium, Wolbachia pipientis, that is capable of reducing insect lifespan. Characterisation of the Wolbachia life-shortening affects in a range of globally important mosquito vectors (Aedes, Culex spp) and the affect of this life-shortening on arbovirus (dengue, Chikungunya, Ross River, and Barmah Forest viruses) transmission efficiency will be determined.

We will also extend our current transcription profiling methods and develop new proteomic based methods for determining insect age, and undertake field assessments of vector population age structure to determine pathogen transmission risk and the applicability of Wolbachia and other novel control strategies.

Projects may include artificial transinfection of mosquito species, study of Wolbachia induced pathogenesis, an examination of mosquito life history traits, characterisation of the human host seeking and biting behaviour of infected mosquitoes, arbovirus vector-competence assessments, laboratory and field based assessments of insect age grading and vector population age structure.
We are seeking students with experience in any of the following fields; molecular biology, evolutionary biology, genetics, entomology, microbiology, and behaviour.

The School of Integrative Biology (SIB) is a vibrant unit with a history of and an ongoing commitment to research excellence and postgraduate mentoring. Examples of SIB support for postgraduates include travel grants, writing workshops, media training, social events with visiting speakers, postgraduate retreat weekends, etc.

The School has strong links with QIMR, the largest medical research institute in the southern hemisphere, which currently has 110 doctoral students covering the breath of clinical and public health translational research. Brisbane offers a beautiful climate and outdoor lifestyle, city nightlife, affordable housing and ease of commute to and from the University of Queensland and QIMR.

Back to Top

Population Studies and Human Genetics Division

Cancer & Population Studies Group
Prof Adèle Green
Dr Rachael Neale
Phone: 3845-3598
Email: Rachel.Naeale@qimr.edu.au

Mutation analysis of high-risk cancer predisposition genes in endometrial cancer

The Queensland Pancreatic Cancer Study (QPCS) was launched in June 2007 with the main aim being to understand the genetic and environmental risk factors of pancreatic cancer.

There is scope for a suitably qualified student to develop a quality of life study nested within this existing pancreatic cancer study. The purpose of the program of research would be to explore the quality of life issues and supportive care needs of patients with this cancer, as well as the correlates of these outcomes.

The project would be suited to a skilled and motivated individual with qualifications in psychology, public health, behavioural or social science. You will need to have a sound understanding of research methods and statistics and be eligible to apply for an external research scholarship.

Back to Top

Cancer & Population Studies Group
Prof Adèle Green
Dr Penny Webb
Dr David Whiteman
Phone: 3845-3598; 3362 0279
Email: Penny.Webb@qimr.edu.au Email: David.Whiteman@qimr.edu.au

Predisposition to Endometrial; Ovarian and Oesophageal cancer

Epidemiology of endometrial cancer

(PhD or Research Masters) - contact Penny Webb

Endometrial cancer (cancer of the uterus or womb) is the 6th most common cancer in Australian women. More than 1450 women were diagnosed with endometrial cancer in 2001 and the numbers are increasing each year. There are two main types of endometrial cancer: "type I" cancers are related to oestrogen and most often occur in women who are overweight; "type 2" cancers are much less common but have a poor prognosis and little is known about what causes them.

We are conducting a national population-based case-control-family study called the Australian National Endometrial Cancer Study (ANECS). This will eventually include more than 1200 women with endometrial cancer and a similar number of women without cancer.

The aims of this project are to investigate risk factors for the two different types of endometrial cancer with a particular emphasis on identifying potential strategies for prevention.
Some experience in statistics and data analysis is essential and a background in epidemiology and/or an interest in cancer are highly desirable.

Pathways to diagnosis of ovarian / oesophageal cancer

(PhD or Research Masters) - contact Penny Webb or David Whiteman

Ovarian cancer is the 7th most common cancer in Australian women and more than 1200 women were diagnosed with ovarian cancer in 2001. Most ovarian cancers have already spread beyond the ovaries at the time of diagnosis and so the prognosis is very poor - about 45% of women are still alive after 5 years. Ovarian cancer is hard to diagnose because the symptoms are often very non-specific and women may see several different doctors in different specialties over a period of several months or years before their cancer is diagnosed.

About 1100 men and women are diagnosed with cancer of the oesophagus every year and these numbers are increasing, particularly in men. This cancer has a very poor prognosis with few patients surviving more than 1 year after their diagnosis. Very little is known about the diagnosis and management of patients with oesophageal cancer in Australia.

The aim of this project(s) is to describe the pathway to diagnosis of

1. women with ovarian cancer and/or
2. men and women with oesophageal cancer in Australia
to identify opportunities to improve diagnosis and thereby potentially improve outcomes for patients diagnosed with these diseases.

The projects will use data already collected from two national studies of ovarian and oesophageal cancer including more than 1500 women with ovarian cancer and 1100 men and women with oesophageal cancer. Some experience in statistics and data analysis is essential and a background in epidemiology and/or an interest in cancer are highly desirable.

Patterns of care for oesophageal cancer

(PhD or Research Masters) - contact David Whiteman

About 1100 Australians are diagnosed with cancer of the oesophagus every year and these numbers are increasing, particularly in men. This cancer has a very poor prognosis with few patients surviving more than 1 year after their diagnosis. Very little is known about the management of patients with oesophageal cancer in Australia.

The aim of this project is to describe the patterns of care for people with oesophageal cancer in Australia. The project will use data already collected from a national clinical follow-up study of oesophageal cancer including more than 1100 men and women with oesophageal cancer. Some experience in statistics and data analysis is essential and a background in epidemiology and/or an interest in cancer are highly desirable.

Back to Top

Molecular Cancer Epidemiology Laboratory
Dr Amanda Spurdle
07-3362 0371
Email Amanda.Spurdle@qimr.edu.au
[ H, P]

Functional Analysis of BRCA1/2 Sequence Variants of Unclassified Clinical Significance

Mutations in the BRCA1 and BRCA2 genes are thought to be responsible for about 40% of breast cancers in multiple-case families. Routine diagnostic BRCA1 and BRCA2 gene screening of individuals from high-risk families identifies numerous nucleotide s equence changes. Rare nucleotide changes predicted to cause missense substitutions are difficult to classify with respect to their clinical significance and are termed unclassified variants (UVs). Some variants may be classified as high-risk using multifactorial likelihood analysis, which estimates odds of causality using data on co-occurrence of the UV with pathogenic mutations in the same gene, co-segregation of the UV with affected status, amino acid conservation and physicochemical properties, and tumour features.

However a large proportion of UVs remained unclassified, and in addition we have evidence to suggest that some variants which are classified as having little clinical significance may nevertheless have partially compromised function.

Project Aims:
This project would aim to use a battery of established functional assays (some domain-specific) to provide proof of compromised function for variants classified as high risk using multifactorial modelling, and to assess the possibility of partially compromised function (level of function, number of assays compromised) associated with variants considered to be of little clinical significance.

In addition, the project plan is to develop generic assays of BRCA1 and BRCA2 function to assess risk of variants irrespective of their location within the protein, to further improve the assessment of clinical significance of UVs, namely assays for epithelial cell transformation - reflecting overall tumour suppressor activity of BRCA1 or BRCA2.

Outcome:
Functional analysis of specific UVs will provide evidence regarding their pathogenicity. Development of generic assays will allow for comparison of functional relevance of variants in domains across the gene.

Intended Supervisors: Amanda B Spurdle (QIMR), Melissa A Brown (UQ).

Characterization of Genetic Defects in Population-based Endometrial Cancer Patients and Their Cancer-affected Relatives

Background:
Endometrial cancer is the most common invasive gynaecological cancer in Australia.
Family history of endometrial cancer among first-degree relatives is associated with up to 3-fold increased risk of endometrial cancer. Such familial cases are thought to be largely due to mutations in the mismatch repair (MMR) genes MSH2, MLH1, MSH6 or PMS2, causing Lynch Syndrome. PTEN genes may contribute to familial endometrial cancer as part of Cowden syndrome.

The breast-ovarian cancer genes BRCA1 and BRCA2 may also predispose to endometrial cancer. We are currently conducting the Australian National Endometrial Cancer Study (ANECS), a specific aim of which is to assess risk of endometrial cancer in women according to history of cancer in extended family members, including 2nd and 3rd degree relatives.

Preliminary review of ANECS data suggests that ~40% of endometrial cases present with a family history suggestive of an underlying genetic defect: 34% of cases report features characteristic of high-risk gene defect (diagnosis <50y, prior cancers, or =2 affected relatives), overlapping with 26% of cases with history suggestive of specific high-risk gene mutations. Indeed, IHC pre-screening results suggest that MMR gene defects may be 3X more common than reported before. Importantly, endometrial cancer cases likely to carry MMR gene mutations report family history profiles that do NOT fit classical criteria for Lynch syndrome families, and 64% of these are unlikely to have been prioritized for MMR gene mutation testing in clinics.

These results highlight the importance of population-based studies in assessing penetrance and cancer phenotype associated with mutations.

Project Aims (a subset of these will form part of the intended PhD):

1. To clarify the family cancer history profile associated with high-risk gene mutation status by mutation screening of known endometrial cancer genes in endometrial probands and their cancer-affected relatives
2. To assess the role of other high-risk cancer genes, particularly "breast-cancer genes" BRCA1 and BRCA2 as candidate causative factors in endometrial cancer probands reporting a family history of endometrial and other cancers
3. To identify tumour features associated with mutation status of high-risk endometrial cancer genes to prioritize mutation screening of cases with little or no family history, using pathology review and assessment of candidate immunohistochemical and somatic genetic tumour markers

Outcome:
Results will inform definitions of familial cancer syndromes from an endometrial cancer perspective. It will thereby improve genetic counselling for endometrial cancer patients and their families. It will also have a more general impact on the g enetic counselling of other cancer patients and their families, since endometrial cancer is a feature of several multi-cancer syndromes.

Intended Supervisors: Amanda B Spurdle (QIMR), Joanne Young (QIMR).

Back to Top

Epigenetics Laboratory
Dr Emma Whitelaw
07-3845 3600
Email Emma.Whitelaw@qimr.edu.au
[H,P]

Epigenetics

We are a molecular genetics lab, interested in mammalian genes where expression is regulated by epigenetic modification. Epigenetic modifications are established in early development and are associated with cell committment during differentiation. Once established these marks are relatively permanent.

Our ENU mutagenesis screen, the first of its kind in the world, has been very fruitful so far, revealing new aspects of the biology of development - (Blewiitt et al (2005) PNAS 102:7629-34 and Chong et al (2007) Nature Genetics, 39:614-22.

We are now about to initiate a major expansion of this screen and it is likely that new members of the laboratory will become involved in some way in this study.

To determine the molecular mechanisms involved in establishing epigenetic states in mammals we have used random mutagenesis in mice to find novel modifiers of epigenetic gene regulation. Mutant mouse lines will be phenotyped by breeding experiments and molecular techniques, eg Northern blots and bisulphite sequencing. Mapping by PCR-based amplification of microsatellite markers will be used to link the mutation to a small chromosome interval, and ultimately gene sequencing will be performed to identify the underlying point mutation.

We are also keen to study the nature of epigenetic differences between monozygotic (genetically identical twins). We believe that these changes could explain the phenotypic differences seen within twin pairs. We are currently establishing genome wide approaches to this problem. These studies will not involve mouse work and may suit some students more than others.

Back to Top

Familial Cancer Laboratory
Dr Joanne Young
07-3362 0490
Email Joanne.Young@qimr.edu.au
[H,P]

Familial Cancer

A Novel Genetic Predisposition to Colorectal Cancer

Approximately 15% of colorectal cancer has a strong familial component. Of this, about one-third has been accounted for by well-characterised syndromes. This leaves a significant proportion in which the gene remains to be identified.

Our group has recently described a novel syndrome of familial colorectal cancer associated with the serrated neoplasia pathway, which demonstrates autosomal dominant inheritance, atypical serrated polyps, BRAF mutations and aberrant methylation of gene promoters. We have given this condition the working title of Serrated Pathway Syndrome.
A related condition, hyperplastic polyposis (HPS) occurs in a recessive pattern of inheritance.

Aim: To determine the underlying genetic cause of SPS and HPS, and to identify genetic and environmental modifiers of phenotype

Research Plan Includes:

• Family-based and population-based approaches including traditional linkage analysis, family segregation analysis, genome-wide sssociation studies, genomic analysis and DNA sequencing
• Tumour characterisation including Immunohistochemistry, methylation and mutation profiling, histology review
• Studies of smoking and polymorphism prevalence in mutation carriers

References:

1. Young, J and Jass JR (2006) The Case for a Genetic Predisposition to Serrated Neoplasia in the Colorectum: Hypothesis and Review of the Literature Cancer Epi Biomarkers Prev 15, 1778-1784.
2. Daniel J. Weisenberger, et al (2006) A Distinct CpG Island Methylator Phenotype in Human Colorectal Cancer Is Tightly Associated with BRAF Mutation and Underlies Sporadic Mismatch Repair Deficiency. Nature Genetics 38, 787-93
3. Parham Minoo, et al (2006) Extensive DNA methylation in normal colorectal mucosa in hyperplastic polyposis. Gut 55, 1467-74
4. Joanne Young, et al (2005). Evidence for BRAF mutation and variable levels of microsatellite instability in a syndrome of familial colorectal cancer. Clin Gastro Hepatol 3, 254-63

Back to Top

Immunology Division

Clinical Immunohaematology Laboratory
Dr Maher Gandhi
07-3845 3792
Email Maher.Gandhi@qimr.edu.au
[H]

Clinical Immunohaematology

Epstein-Barr virus (EBV) is a ubiquitous herpesvirus that has infected more than 90% of us. It can cause glandular fever (or kissing disease). EBV is implicated in the aetiology of a range of disorders including a variety of different malignancies.
These include lymphomas (cancers of the glandular system), examples of which include some cases of Hodgkin's Lymphoma, Burkitts Lymphoma, and Post-transplantation Lymphoproliferative Disorder.

In Australia, it is estimated that EBV is implicated in 150 cases of lymphoma per year. This number is far higher in developing countries. At present, there is no anti-viral treatment or vaccine against EBV. It is known that restoration of EBV-specific immunity can in some cases induce tumour regression. There is therefore a high priority to develop novel immunotherapies for EBV treatment.

The Clinical Immunohaematology laboratory has a broad interest in the immunobiology of the virus, with particular reference to immunotherapeutic strategies for EBV-positive lymphomas.

A variety of projects provide excellent opportunities for the involvement of Honours and PhD students.

These include:

1. Viral and immune biomarkers
2. Immuno-evasion strategies
3. Viral microRNA expression
4. Optimization of cellular immunotherapies

These projects are supported by a variety of different experimental approaches involving flow cytometry, immunohistochemistry, assays of immune effector function, real-time PCR, and genetic polymorphism analysis. Students in our laboratory would become familiar with all of these techniques. There will also be opportunities for successful Honours students to enrol for PhD studies and continue work in the laboratory.

Back to Top

How to apply: Contact the Laboratory Head related to the project area of interest (see above) in the first instance.

Application details here.