Student Projects 2004

Infectious Diseases & Immunology Division

• Immunity and Infection in Malaria
  
• Clinical Tropical Medicine
  
• Novel vaccine design and delivery approaches
• Bone Marrow Transplantation
• Towards the development of a GAS vaccine
• Schistosomiasis in China
• Mosquito-borne Arboviruses and their Control

Cancer & Cell Biology Division

• Cancer Immunotherapy
• Membrane Trafficking
• Identification of genes that cause breast and ovarian cancer
• The use of functional complementation to isolate tumour suppressor genes
• Eph genes in development and cancer
• Signal transduction pathways and DNA damage
• Breast cancer predisposition and BRCA1
• Merkel cell carcinoma
• Colorectal Cancer

Population Studies & Human Genetics Division

• Melanoma genomics
• Genetic Epidemiology and Gene Mapping
• Cancer Epidemiology and Population Studies
• Hepatic Fibrosis and Cirrhosis in adult and paediatric liver disease
• Molecular Basis of Intestinal Nutrient Transport

How to apply: Contact the Laboratory Head related to the project area of interest (see below).

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Application details here

Legend:
P = PhD, MPhil project(s)
H = Honours project(s)
TU = Lab Top-up project(s)
SV = Summer Vacation project(s)

Infectious Diseases & Immunology Division

Immunology and Infection in Malaria

Contact: Dr Christian Engwerda - tel 07-3362 0428, fax 07-3362 0104; e-mail chrisE@qimr.edu.au
Immunology and Infection Laboratory [P, H,  TU, SV]

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 contributes 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, but allow immunological memory responses to develop and protect against future infections.
We now 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 tissue. 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 be exposed to all of these techniques.

Project 1. Defining the role of chemokines in parasitic infections.
CXCR3 is a receptor for CXCL9 (MIG), CXCL10 ( IP-10) and CXCL11 (I-TAC), chemokines known to attract leukocytes to sites of infection and inflammation. In order to define the role of these molecules in infectious diseases such as CM and VL, we need to be able to effectively block their activity. One way to achieve this is by generating a soluble CXCR3 molecule using molecular and cell biology techniques established in our laboratory. Once this reagent has been produced, the role of CXCL9, 10 and 11 in CM and VL will be investigated using both live infection models and in vitro cell migration assays. This work will be the first step in identifying the chemokines that recruit leukocytes to infected tissue. If these chemokines are found to recruit lymphocytes that mediate tissue pathology, we can begin to devise strategies to prevent this recruitment with the aim of reducing inflammatory responses without hindering the control of infection. Techniques used in this project will include molecular biology, cell biology, microscopy, immunohistochemistry and whole-tissue imaging.

Project 2. The generation of parasite-specific T cell hybridomas. In order to study immune responses at the single cell level in situ, we require appropriate research tools. One such tool is a parasite-specific T cell receptor (TCR) transgenic T cell. Therefore, mice will be immunised with a defined Plasmodium antigen to generate antigen-specific T cells. These cells will then be isolated and re-stimulated in vitro, prior to being fused to a T cell thymoma to produce a Plasmodium-specific T cell hybridoma. The Plasmodium-specific T cell hybridomas will then be used to study interaction between antigen presenting cells (APC) and T cells in vitro. The TCR from T cell hybridomas will also be amplified and sequenced, before being cloned into an appropriate plasmid vector for the generation of a Plasmodium-specific TCR transgenic mouse. This work will define the initial interaction between T cells and APC bearing parasitic antigens. In addition, it will contribute to the construction of a TCR transgenic mouse which will help define how pathogenic and protective T cell responses are generated during malaria infection.
The techniques used in this project will include molecular biology, cell biology, fluorescent activated cell sorting (FACS) and bioassays for the measurement of T cell activity.

Project 3. Characterising liver granulomas produced during visceral leishmanisis.
Kupffer cells (KC) are resident macrophages in the liver and an initial site of Leishmania donovani infection. Shortly after infection, KC produce chemokines that attract other leukocytes to form a granuloma. The granuloma is an essential structure for the control of VL in the liver, yet we know little about its composition or the molecules generated within it that contribute to the killing of parasites in KC. Therefore, we will isolate hepatic granulomas at various stages of L. donovani infection from tissue sections using laser micro-dissection. The isolated tissue will then be analysed for cytokine and chemokine mRNA levels using real-time RT-PCR. In addition, isolated mRNA will be analysed using a microarray to try and identify molecules that are up-regulated within the granuloma at various stages of disease. It is anticipated that this work will identify important molecules involved in recruiting leukocytes to the site of infection and for controlling parasite growth within the KC. This will form the basis to develop rational strategies for vaccine and therapeutic design.
The techniques used in this project will include immunohistochemistry, laser micro-dissection, molecular biology, micro-array analysis and cell culture techniques.

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Clinical Tropical Medicine

Contact: Dr James McCarthy - tel 07-3845 3796; fax: 07-33620104 ; e-mail jamesM@qimr.edu.au
Clinical Tropical Medicine Laboratory [P, H,  TU, SV]

The focus of this laboratory is defining the mechanism of drug resistance in a range of parasites (including scabies, hookworm and Strongyloides), and applying this information to develop tests to diagnose resistance.

Scabies project
Scabies is a disease of the skin caused by the 'itch mite', Sarcoptes scabiei. It is a disease that is endemic in northern Australian Aboriginal populations but is also of worldwide importance. The morbidity caused by this ectoparasite is significantly underappreciated. The most severe form of disease, crusted scabies (hyperinfestation) carries a high mortality rate (up to 50%), and such patients are core reservoirs of the parasite. To date however, little attention has been paid to the issue of drug resistance.
In order to detect and control the development and spread of resistance to acaricides there is a critical need to define the mechanisms of resistance in the scabies mite. This will enable the development of sensitive detection and monitoring methods.

Project aim
The aim of this project is to define the mechanisms of drug resistance in S. scabiei. This will enable the development of molecular diagnostic techniques to detect drug resistance

Outcomes and Significance
The tools developed in this project will enable the assessment of drug treatment failures, and assist in the development of more sensitive methods for monitoring resistance in the community, including the potential for reversing it.
Molecular diagnosis of 'resistant variants' as part of parasite surveillance will enable new drug resistant genetic variants to be rapidly detected, enabling the early implementation of strategies for management of resistance.

Nematode Project
Molecular studies of benzimidazole-resistant veterinary parasitic nematodes have demonstrated that drug resistance is due to specific mutations in the gene encoding the parasite tubulin protein. These findings have enabled the development of PCR-based methods to determine drug resistance.
Such assays offer the potential to bypass both clinical and ex vivo culture methods for detection of drug resistance. We have cloned and sequenced the Ancylostoma duodenale, and Strongyloides stercoralis-tubulin genes, and have proceeded to develop a PCR assay to genotype the hookworm parasite.

Project aim
To define changes in the polymorphism of the tubulin gene of intestinal nematode parasites from human populations with exposure to benzimidazole drugs, and to correlate these molecular changes with the data from the clinical and ex vivo experiments.

Experimental Design and Methods
Using methods established in our laboratory, single hookworm larvae will be isolated by laser capture microdissection from field isolates already collected, and the tubulin gene PCR amplified and subject to direct DNA sequence analysis. Genotyping of representative isolates from parasite-positive subjects,will determine if drug resistance is conferred by the same amino acid change as that seen in veterinary parasites.

Outcomes and Significance
The further development of a the molecular technique for genotyping parasites to detect drug resistance will be of major use in the World Health Organization-sponsored program to control the morbidity due to human nematode infections throughout the world.

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Infectious diseases: Novel vaccine design and delivery approaches

Contact: Dr Colleen Olive - tel 07- 3362 0431, fax 07-3362 0103; e-mail: colleenO@qimr.edu.au
Molecular Immunology Laboratory [P,  H]

Synthetic peptide-based vaccines are currently being investigated as alternatives to conventional vaccine approaches for the prevention of infectious diseases. These vaccines utilise novel lipid technologies and their delivery via the mucosal route is being explored.

Our research is focused on vaccine development against the bacterial pathogens, group A streptococcus (GAS) and helicobacter pylori. Specifically, the research projects available will involve the use of animal disease models with which to determine the immunological responses to various vaccine candidates, as well as their protective potential. Various immunological techniques will be used including ELISA, cell culture, T-cell proliferation assays and analysis of cytokine gene expression.

Bone Marrow Transplantation

Contact: Dr Geoff Hill - tel 07-3845 3763; e-mail geoffH@qimr.edu.au or
Dr Kelli MacDonald -tel 07-3362 0404; e-mail kelliM@qimr.edu.au
Bone Marrow Transplantation Laboratory  [P, H]

Bone Marrow Transplantation remains the procedure of choice for the cure of a number of haematologic malignancies (e.g. leukemia and lymphoma). The procedure results in cure rates up to 75% but is limited by its serious complications, particularly graft-versus-host disease (GVHD).
This is the process whereby the newly transplanted immune system recognises the transplant recipient as "foreign" and mounts a rejection response. Recently the use of cytokines has allowed the transplantation of blood stem cells (referred to as stem cell transplantation-SCT) that has replaced BMT in clinical practise. Our laboratory has been at the forefront of understanding how these cytokines effect GVHD.

We aim to improve transplant outcome by utilising preclinical transplant models where immunological mechanisms of transplant rejection can be dissected so that rational therapeutic strategies can be developed and trialed in clinical practise. We have a number of projects suitable for honours and PhD students.

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Development of a group A streptococcal (GAS) vaccine

Contact: Dr Kadaba Sriprakash - tel 07-3362 0407;email sriS@qimr.edu.au or
Dr David McMillan - tel 07-3362 0431;e-mail davidM@qimr.edu.au
Bacterial Pathogenesis Laboratory  [P, H,  SV]

Molecular and functional analysis of the PrtFII gene Contact: Dr Jason McArthur - tel 07-3362 0431; e-mail jasonM@qimr.edu.au

PrtFII is another extracellular GAS protein with fibronectin binding activity. It is unknown at present if PrtFII is also involved in the internalisation of GAS. A project exists investigating the contribution of PrtFII to the internalisation of GAS by eukaryotic cells. This project will assess whether the different sections of the PrtFII protein can assist prtFII-negative GAS strains to invade eukaryotic cells. This project will involve expression and purification of PrtFII, cell culture and eukaryotic attachment and invasion assays.

Understanding the immunopathogenesis of post-streptococcal acute glomerulonephritis Contact: Dr David McMillan - tel 07-3362 0431; e-mail davidM@qimr.edu.au

The pathogenesis of PSAGN is unknown although strong evidence indicates an immune complex-mediated basis, with the involvement of one or more secreted GAS proteins which deposit in affected glomeruli. The proteins associated with PSAGN are not clear but may involve SIC, a highly polymorphic secretory protein and an inhibitor of complement function, in the pathogenesis of this disease. Our research involves investigating the contribution of SIC and SIC antibodies to PSAGN pathology utilising an animal model, and investigating the interaction of SIC with components of the host immune system. The research will further our understanding of this complex disease.

Construction of a new vectors for integration into the streptococcal chromosome Contact: Dr David McMillan - tel 07-3362 0431; e-mail davidM@qimr.edu.au

We are constructing novel vectors to facilitate the better understanding of the function and regulation of specific GAS genes. These vectors are based on novel integration shuttle vectors designed by Tao et al (Gene 120:105-110). These vectors are able to replicate in E. coli but not in streptococcal species as they lack a streptococcal origin of replication. This project involves cloning a new segment of DNA, encompassing streptococcal ribosomal RNA, a multiple cloning site and an selectable marker into these vectors. Once constructed, streptococcal or other genes will be cloned into the multiple cloning site, and the vectors introduced into the GAS chromosome. As proof of principle the Green Fluorescent Protein gene will be cloned into the multiple cloning site and expression tested after transformation into GAS.

Evaluation of novel GAS vaccine candidates Contact: Dr David McMillan - tel 07-3362 0431; e-mail davidM@qimr.edu.au

The complete genome of four GAS isolates are now available. We have searched these genomes for novel vaccine candidates. We have hypothesised that these candidates should be i) surface exposed, ii) conserved across GAS strains iii) immunogenic and iv) not contain immunogenic epitopes that may invoke cross reactive antibodies. We have identified a number of these proteins and have identified peptides from the amino terminus that may be exposed to the host immune system. These peptides are currently being tested for their vaccine potential. Experiments will include a) the immunisation of mice with peptide-carrier constructs, b) the measurement of antibody response via ELISA, c) opsonisation assays d) effectiveness of anti-peptide antibodies to protect against GAS challenge e) PCR and western analysis of the distribution of the antigens across multiple GAS isolates. As an extension of this project, we will also look at the vaccine potential of whole recombinant proteins.

Regulation of the expression of GAS virulence factors Contact: Dr David McMillan - tel 07-3362 0431; e-mail davidM@qimr.edu.au

The first point of contact between GAS and the human host is the respiratory tract or skin surface. Recent work by Fischetti et al., has shown that in the presence of pharangyeal cells, SpeC expression is upregulated. In addition, other streptococcal proteins are released during coculture with pharangyeal cells. Our lab works on a number of GAS virulence determinants which aid in colonisation or a associated with disease and protection from host immune responses. We now wish to examine the expression of these molecules in the presence of a respiratory cell line and a skin cell lines. After exposure to these cell lines, changes in the expression profile of virulance determinants will be examined by Western blot and RT-PCR.

Contribution of selected surface proteins to the pathogenicity Group A streptococci Contact: Dr David McMillan - tel 07-3362 0431; e-mail davidM@qimr.edu.au

GAS express a number of putative virulence factors on their which may contribute to the pathogenicity of this organism. Three of these proteins, MtSA, GRAB and superoxide dismutase (SOD) are under investigation as potential vaccine candidates. To complement this research, we will construct GAS strains in which the expression of each of these genes has been eliminated. Once constructed, each mutant will be characterised with respect to a) growth characteristics, b) ability to attach and invade eukaryotic cell lines and c) ability to infect and maintain infection in a mouse model. Experiments will include a) PCR and cloning, b) transformation of group A streptococci, c) growth analysis in a variety of media d) tissue culture and eukaryotic cell attachment experiments and d) animal infection studies.

Identification of group A streptococcal surface proteins Contact: Dr David McMillan - tel 07-3362 0431; e-mail davidM@qimr.edu.au

The identification of GAS surface proteins is important in the understanding how GAS interacts with the host and in the development of new vaccine strategies. Many of these proteins contain a cell wall anchor motif and signal peptide. Other proteins (e.g. superoxide dismutase) do not contain these motifs, yet are expressed of the GAS surface. Using an alkaline phosphatase (AP) gene fusion reporter system, we will identify GAS surface proteins. A DNA library containing GAS chromosomal DNA cloned into the reporter plasmid pAN200 will be constructed. The library will then be screened for clones that express AP. The system has been designed such that AP activity occurs maximally when the fusion protein is secreted or present on the surface of the bacteria. Positive clones will be sequenced and putative secreted proteins identified.

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Human Susceptibility and Immuno-genetic Factors Associated with Oriental Schistosomiasis in China

Contact: Prof. Don McManus - tel 07-3362 0401; fax: 07-3362 0104; email: donM@qimr.edu.au
Molecular Parasitology Laboratory
[P,  H, TU,  SV]

Schistosomiasis is characterized by low mortality and long-term chronicity which creates an economic burden surpassing that of most other parasitic diseases. Immunoepidemiological data collected over the past 20 years provide good evidence that human acquired immunity has been demonstrated for S. mansoni, S. haematobium and, more recently, S. japonicum infections. An understanding of host immune responses and genetic factors is critical in the development of strategies for the control of both infection and pathology. Resistance to re-infection may depend on the balance between two antagonistic effects, protective IgE and immunity-blocking IgG4.

The influence of genetic factors has been investigated and there is convincing evidence for single co-dominant gene controlling susceptibility or resistance in S. mansoni. However, many gaps remain in our understanding of the relationships linking infection, morbidity, immunity and genetic factors in Asian schistosomiasis. Thus, the result from this project will fill the void of our knowledge (cytokine and genetic factors) in S. japonicum.

This study will be carried out on an island in the Dongting Lake region of China. Kinship and familial study design will be adopted into the study. A total of 250 families (about 1000 individuals) will be selected for participating in this study. During the first 2 years of this project, extensive field study will be undertaken to verify their exposure, classify putative infection status and identify residents potentially susceptible or resistant to re-infection and disease development, as a prelude to further immunogenetic studies.

The methods that have previously been field tested will include a questionnaire (basic history and current information for each individuals), actual exposure measurements, infection intensity (multiple stool examinations) and disease (detection of ultrasound and fibrosis markers) classification. Immunological correlates (antibody isotypes and cytokines) will be determined. Familial aggregation of infection and liver fibrosis related phenotypes, which can result from genetic relationships, shared environment, and cultural habits, will be discriminated by using segregation analysis. Genetic markers to be tested in this project will focus on two genomic regions (5q31-33, 6q22-q23) Linkage analysis will be used to test whether, in families, the phenotype locus is transmitted with genetic markers of known chromosomal location.

All field costs for the project will be provided by a Wellcome Trust Grant recently awarded to Professor McManus. The project will involve field work in China and laboratory studies in Brisbane (immunology) and France (genetic analysis).

Mosquito-Borne Arboviruses and their Control

Contact: Dr Peter Ryan - tel 07-3362 0351, fax 07-3362 0104; e-mail: peterR@qimr.edu.au; or
Professor Brian Kay - tel 07-3362 0351; e-mail brianK@qimr.edu.au
Mosquito Control Laboratory
[P, H,  TU]

We work with dengue(in Australia and overseas). Ross River and Barmah Forest viruses, their mosquito vectors, ecology/epidemiology and develop surveillance and control strategies. We are interested in bright graduates from a variety of backgrounds (eg entomology, virology, epidemiology, social sciences) to help solve some of these problems.
Projects will be tailored to your interests and are suitable for honours, Masters or PhD. If you bring a scholarship with you we pay a top-up.

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Cancer & Cell Biology Division

Cancer Immunotherapy

Contact: Dr Chris Schmidt - (07) 3362 0313 or at chrisS@qimr.edu.au
Cancer Immunotherapy Laboratory   
[P, H,  TU, SV]

The Cancer Immunotherapy Laboratory at QIMR studies the relationship between the clinical and immunological effects of dendritic cell-based therapies for solid malignancies such as melanoma and prostate cancer.
Our partners in the clinical trials are the Mater, Princess Alexandra, and Royal Brisbane Hospitals. Our particular goals are to
• improve the design of these therapies,
• monitor patients' overall and tumour-specific immune reactivity,
• examine tumour cell characteristics related to patient outcome, and
• improve methods of monitoring the tumour burden.
We are also researching gene-modified "off-the-shelf" therapeutics for cancer. Opportunities exist for suitably qualified students to conduct their Honours and PhD research in our laboratory, focussing on these areas.

Membrane Trafficking

Contact: Dr Nathan Subramaniam - tel 07-3362 0179, fax 07-3362 0191; e-mail nathanS@qimr.edu.au
Membrane Transport Laboratory
[P, H,  TU, SV]

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.
In particular, the Membrane Transport Laboratory is studying two of the most common human genetic disorders of impaired ion homeostasis, haemochromatosis and cystic fibrosis, through the molecular, cellular and functional analysis of the proteins found to be mutated in these diseases.


Projects in the laboratory fall under two general headings:

• Defining the role of the proteins implicated in iron homeostasis. Using a variety of tools we are studying the synthesis, assembly, trafficking and regulation of three proteins, HFE, transferrin receptor 2 and ferroportin 1, found to be mutated in various types of hereditary haemochromatosis.
• Studying the mechanism by which SNAREs influence trafficking of membrane proteins. Receptors on both exocytic and endocytic vesicles, termed SNAREs, 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, TfR2 and CFTR.

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Identification of genes that cause breast and ovarian cancer

Contact: Dr Georgia Chenevix-Trench - tel 07-3362 0390, fax 00-3362 0105; e-mail georgiaT@qimr.edu.au or
Dr Amanda Spurdle mandyS@qimr.edu.au
Cancer Genetics Laboratory
[P, TU, H]

Women who have a family history of breast or ovarian cancer are much more likely to develop the disease themselves. This suggests that there is a genetic basis to these cancers. While some breast/ovarian cancer predisposing genes have been identified (such as BRCA1 and BRCA2), these don't account for more than a small amount of the familial clustering so other genes must exist.

Some of these may have rare mutations with a high risk of developing cancer (like BRCA1 and BRCA2),while others may have common mutations (or polymorphisms) and confer a lower risk but be more important on a population basis because of the high frequency of the mutations. We are using association studies and linkage analyses to identify new breast/ovarian cancer predisposing genes.

We are targeting in particular candidate genes involved in hormone metabolism and DNA repair because epidemiological data suggest that exposure to estrogen and to radiation increase the risk of these cancers. We have recently found that certain dominant-negative mutations in the ATM gene also contribute to familial breast cancer and are exploring this further to determine the downstream consequences of these mutations, and to develop novel screening tools to identify ATM mutations.

The use of functional complementation to isolate tumour suppressor genes on chromosome 8

Contact: Dr Georgia Chenevix-Trench - tel 07-3362 0390, fax 00-3362 0105; e-mail georgiaT@qimr.edu.au or
Dr Amanda Spurdle mandyS@qimr.edu.au
Cancer Genetics Laboratory
[P, TU, H]

There is considerable circumstantial evidence from analysis of tumours that the short arm of chromosome 8 contains one or more tumour suppressor genes. We have confirmed this by using chromosome transfer to move a normal copy of chromosome 8 into tumour cell lines, resulting in hybrid cell lines that are less tumorigenic because the putative, inactive, tumour suppressor genes have been complemented. Spontaneous deletions in the donated chromosomes have allowed us to map the tumour suppressor genes to small intervals, allowing us to evaluate the candidate genes in the suppressing regions. Some promising candidates have been identified, and now will be evaluated with additional genetic and functional assays

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Eph genes in development and cancer

Contact: Professor Andrew Boyd - tel 07-3362 0302, fax 07-3845 3509; e-mail andrewBo@qimr.edu.au
Leukemia Foundation of Queensland Experimental Haematology Laboratory
[P, H,  TU, SV]

The Eph receptors function to control cell movement during embryogenesis but re-appear at high levels on tumours. We have shown that the genes for the Eph receptors are entirely normal indicating a regulatory defect in cancer cells. By uncovering the nature of these defects we expect to find novel cancer related genes which have been disrupted in the development of the tumour. This project would be very suitable for a medically related PhD or MD project.

Molecular analysis of signal transduction pathways that control the cell's response to DNA damage

Contact: Dr Kum Kum Khanna - tel 07-3362 0338, fax 07-3362 0106; e-mail kumkumK@qimr.edu.au
Signal Transduction Laboratory
[P, H,  TU, SV]

Cancer results from a number of changes that occur in the normal genetic make up of a cell. Deficiencies in the ability to sense and repair damage that can occur in cells may also increase the risk of developing cancer. Key regulators of the cellular response to DNA damage include the ATM and ATR kinases that act in the detection and signalling of DNA damage. Genes that lie downstream of ATM and ATR, including BRCA1, p53 and Chk2, are associated with familial predisposition to breast cancer or with one or the other forms of cancers.
Our current area of research include:
1. To understand the regulatory mechanisms that regulates the normal functions of these tumor suppressors
2. Identify and characterize proteins that bind to these tumor suppressors using the conventional approaches such as a Yeast Two Hybrid Screen and expression library screen using a Far-western approach to understand how these tumor-suppressors work together with other proteins to perform multiple functions.
3. Use haplotype, mutation and functional analysis of candidate genes involved in sensing, signalling and repair of DNA damage in multiple-case breast cancer families to identify novel high-penetrance breast cancer susceptibility genes. This will be done in collaboration with Dr G. Chenevix-Trench.

To understand the role of a novel BRCA1 interactor in breast cancer predisposition

Contact: Dr Kum Kum Khanna - tel 07-3362 0338, fax 07-3362 0106 e-mail kumkumK@qimr.edu.au
Signal Transduction Laboratory
[P, H,  TU, SV]

A family history of breast cancer appears to be a major risk factor for breast cancer. Two dominant breast cancer predisposition genes, BRCA1 and BRCA2, have been identified but the highly penetrant mutations in these genes account for much less than 40% of familial cases of breast cancer. It is possible that a portion of the familial aggregation for breast cancer is explained by the defective regulation of these gene products.
We have recently identified a novel interactor of BRCA1.
The aim of this project is to functionally characterize the encoded protein and screen for possible mutations in breast cancer patients for this novel gene, which may improve our understanding of the actions of BRCA1 in genome maintenance and cancer development.

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Merkel cell carcinoma

Contact: Dr Helen Leonard - tel 07-3362 0309, fax 07-3362 0107 e-mail helenL@qimr.edu.au
Queensland Radium Institute Laboratory
[P, H,  TU]

Small cell carcinomas of skin and lung are very aggressive diseases which are almost uniformly lethal and share common histology, cytological derivation and tumour biology. SCLC represents one quarter of all human lung cancer and MCC is being seen at increasing frequency in Queensland as the population ages. They are derived from neuroendocrine cells, which migrate from the neural crest during embryogenesis, and it is their propensity for early metastasis that leads to very poor patient prognosis. The process of neuroendocrine carcinogenesis and basis of therapeutic responsiveness of these tumours remains poorly understood, limiting opportunities for improving clinical outcomes.

Most of the required techniques have been established in the QRI laboratory, we have access to cell lines, clinical samples, and the necessary technical expertise. The project will determine the role of neuroendocrine transcription factors in maintenance of the neuroendocrine phenotype and carcinogenesis, and will identify therapeutic targets for treating metastatic neuroendocrine cancer. We previously identified a novel DNA binding protein, Merkel Nuclear Factor, in Merkel cell carcinoma (small cell or neuroendocrine carcinoma of the skin) cell lines. We now shown this is Brn-3c, a member of the POU domain Family of transcription factors. Gene knock-outs in mice have shown Brn-3c, and the basic helix- loop -helix transcription factor HATH1, are critical for normal Merkel cell function and neuroendocrine cell differentiation leading to a post-mitotic, non-dividing cell. Using immunohistochemistry we demonstrated Brn-3c and HATH1proteins are both present in normal human Merkel cells but are in only a subset of Merkel cell carcinomas (MCCs). These MCCs produce cell lines of ‘Classic' phenotype. Tumours lacking Brn-3c and HATH1 result in cell lines of ‘Variant' phenotype. Patients with tumours from whom Variant cell lines are established have a poorer prognosis than those from whom Classic cell lines are derived.

The project will



1. Define the protein expression profile of proneuroendocrine transcription factors Brn-3c, HATH1 and HASH1, in normal cells, tumours and tumour cell lines in order to correlate their expression with maintenance of the neuroendocrine phenotype in these cells. Techniques involved are fluorescent microscopy, cell culture and immunohistochemistry.
2. Use transfection studies with sense and antisense constructs to confirm the role of proneuroendocrine transcription factors in neuroendocrine phenotype maintenance. Techniques involved, as above and RT-PCR and Western blots.
3. Once stable transfectants are established in Aim 2, use microarray expression profiling to identify novel genes regulated by proneuroendocrine transcription factors. Techniques involved. RT-PCR , cDNA microarrays (glass slide) and computer analysis of results.
For Background reference see
1. Leonard, J.H, Cook, A.L, Van Gele, M, Boyle, G.M, Inglis, K.J, Speleman, F., and Sturm, R.A. Proneural and Proneuroendocrine Transcription Factor Expression In Cutaneous Mechanoreceptor (Merkel) Cells and Merkel Cell Carcinoma. Int J Cancer, 2002; 101: 103–110.
2. Ben-Arie, N., et al., Functional conservation of atonal and Math1 in the CNS and PNS. Development, 2000. 127(5): p. 1039-48.
3. Xiang, M., et al., Requirement for Brn-3c in maturation and survival, but not in fate determination of inner ear hair cells. Development, 1998. 125(20): p. 3935-46.

Colorectal Cancer

Contact: Dr Joanne Young - tel 07-3362 0490, fax 07-3362 0108 e-mail joanneY@qimr.edu.au
RBH Foundation - Conjoint Gastroenterology Laboratory
[P, TU]

There is considerable phenotypic variability in colorectal cancers driven by a diverse group of mutations in important cancer-related genes. Until recently, it was generally accepted that most colorectal cancers developed in a type of epithelial polyp called an adenoma, and that a defined sequence of gene changes was responsible for this.

However, another type of polyp (the serrated polyp) may also act as a precursor lesion for colorectal cancers. Cancers which develop in this way comprise up to 40% of the total and can be distinguished by molecular and pathology features such as serrated architecture, tumour infiltrating lymphocytes, poor differentiation and methylation of tumour suppressor genes.

Projects in our laboratory centre around the study of the serrated pathway in both sporadic disease and that seen in families and include characterisation of the novel genes HPP1 and MSI1 which are silenced in serrated neoplasia.

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Population Studies & Human Genetics Division

Melanoma genomics

Contact: Dr Peter Parsons - tel 07-3362 0316, fax 07-3845 3508; e-mail peterP@qimr.edu.au
Melanoma Genetics Laboratory [P, H,  TU]

The overall theme is to identify and study the function of genes that are important in the development and treatment of melanoma. Such information might help us understand the peculiar epidemiology of melanoma and suggest new forms of therapy. Techniques include cell culture, protein purification and sequencing, derivation of monoclonal antibodies, immunohistochemistry, transcription assays, and microarrays. There is collaboration with molecular biologists for cloning genes of interest and with epidemiologists and clinicians for application of the results. Areas of interest are as follows:
• Action of solar UV in vitro and in vivo: Methods are being developed for measurement of DNA damage and mutations in human skin. The effect of UV-B and UV-A on pigmentation genes, tumour suppressor genes and gene promoters will be determined in different types of skin cells to identify the molecular responses to solar UV. An animal model is available for studying possible interactions between solar exposure and other environmental factors.
• cDNA microarrays: This new technology, scanning thousands of unique sequences in one experiment, is being used to identify new genes involved in the UV response and in the development of melanoma.
• Novel approaches to the treatment of melanoma: Two different types of differentiating agent are under study in cultured cells and in an in vivo model.

Genetic Epidemiology and Gene Mapping

Contact Professor Nick Martin - tel 07-3362 0278, fax 07-3362 0101; e-mail nickM@qimr.edu.au
Genetic Epidemiology Laboratory
[P, H,  TU, SV]

If you are a student who may be interested in a research career, and you like genetics, statistics/maths, and computing, why not try a studentship in GENETIC EPIDEMIOLOGY. We investigate the ways in which genes and environment influence common diseases and behavioural traits. We collect phenotypic data and DNA samples on thousands of pairs of twins and their families and carry out genetic linkage and association studies. We study asthma, anxiety, alcoholism, eczema, endometriosis, cognition, personality, height, weight, smell sensitivity, migraine, diabetes, handedness, depression, smoking and many other traits. But the main emphasis is the rigorous statistical genetic analysis of data, so you have to like statistics and sitting in front of a computer. 100 people here do ( we are the largest research group at QIMR, with a healthy honours, postgraduate and postdoctoral program) so why not give it a whirl.

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Cancer Epidemiology and Population Studies

Contact: Professor Adèle Green - tel 07-3362 0234, fax 07-3845 3503; e-mail adeleG@qimr.edu.au
Cancer and Population Studies Group [P, H,  TU]

The group has recently received major funding from Australian and US agencies to undertake very large, nation-wide studies of cancer. We aim to find the environmental and genetic causes of cancer by combining traditional epidemiological methods with laboratory-based molecular techniques. Exciting projects are available in the areas of melanoma, skin cancer, ovarian cancer and oesophageal cancer, as well as other health issues such as clinical care of cancer patients, women's health and indigenous health. Prior epidemiological experience is desirable but not mandatory - successful applicants will be thoroughly schooled in the art and science of epidemiology.

Hepatic fibrosis and cirrhosis in adult and paediatric liver disease

Contact: Dr Grant A. Ramm - tel 07-3362 0177, fax 07-3362 0191; e-mail grantR@qimr.edu.au
Hepatic Fibrosis Laboratory
[P, H,  TU]

The Hepatic Fibrosis Group is principally involved in investigating the cell biology of hepatic stellate cells (HSC). HSC are transformed into myofibrobalsts when exposed to liver toxins such as excess iron, alcohol, or bile salts due to cholestasis, viral infection or tumour invasion. As such these "activated" HSC are responsible for excess collagen deposition, fibrosis and cirrhosis in liver injury. Over the past 18 months our studies have established that HSC are responsible for liver cirrhosis in a subset of patients with cystic fibrosis.

We are currently investigating the role of chemoattraction as a mechanism for HSC migration and inflammatory cell infiltration of the periductular region of the acinus in cystic fibrosis liver disease and biliary atresia (a congenital condition where infants are born without functional bile ducts). We have identified a number of potential serum markers of early fibrogenesis and genes associated with liver injury in these patients and are currently investigating their utility in clinical practise.
Our work has also demonstrated a role for the iron-storage protein ferritin in the cytokine-like regulation of HSC activation, through the activation and translocation of the transcription factor, NFkB. We believe that ferritin and another iron-binding protein, transferrin, may be involved in the development of fibrosis in haemachromatosis and we are currently investigating the cell signalling pathways which may be involved in HSC activation in iron overload. Available projects include:

1. What is the cellular and molecular basis for the development of cirrhosis in the liver as a disease associated with biliary atresia in infants?
2. Early detection of severe liver injury in children with cystic fibrosis liver disease.
3. Investigating the role of excess iron and liver cell signalling in the liver injury associated with the inherited iron-overload disease, HFE haemochromatosis.
These project areas are suitable for PhD students. Top-up scholarships to supplement income from PhD scholarships are available to suitable applicants.

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Molecular Basis of Intestinal Nutrient Transport

Contact Dr Greg Anderson on (07) 3362 0187 or email gregA@qimr.edu.au
Iron Metabolism Laboratory
[P, H,  TU, SV]

The major focus of our laboratory is to elucidate the mechanisms of cellular iron transport and the way in which these processes are regulated. A particular goal is to describe the pathways of intestinal iron absorption and to understand how absorption is altered in disorders of iron metabolism, such as the iron loading disease heamochromatosis.
Over the last few years the identification of several novel metal transport molecules has revolutionised our understanding of this important class of human diseases. The project areas listed below are all designed to enhance our understanding of iron homeostasis by integrating contemporary genetic and molecular studies with biochemical and physiological approaches.
Projects are available in the following areas:
• Structure-function analysis of the iron transport proteins DMT1, hephaestin and IREG1
• Molecular and phenotypic analysis of inherited rodent anaemias
• The molecular basis of the anaemia of chronic disease
• Transcriptional analysis of intestinal iron transporrt genes
• The cell biology of brush border and basolateral iron transporters
Opportunities exist for suitably qualified students to conduct their Honours and PhD research in the Iron Metabolism Laboratory.

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