MBBS Honours Projects 2008-2009
Cancer & Cell Biology Division Infectious Diseases & Immunology Division- Schistosomiasis and other parasitic diseases
- Immune events in Malaria and Leishmaniasis
- Chikungunya arthritis
- Dendritic cells and Malaria
- Supportive Care Needs of Indigenous Cancer Patients
- Iron Metabolism and Haemochromatosis
- Skin Cancer: Gene expression, Sunscreen application and Medication use
How to apply:
Contact the Laboratory Head related to the project area of interest (see below). or
Education Coordinator
Mrs Simone Cross
Phone: 61 (0)7 3362 0307
Email: education@qimr.edu.au
Application and admission details in "Becoming a Student".
Cancer and Cell Biology Division
Membrane Transport LaboratoryDr Nathan Subramaniam
07-3362 0179
Email nathanS@qimr.edu.au
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:
- 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. - 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. - 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.
Infectious Diseases and Immunology Division
Molecular Parasitology Lab
Prof Don McManus
Dr Giovanna Raso
Ph: 07-3362 0401
Email Don.McManus@qimr.edu.au
Geographic information system and remote sensing to predict the spatio-temporal distribution of schistosomiasis in the Dongting Lake region, China
Schistosomiasis, one of the most serious of all the water-borne diseases, is caused by the trematode blood fluke S. japonicum in China, whose life cycle includes an amphibious intermediate host snail of the genus Oncomelania. Schistosomiasis japonica is typified by long-term chronicity and remains an economic and social burden and major health risk for more than 40 million people in China. The disease disabled and killed millions of Chinese peasants before systematic control programs began in the mid-1950s. The peak estimates of human prevalence, which exceeded 10 million infected people in the mid-1950s, have been reduced by more than 90%. Indeed, the national schistosomiasis control program for China is recognized as one of the most successful worldwide.
Nevertheless, schistosomiasis still remains of considerable public health significance in China. It is estimated that up to 1 million people and several hundred thousand livestock are infected with recent data indicating that the disease is re-emerging in some areas and is likely to emerge in others. Bovine infections (water buffaloes are particularly relevant), are responsible for the persistence of human schistosomiasis transmission in southern China.
Major endemic foci occur in the marsh and lake regions (Dongting and Poyang Lakes) which cover a vast area of five provinces, namely Anhui, Hubei, Hunan, Jiangsu and Jiangxi along the Yangtze River basin. There is concern that schistosomiasis might re-emerge, as active transmission has been reported from areas that had previously reached transmission interruption or transmission control.
The frequency and transmission dynamics of schistosomiasis japonica is intimately linked with the distribution of Oncomelania, which in turn is a result of the distribution and abundance of suitable snail habitats that consist of an appropriate mix of vegetation and aquatic environments. The advent of geographic information systems (GIS) and remote sensing (RS) technologies has opened new avenues to evaluate digital map data generated by earth observing satellite sensors for spatial and temporal environment analyses. These technologies make it possible to identify appropriate environmental indicators and hence to predict snail habitats in a spatial and temporal framework. This facilitates spatial and temporal prediction of schistosomiasis transmission and in turn provides guidance to local authorities in decision-making and policy planning for cost-effective resource allocation.
In 1999 and 2004 two nationwide cross-sectional epidemiological surveys were carried out by the Chinese Ministry of Health in schistosomiasis endemic areas of China. In Hunan province, the survey was conducted in a number of villages in the Dongting Lake region where schistosomiasis is endemic. The Dongting Lake region covers an area of approximately 15 000 km². All inhabitants of the selected villages aged between 5 and 65 years were invited to participate to the surveys. Serological examinations were performed using the enzyme linked immunosorbent assay technique and human stool samples were examined by the Kato-Katz method. Stools from buffaloes and other domestic animals were examined for schistosome infection by the miracidial hatching test.
This study aims at identifying environmental risk factors that influence the spatial and temporal heterogeneity of schistosomiasis infection prevalence and intensity in humans and buffaloes in the Dongting Lake area. It includes the gathering of environmental data from satellite images for the period of 1999 and 2004, and processing and storing these data into a comprehensive GIS database. A further step will include identification of significant environmental indicators that are significantly associated to schistosomiasis infection prevalence and intensity through regression analyses. The final objective of this study will be to produce schistosomiasis risk maps using GIS software.
Immunology and Infection
Dr Christian Engwerda
Ph: 07-3362 0428
Email Christian.Engwerda@qimr.edu.au
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.
Immunovirology Laboratory
A/Prof Andreas Suhrbier
07-3362 0415
Email andreasS@qimr.edu.au
A mouse model of Chikungunya arthritis
The pathogenisis of viral arthritis is poorly understood, as is its relationship with autoimmune arthritides. Human symptomatic infections with alphaviruses like chikungunya and Ross River are unique in that nearly all cases result in polyathritis or arthragia. The study of viral arthritides has been hindered by the lack of a mouse model. However, a model of Ross River virus disease has recently been established in weanling mice, which displays some but not all the features of human disease.
In this project we seek to establish a mouse model of chikungunya virus disease, a PC3 pathogen that has recently infected over 250,000 people in Reunion Island (France) and over 1.3 million people in India. Pretreatments are being sought that would predispose animals to symptomatic infection, since current infections in mice are entirely asymptomatic.
Once a disease model has been established a number of potential anti-rheumatic treatments will be tested based on our understanding of the immunological processes that give rise to arthritic manifestations. Rheumatology input into the project is sought as are insights into potential factors which might predispose to disease.
For further enquires please contact A/Prof Andreas Suhrbier.
Affiliations;
Australian Centre for International & Tropical Health & Nutrition.
University of Queensland.
Griffith Medical Research College.
Malaria Immunology Laboratory
Dr Michelle Wykes
07-3362 0429
Email michelleW@qimr.edu.au
Role of Dendritic Cells in Malaria Infection
Background and Introduction
Plasmodium falciparum Malaria is a complex disease and there is little data on why Plasmodia infections have different outcomes which can range from asymptomatic to lethal infections. Since immunity is initiated by Dendritic cells (DC) several studies have investigated DC function during malaria. Current data on the effects of infection on DC functions are inconclusive with one school of thought being that DC function is normal and the other that DC function is compromised. However, these studies have used different species and strains of Plasmodium.
Our group recently compared DC function between 5 strains of mouse parasites and found a dichotomy in the phenotype and function of DC between lethal and non-lethal parasites [Wykes, 2007 #1426; Wykes, 2007 #1425]. These studies found that DC from non-lethal P.yoelii 17XNL and P. chabaudi infections were fully functional and in particular secreted an abundance of IL-12 [Wykes, 2007 #1426; Wykes, 2007 #1425]. When these DC were transferred to naive mice, the recipient mice survived challenge with a lethal infection, mediated by the IL-12 [Wykes, 2007 #1426].
In contrast, DC from three lethal strains of parasite P. yoelii YM, P. vinckei and P.berghei were not functional and as such were unable to prime T cells or secrete IL-12 [Wykes, 2007 #1426; Wykes, 2007 #1425]. In the case of the P. vinckei and P.berghei, TNF partially mediated loss of DC function [Wykes, 2007 #1425]. These studies show that the strain of parasite determines DC function, which explains the differences seen between studies.
Project
The proposed project will dissect the mechanism by which DC in non-lethal infections are able to protect mice and mediate survival from a lethal disease. To identify the mechanism, we will use a standard protocol that we have developed and published. Mice will be given a non-lethal infection, after 10 days DC isolated and transferred to groups of naïve mice. These mice will then be given a lethal challenge. To identify the specific mechanism which mediates survival, eg CD4 T cells, then CD4 T cells will be depleted from a group of recipient mice. If that group of mice succumb to infection, then the role of CD4 T cells in mediating protection is confirmed. However if the mice remain resistant, then this mechanism is ruled out. For identifying specific cytokines, we will infect mice in which do not secrete that cytokine and then isolate DC for transfer.
Population Studies and Human Genetics Division
Indigenous Health Program
Ms Gail Garvey
Phone: 3845-3576
Email: Gail.Garvey@qimr.edu.au
Supportive Care Needs of Indigenous Cancer Patients
In Australia, the reported incidence of cancer in Indigenous people is lower or similar to the whole population (ABS 2005, Coory 2000) but the mortality rate is higher (Zhao, 2005). Indigenous Australians have a relatively high incidence of rapidly fatal cancers such as cancers of the lung and liver and an extremely low incidence of cancers with better survival, particularly melanoma (one of the most common cancers in Caucasian Australians) (Condon, 2003). However studies that have adjusted for the differences in cancer types and stage at diagnosis found that case-fatality rates among Indigenous Australians with cancer persisted at twice the rates in their non-Indigenous counterparts (Condon, 2005; Registry SAC, 1997). Little is known about why this should be so, though possible reasons include less access to high-quality treatment and a higher prevalence of co-morbidities that may limit treatment options, such as diabetes, acute coronary conditions and chronic renal failure.
In a study conducted by QIMR (Valery, 2006), cancer survival rates were 30% lower for Indigenous patients compared to non-Indigenous patients even after adjusting for stage at diagnosis, reduced uptake of cancer treatment and greater co-morbidity amongst Indigenous cases. Indigenous cases were less likely to undergo cancer treatment (surgery, chemotherapy, radiotherapy) and waited longer for surgery.
Indigenous patients face many additional barriers that prevent them from gaining access to care. To date there has been no rigorous study conducted in Australia to determine the prevalence of the supportive care needs of adult Indigenous cancer patients.
We are currently seeking a student to conduct a pilot study to:
- determine the appropriateness and sensitivity of an existing supportive care needs survey within a sample of Australian Indigenous cancer patients
- determine what addition items should be included in a supportive care needs survey subscale specifically for Australian Indigenous cancer patients
- served as a test drive for the process of recruitment and follow-up outlined within the main study
Further Information is available from Gail Garvey on (07) 3845 3576 or Vanessa Beesley on (07) 3362 0270
Iron Metabolism Lab
Dr Greg Anderson(QIMR)
Prof Lawrie Powell(RBWH)
Phone: 3362-0187
Email: Greg.Anderson@qimr.edu.au
Iron Metabolism in Chronic Liver Disease
Project 1. Patterns of hepatic iron deposition in chronic liver disease
An increased hepatic iron concentration is commonly associated with various forms of chronic liver disease. Since iron has pro-oxidant properties, this is thought to contribute to the severity of the disease. Why excess iron should deposit in the liver is incompletely understood, but it reflects a range of processes that ultimately disrupt the expression of regulatory proteins that control iron trafficking into and around the body. In this project, the student will examine patterns of iron deposition in the liver of patients with various forms of liver disease and correlate them with clinical and biochemical features of the patients. This will provide important clues to the mechanism of disrupted iron trafficking in these conditions.
Project 2 Factors determining clinical expression in hereditary haemochromatosis
Haemochromatosis is a common inherited disease of iron loading. The clinical penetrance in genetically predisposed individuals is quite variable and reflects a range of environmental and genetic factors. In this project the student will take advantage of our extensive database of haemochromatosis patients to assess the influence of various environmental factors on disease expression.
Cancer and Population Studies Group
Dr Jolieke van der Pols
Phone: 3845-3591
Email: Jolieke.vanderPols@qimr.edu.au
Gene expression in the skin and associations with medication use, and sunscreen application
Background
The p53 gene is a tumour suppressor gene that is commonly mutated in skin cancer and sun-exposed skin. In previous work we have shown for the first time that expression of p53 in the skin is a marker of past UV exposure and that this may be mitigated by regular application of sunscreen (van der Pols et al. Am J Epidemiol 2006). We now want to investigate whether expression of NFkappaB, a UV-induced transcription factor with tumour promoting effects, can also be mediated by sunscreen use. UV exposure also enhances COX-2 expression, which increases keratinocyte proliferation. Non-steroidal anti-inflammatory drugs inhibit COX-2 (6), but evidence is needed whether use of such medication can modify cutaneous COX-2 expression levels in the population.
Aims
Determine whether:
- sunlight exposure and use of sunscreen is associated with expression of NFkappaB in the skin and
- use of NSAIDs is associated with reduced cutaneous expression of COX-2 in the skin .
Immunohistochemical staining of 120 dorsal hand skin biopsies from the Nambour skin cancer study for COX-2 and NFkappaB has already been carried out. The student will interpret and score staining patterns followed by basic statistical analyses to study associations between gene expression levels and UV-exposure/sunscreen use and medication use (and related) variables.
Student requirements
This project is very suitable for a student with variable working hours since no
lab work other than microscopic reading of the slides is required and data analyses
can be carried out off-site (e.g. on laptop). A basic understanding of statistics
is required. Aim is publication in peer-reviewed journal at completion of project
Public health significance
Knowledge generated by this project will provide evidence to improve skin cancer
prevention, for example through better identification of high risk individuals
and identification of targets for therapeutic interventions.
Reference: "Expression of p53 Tumor Suppressor Protein in Sun-exposed Skin and
Associations with Sunscreen Use and Time Spent Outdoors: A Community based Study"
Am.J.Epidemiol. Vol 163(11):2006
Click here for a pdf of this reference
Collaborations
Dr. Glen Boyle, Drug Discovery Group (QIMR) and Prof. Konrad Muller, pathologist
at the Royal Brisbane and Women's Hospital.
Infectious Diseases & Immunology Division /
Therapeutic Development & Clinical Research Division
Clinical Immunohaematology Laboratory
Dr Maher Gandhi
A/Prof / Consultant Haematologist
07-3845 3792
Email Maher.Gandhi@qimr.edu.au
Mechanisms of action and predictors of response to rituximab in immune thrombocytopenic purpura
Adult immune thrombocytopenic purpura (ITP) is an autoimmune condition associated with frequent relapses and / or refractoriness to initial therapy such as steroids, intravenous immunoglobulin and splenectomy. ITP occurs as a result of autoantibodies against the patients' own platelets, producing thrombocytopenia which predisposes the patient to bleed. Accelerated destruction of platelets is mediated by the reticuloendothelial system via the activity of FcGamma Receptor bearing phagocytic cells. We hypothesize that polymorphisms of the FcGamma receptors are involved in the pathogenesis of ITP, and are likely to be implicated in the response of ITP to the monoclonal antibody rituximab. We have teamed up with hospitals across Australia to evaluate the benefit of rituximab in patients with relapsed / refractory ITP. Being involved with this prospective study has given us access to a large (over 100) uniformly treated group of ITP patients. This is an invaluable resource with which to study scientific aspects of ITP: specifically the genetic determinants which influence susceptibility to ITP and the mechanisms by which rituximab works in ITP.
Research Aims:
- To determine the incidence of FcGamma Receptor polymorphisms in adult ITP
- To assess the impact of FcGamma Receptor polymorphisms on the efficacy of rituximab
Ours will be the largest study to examine FcGamma receptor polymorphisms in adult ITP to date, the only one to study a uniformly treated population and the only study to correlate the data with therapeutic response. Accrual is on target for completion by mid-2008.
Work involved:
Determination of the frequency of FcGamma Receptor polymorphisms in a healthy
control population, comprising 100 volunteers. We need this to make sense of the
data in our patient population. The work will involve obtaining samples (buccal scrapes)
from volunteers, DNA extraction, and PCR. Obtaining the buccal scrapes should take
no more than a few days. The assays involved are already up and running and lend
themselves to the time constraints of a MBBS Honours student: i.e. since DNA is
so stable, they can be performed as and when time permits. They also lend themselves
to being done in batches
Type of candidate we are looking for:
Someone who is motivated, efficient, friendly and can keep meticulous laboratory
records. Prior experience of PCR is preferable but not essential, as hands on
training will be given.
What's in it for you:
- You'll work in a pleasant, friendly supervised environment
- An opportunity to perform research that lends itself to flexibility: necessary given your time constraints
- You will gain experience of applied scientific research
- There is a strong possibility that the results generated will advance medical knowledge of a debilitating condition and result in your being a co-author in a good medical publication .
How to apply: Contact the Laboratory Head related to the project area of interest (see above) in the first instance.
Printable pdf version of projects - click here
Apply for QIMR Honours awards here.