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Available projects
2010 - Bachelor of Science (Honours)
- Mapping neural control of human intestine: cholinergic innervation
- Use of trancutaneous stimulation to speed up the bowel in children with chronic constipation.
- Developing a pig model to study intestinal motility and effects of electrical stimulation.
- Arthritis studies: Identifying the mechanism of ADAMTS-5 action in ADAMTS-5 null, ADAMTS-5-deficient, and ADAMTS-5-resistant mice
- Experimental arthritis in genetically-modified mice
- Arthritis Research: Detecting bioactivity in a naturally-occurring aggrecan fragment
- Using children's genes in research
- The ethics of surgically assigning sex to children
- Characterisation And Treatment Of Mice With Mitochondrial Cardiomyopathy
- Using Next Generation Sequencing to Discover Novel Genes that cause Mitochondrial Disorders.
- Epithelial damage and repair in asthma
- Association of lung function genes and airway remodelling
- Examination of pneumococcal immune responses
- Characterization of pneumococcal immune response dynamics following vaccination
- Immunological effects following prenatal probiotic supplementation for the prevention of eczema
- Gaining new insights into the neuropathology of mitochondrial disorders
- Impact of probiotics on Streptococcus pneumoniae colonisation
- Identifying the molecular mechanisms underlying a common craniofacial disorder, Pierre Robin Sequence
- Large-scale screen of genes controlling skeletal development
- Epigenetic factors in Friedreich ataxia
- Evidence based paediatric bioethics in Australia:
- Ethical challenges in new public health research methods.
- Addiction and moral identity: Theoretical and empirical approaches
- Developing lentiviral vectors for gene therapy of Friedreich ataxia
- Determining the age-related differences in binding partners of the anticoagulant Heparin.
- Establishing whether mutations in mouse genes which cause IBD also play a role in human Crohns disease and ulcerative colitis in childhood
- How the cytokine IL-11 promotes gastric cancer development
- GREMLIN (GREM1): oncogenic target of cytokine signalling in cancer
- Genes which prevent cancer development: gastrokine 2 as a tumour suppressor gene
- Genetic counselling intervention for family communication following sudden death due to an inherited condition
- Neuropathogenic mechanisms of mitochondrial dysfunction
- Identifying TRPV4 interacting proteins using proteomics and pharmacology
- TRPV4 and skeletal development
- Understanding the role of infectious agents in children with early onet Crohn's disease
- mRNA surveillance in human disease: How cells detect and degrade deleterious mutant mRNA (nonsense-mediated mRNA decay)
- The molecular signalling pathways that cause osteoarthritis
- The contribution of protein misfolding (“unfolded protein responseâ€) to inherited cartilage and bone disease
- Characaterisation of viral agents responsible for acute diarrhoea in children
- Characterisation of the role of PArkin Co-Regulated Gene (PACRG) in neurodegenerative disease
- Characterisation of a novel gene and mouse model of ciliary dyskinesia
- Determining of the molecular basis of childhood dystonia
- Cardiac molecular signaling mechanisms during the progression of heart failure
- Cardiac molecular signaling mechanisms in survival adaptation to hypoxia and post-operative stress recovery
- Determining cord blood stem cells with cardiac fate for the repair of congenital myocardial dysfunction
- Understanding the immunological properties of cord blood derived-multilineage stem cells
- Cellular basis of skeletal muscle hypertrohy
- Formation of endoderm progenitor/stem cells from cord blood – towards regenerative therapies for lung, liver, pancreas, gut and thymus
- Epigenetic regulation of telomere chromatin in embryonic stem cells
- Epigenetic determinants of neocentromere and centromere chromatin
- ATRX is a key chromatin regulator at the telomere in cancer cells
- Hearing loss: identifying the genetic causes underlying childhood and adult deafness
- Understanding age-related differences in the structure of coagulation proteins and their interaction with anticoagulants
- Uptake of prenatal screening tests for Down syndrome: ‘Chance or Choice’
- Formation of the Neuromuscular Synapse in the Cremaster Muscle
- Mechanisms Underlying the Normal Formation of the Gubernaculum/Scotal Interface
- Novel mechanisms of chromosome and genome regulation and disease aetiology
- Epigenetic regulation of centromeres and neocentromeres
- Stem cells and gene therapy: Targeted integration of functional genomic loci
- RNAi therapy: Applications in ß-thalassaemia
- Determining the link between GM-CSF signaling and Bcl-2 family proteins
- Defining the role of p53 for Interleukin-3 (IL-3) in myeloid progenitor cells
- Investigations into chromosome instability and human disease predisposition
- Can neural stem cells repair Hirschsprung’s Disease?
- Project 1. Stem cell transplantation for the treatment of MMA
- Project 2. Pharmacological upregulation of MUT for the treatment of MMA
- How do cancer cells move in tissues?
- Identification of novel Wilms tumor 1 (WT1) gene mutations in cancer.
- Investigating the role of altered methylation in schizophrenia
- Epigenetics and the interaction between folate and vitamin D metabolism at the fetomaternal interface
- Is there an association between altered epigenetic profile in first trimester placenta with adverse pregnancy outcome?
- The role of Epigenetics in Paediatric Leukaemia development and outcome.
- Folate supplementation, neurodevelopment and epigenetics
- DEVELOPMENT OF THE HUMAN PLASMA PROTEOME
- Epigenetic variation in newborn twins: effect of maternal diet and environment and underlying genetic make up.
- Copy Number Variation of candidate genes in myopia
- Analysis of candidate sex-determining genes in an avian model
- Analysis of genes responsible for male germ cell development and germ cell tumours
- Genes involved in Disorders of Sex Development: identification and regulation
- Analysing synovial fluids from children with juvenile arthritis
1. Mapping neural control of human intestine: cholinergic innervation
Dr Bridget Southwell
Surgical Research
Infection, Immunity and Environment
T 93455069
E bridget.southwell@mcri.edu.au
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Professor John Hutson
Surgical Research
Infection, Immunity and Environment
T 93455805
E john.hutson@rch.org.au
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Movement of food along the gut is controlled and coordinated by neurons located in the walls of the gut tube. More than 20 different neurotransmitters are involved in contraction and relaxation pathways. Acetylcholine, the major excitatory transmitter in the intestine, binds to both ionotrophic (ion channels) and muscarinic (7 transmemembrane G protein-coupled) receptors. There are 5 different muscarinic receptors and we have mapped the location of Mr1-3. This project will map the distribution of muscarinic receptor 4 and 5 in guinea pig and human large intestine (colon) using fluorescent antibodies and confocal microscopy. Methods will include immunofluorescence and confocal microscopy, western blotting and PCR.
2. Use of trancutaneous stimulation to speed up the bowel in children with chronic constipation.
Dr Bridget Southwell
Surgical Research
Infection, Immunity and Environment
T 93455069
E bridget.southwell@mcri.edu.au
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Professor John Hutson
Surgical Research
Infection, Immunity and Environment
T 93455805
E john.hutson@rch.org.au
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Transcutaneous electrical stimulation overcomes constipation in children. We have been running a clinical trial on children with slow transit constipation comparing placebo (sham stimulation) and electrical stimulation through electrodes on the belly. This trial has established that electrical stimulation 3 times a week speeds up the bowel and increases contractions. This trial suggests that daily stimulation is more effective in speeding up the bowel and increasing defecation. This study will use daily stimulation, comparing different positions of electrodes. Two groups of children will be studied, those with 1) with slow colonic transit and 2) outlet obstruction. This study will use questionaires, data entry and database analysis and patient interaction and would suit physiotherapy, nursing or medical technology students.
3. Developing a pig model to study intestinal motility and effects of electrical stimulation.
Dr Bridget Southwell
Surgical Research
Infection, Immunity and Environment
T 93455069
E bridget.southwell@mcri.edu.au
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Professor John Hutson
Surgical Research
Infection, Immunity and Environment
T 93455805
E john.hutson@rch.org.au
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Transcutaneous electrical stimulation overcomes constipation in children. We have been running a clinical trial on children with slow transit constipation comparing placebo (sham stimulation) and electrical stimulation through electrodes on the belly. To understand how the electrical stimulation affects bowel motility we are developing a large animal model. We have begun preliminary studies on young pigs. In this study, surgery will be performed to place electrodes and strain gauges into the muscle of the large intestine, and pressure measuring catheters inside the intestine. Pigs will recover from the operations and then measurements will be collected each day for a week. Once normal motility is measured, the pigs will be given transcutaneous electrical stimulation and changes in bowel motility will be measured. This project is performed in collaboration with Monash University Physiology and Bioengineering Departments.
4. Arthritis studies: Identifying the mechanism of ADAMTS-5 action in ADAMTS-5 null, ADAMTS-5-deficient, and ADAMTS-5-resistant mice
A/Professor Amanda Fosang
Arthritis and Rheumatology
Musculoskeletal Disorders
T 83416466
E amanda.fosang@mcri.edu.au
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Dr Fraser Rogerson
Arthritis and Rheumatology
Musculoskeletal Disorders
T 83416467
E fraser.rogerson@mcri.edu.au
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Arthritis studies: Identifying the mechanism of ADAMTS-5 action Arthritis can affect adults, children and babies. We have discovered that the multi-domain enzyme, ADAMTS-5, mediates cartilage destruction in arthritic disease. ADAMTS-5 degrades a structural molecule in cartilage, called aggrecan. Our laboratory has spent many years investigating aggrecan and cartilage destruction by ADAMTS-5. We have developed mutant mice with catalytically-deficient ADAMTS-5 and shown that these mice are protected against arthritis in the early phases of a mild inflammatory arthritis model. We have recently obtained preliminary data suggesting that although catalytic deficiency in the ADAMTS-5 mouse partly explains the protection against arthritis in these mice, the catalytic deficiency is only part of the story and that there are other, as yet unknown consequences of the ADAMTS-5 mutation that influences inflammation the in mutant mice. This project will compare ADAMTS-5-deficient mice, ADAMTS-5 null mice and ADAMTS-5-resistant mice in order to better understand the role of ADAMTS-5 in arthritis.
5. Experimental arthritis in genetically-modified mice
A/Professor Amanda Fosang
Arthritis and Rheumatology
Musculoskeletal Disorders
T 83416466
E amanda.fosang@mcri.edu.au
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Dr Fraser Rogerson
Arthritis and Rheumatology
Musculoskeletal Disorders
T 83416467
E fraser.rogerson@mcri.edu.au
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Dr Stephanie Gauci
Arthritis and Rheumatology
Musculoskeletal Disorders
T 83416431
E steph.gauci@mcri.edu.au
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Arthritis is a debilitating disease that affects children as well as adults. A common feature of all arthritides is the gradual loss of articular cartilage from the surface of long bones, leading to long-term joint dysfunction. In arthritic cartilage, the major matrix molecules, collagen and aggrecan, are destroyed by enzymes of the metalloproteinase family. We have generated genetically-modified mice, with knock-in and knock-out mutations designed to help elucidate the role of specific metalloproteinases in arthritis. A number of projects are available to characterise these genetically-modified mice in vivo and in vitro. The projects involve biochemical analysis of cartilage matrix molecules, cell and tissue culture and mouse models of experimental arthritis.
6. Arthritis Research: Detecting bioactivity in a naturally-occurring aggrecan fragment
A/Professor Amanda Fosang
Arthritis and Rheumatology
Musculoskeletal Disorders
T 83416466
E amanda.fosang@mcri.edu.au
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Dr Fraser Rogerson
Arthritis and Rheumatology
Musculoskeletal Disorders
T 83416467
E fraser.rogerson@mcri.edu.au
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ARTHRITIS disturbs the dynamic balance of anabolic and catabolic processes in healthy cartilage by increasing catabolism leading to irreparable cartilage damage. We will study the ability of a naturally-occurring aggrecan fragment to modulate cartilage catabolism. Our in vitro and in vivo experiments suggest that the aggrecan fragment limits cartilage destruction. This project will explore the mechanism by which the naturally occurring aggrecan fragment antagonises cartilage damage and promotes cartilage repair.
7. Using children's genes in research
Dr Merle Spriggs
Ethics
Laboratory and Community Genetics
T 90905237
E merle.spriggs@mcri.edu.au
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A/Professor Lynn Gillam
Ethics
Laboratory and Community Genetics
T 90905203
E l.gillam@unimelb.edu.au
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Increasingly, genetic testing of children is becoming part of pediatric research. While a considerable amount of attention has been paid to the ethics of predictive testing in children for adult onset conditions there is little written about the ethical conduct of pediatric genetic research, especially that involving complex behavioural traits. Questions that arise include: • Is it ethically acceptable to enroll children and young people in gene-based prevention trials for traits such as obesity, addiction and ADHD? • When is it ethically defensible for a parent to consent to their child taking part in such research? Ethical issues include competence to consent, proxy consent, autonomy and developing autonomy, best interests, discrimination, stigma, privacy, genetic determinism and the right not to know. This project could be literature based, interview based or based on a questionnaire. The precise topic is negotiable and the methods are negotiable. Other ethics projects can be negotiated.
8. The ethics of surgically assigning sex to children
Dr Merle Spriggs
Ethics
Laboratory and Community Genetics
T 90905237
E merle.spriggs@mcri.edu.au
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A/Professor Lynn Gillam
Ethics
Laboratory and Community Genetics
T 90905203
E l.gillam@unimelb.edu.au
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Intersex conditions are variously referred to as ‘developmental anomalies of the external genitalia’, ‘atypical sexual differentiation’, and ‘ambiguous genitalia’. Controversy surrounding the surgical management of intersex conditions in newborns is an important ethical issue because it: • Raises questions about the authority of parents and others to make irrevocable decisions for young children • Tests the idea that surgery is only justified when it is for disease or malfunction • Raises questions about what constitutes disease or malfunction • Poses questions about what we should base treatment decisions on when there is little guidance in terms of evidence of outcomes • Illustrates the shift from physician-centred medicine and paternalism to patient-centred medicine • Highlights the need for evidence in the form of systematic outcome studies This project could be literature based, interview based or based on a questionnaire. The precise topic is negotiable and the methods are negotiable. Other ethics projects can be negotiated
9. Characterisation And Treatment Of Mice With Mitochondrial Cardiomyopathy
Dr Bi-Xia Ke
Mitochondrial & Metabolic Research
Laboratory and Community Genetics
T 83416287
E bi-xia.ke@mcri.edu.au
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A/Professor David Thorburn
Mitochondrial & Metabolic Research
Laboratory and Community Genetics
T 83416235
E david.thorburn@mcri.edu.au
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Disorders of mitochondrial energy generation cause a wide range of diseases. Severe mitochondrial defects affect ~1/5000 individuals, often causing childhood neurodegenerative diseases. Complex I deficiency is the most common mitochondrial enzyme defect in humans. Currently, no effective treatment for mitochondrial disease is available. Suitable animal models will be useful for the study of novel treatments. We recently generated one of the first mouse models of complex I deficiency by knockdown of the Ndufs6 gene. The mice have gross Complex I deficiency in the heart, which becomes enlarged, more markedly in males than females. This project will further characterise the cardiac phenotype of mice using a range of echocardiographical, histological, metabolic, physiological, molecular and immunochemical approaches. In addition, therapeutic trials will be carried out on this mouse model using bezafibrate, a drug that can stimulate mitochondrial biogenesis to upregulate transcription of respiratory chain genes. Our expectation is that this project will lead to a better understanding of pathogenic mechanisms of complex I deficiency and improvement of treatment strategies.
10. Using Next Generation Sequencing to Discover Novel Genes that cause Mitochondrial Disorders.
Dr Alison Compton
Mitochondrial & Metabolic Research
Laboratory and Community Genetics
T 6287
E alison.compton@mcri.edu.au
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A/Professor David Thorburn
Mitochondrial & Metabolic Research
Laboratory and Community Genetics
T 83416235
E david.thorburn@mcri.edu.au
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Mitochondria are the powerhouses of the cell, generating cellular energy through the oxidative phosphorylation (OXPHOS) system. Pathogenic mutations in genes required for correct assembly of the OXPHOS protein complexes result in a variety of neurodegenerative disorders collectively known as mitochondrial diseases. Nearly 100 (nuclear and mitochondrial) genes are known causes of mitochondrial disease, however ~50% of patients still do not have a molecular diagnosis with many more novel disease genes awaiting discovery. We recently identified four novel (nuclear) disease genes in which mutations cause severe childhood-onset OXPHOS complex I deficiency, the most common mitochondrial enzyme defect in humans. Our collaborators at the Broad Institute, Harvard have used phylogenetic profiling to identify another 19 novel genes proposed to be involved in OXPHOS complex I biogenesis (Pagliarini et al., 2008 Cell 134:112–123). Recently we performed high throughput sequencing of 89 ‘mitochondrial’ genes in 103 of our patients with defined complex I defects and have identified mutations in putative novel ‘disease genes’ as well as novel mutations in known disease genes. This project will follow up on several of the many sequence variants identified to discover novel Complex I disease genes and determine their normal function and disease pathogenesis using a combination of cell biology, molecular biology and biochemical approaches.
11. Epithelial damage and repair in asthma
Dr Simon Royce
Allergy and Immune Disorders
Infection, Immunity and Environment
T 93456882
E simon.royce@mcri.edu.au
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A/Professor Mimi Tang
Allergy and Immune Disorders
Infection, Immunity and Environment
T 93455911
E mimi.tang@rch.org.au
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Airway remodelling refers to the structural changes that occur in the airways of asthmatics. During the pathogenesis of this disease airway remodelling results in thickening of the airway wall, and the consequent reduction in luminal diameter results in worsened lung function and susceptibility to death. We will be testing the hypothesis that there is an inherent defect in the epithelium in asthma and investigating how this defect in epithelial repair drives other remodelling changes. Knockout and epithelial damage mouse models of asthma, asthma cell and tissue samples will be probed for remodelling parameters using techniques including morphometry, immunohistochemistry, ELISA, molecular biology and cell culture. This investigation has direct links with other studies underway in the laboratory to develop new therapies for airway remodelling in asthma.
12. Association of lung function genes and airway remodelling
Dr Simon Royce
Allergy and Immune Disorders
Infection, Immunity and Environment
T 93456882
E simon.royce@mcri.edu.au
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A/Professor Mimi Tang
Allergy and Immune Disorders
Infection, Immunity and Environment
T 93455911
E mimi.tang@rch.org.au
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Asthma is the commonest chronic disease of Australian children and although generally well managed, asthma still accounts for 1 in 250 deaths. A subset of asthma sufferers is unresponsive to current therapies and develops structural changes in the airways that worsen lung function. We are interested in developing new therapies for asthma that target airway remodelling. Two endogenous peptides (relaxin and tff2) have been extensively studied in mouse knockout and allergic airways disease models. We now wish to investigate their role in human asthma using archival tissue samples, and lung cell lines, including primary cells from patients with asthma. Antibody based and molecular techniques will be used in the investigation and results will be correlated with clinicopathological data already collected as part of a large asthma study
13. Examination of pneumococcal immune responses
Dr Paul Licciardi
Allergy and Immune Disorders
Infection, Immunity and Environment
T 93455554
E paul.licciardi@mcri.edu.au
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Anne Balloch
Allergy and Immune Disorders
Infection, Immunity and Environment
T 93456419
E anne.balloch@mcri.edu.au
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A/Professor Mimi Tang
Allergy and Immune Disorders
Infection, Immunity and Environment
T 93455911
E mimi.tang@rch.org.au
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Pneumococcal disease is a significant global health problem with approximately one million child deaths each year. Infection with the bacterium Streptococcus pneumoniae (pneumococcus) can lead to invasive pneumococcal diseases (IPD) such as pneumonia, meningitis and bacteraemia. Polysaccharides on the capsule of the organism (of which there are 91 different serotypes) are the predominant virulence factor and are included in pneumococcal vaccines to elicit specific antibody-based protection. The Pneumococcal Laboratory at MCRI is currently undertaking a large-scale clinical trial in Fiji (FiPP Study; NHMRC and NIH funded) based on alternative pneumococcal vaccination strategies. Recent studies in the laboratory have identified novel cross-reactivity of specific antibodies recognising several different pneumococcal serotypes. This has important implications in the diagnosis of primary immunodeficiencies such as specific antibody deficiency (SAD) characterized by poor immunity to polysaccharide antigens. This project will further examine the role of cross-reactivity on the pneumococcal immune response and correlation with functional antibody capacity. Experimental techniques include indirect and competition ELISA as well as functional opsonophagocytic assays
14. Characterization of pneumococcal immune response dynamics following vaccination
Dr Paul Licciardi
Allergy and Immune Disorders
Infection, Immunity and Environment
T 93455554
E paul.licciardi@mcri.edu.au
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Anne Balloch
Allergy and Immune Disorders
Infection, Immunity and Environment
T 93456419
E anne.balloch@mcri.edu.au
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A/Professor Mimi Tang
Allergy and Immune Disorders
Infection, Immunity and Environment
T 93455911
E mimi.tang@rch.org.au
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Infection with Streptococcus pneumoniae (pneumococcus) is a leading cause of morbidity and mortality worldwide. It is estimated that more than 1 million children die each year from invasive pneumococcal disease (IPD). In Australia, the highest rates of IPD are seen in the Indigenous population where disease burden is 10-fold greater than non-Indigenous Australians. More than 90 serotypes have been identified to date with the current seven-valent conjugate vaccine (PCV, Prevenar) and the 23-valent polysaccharide vaccine (23vPPV; Pneumovax) protecting against serotypes causing >80% and >90% of disease, respectively. Immunization with 23vPPV has recently been shown to induce immunological hyporesponsiveness following subsequent booster doses, possibly increasing susceptibility to disease. This is a major concern for current public health strategies. The Pneumococcal Laboratory at MCRI is interested in examining the pneumococcal antibody and cellular immune response following immunization with particular emphasis on cellular immunity. This project will use a range of experimental techniques including ELISA, antibody subclass analysis, in vitro opsonophagocytosis assays, flow cytometry and ELISPOT (if time permits).
15. Immunological effects following prenatal probiotic supplementation for the prevention of eczema
A/Professor Mimi Tang
Allergy and Immune Disorders
Infection, Immunity and Environment
T 93455911
E mimi.tang@rch.org.au
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Dr Paul Licciardi
Allergy and Immune Disorders
Infection, Immunity and Environment
T 93455554
E paul.licciardi@mcri.edu.au
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Allergic diseases are the commonest chronic illnesses affecting Australian children with over a third suffering from one or more of these disorders. For example, the prevalence of atopic dermatitis (AD, eczema) and asthma among Australian schoolchildren are 20% and 25% respectively, and these are increasing each year. Currently there is no cure for the allergic conditions and management can only control symptoms. Prevention strategies provide a logical approach to reducing the burden of disease in our community. Probiotics offer a promising approach to prevention of allergic disease. Evidence to date suggests that treatment with probiotics can modulate infant microbiota and immune function by resetting the allergic TH2-dominant phenotype towards the healthy TH1 state. A randomised controlled trial has been undertaken (CI: A/Prof Mimi Tang) to evaluate the efficacy of prenatal Lactobacillus GG (probiotic) supplementation to mothers during the last four weeks of pregnancy for the prevention of eczema. This project aims to examine the effect of probiotic supplementation on TH1/TH2 cytokine profiles as well as on the regulatory T cell compartment. Techniques used in this project will include multiplex assay and ELISA.
16. Gaining new insights into the neuropathology of mitochondrial disorders
Dr Jasper Komen
Mitochondrial & Metabolic Research
Laboratory and Community Genetics
T 83416287
E jasper.komen@mcri.edu.au
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A/Professor David Thorburn
Mitochondrial & Metabolic Research
Laboratory and Community Genetics
T 83416235
E david.thorburn@mcri.edu.au
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The oxidative phosphorylation (OXPHOS) system in mitochondria consists of five protein complexes (I-V) and is responsible for the generation of energy for the cell in the form of ATP production. Pathogenic mutations in genes encoding OXPHOS proteins result in a variety of neurodegenerative disorders collectively called mitochondrial disorders. The mitochondrial disorders are among the most common type of inherited diseases. Furthermore, OXPHOS dysfunction is believed to play an important role in more common diseases, such as Parkinson disease and diabetes. Our laboratory has obtained a mouse model for Complex I deficiency (Ndufs4-/- , a.k.a. Funky mice), the most common type of mitochondrial disorder. Funky mice develop neurodegenerative symptoms similar to those seen in children with mitochondrial disorders. Funky mouse brains lack any gross anatomical abnormality but in this project we will take a closer look at the brain using various techniques (i.e., SDS-PAGE, immunohistochemistry, RT-PCR and functional studies) in order to increase our understanding of the neuropathology. We anticipate that the results obtained in this project will be used to monitor disease progression and effects of treatments to ameliorate the symptoms of the Funky mice.
17. Impact of probiotics on Streptococcus pneumoniae colonisation
Dr Paul Licciardi
Allergy and Immune Disorders
Infection, Immunity and Environment
T 93455554
E paul.licciardi@mcri.edu.au
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Dr Catherine Satzke
International Child Health
Infection, Immunity and Environment
T 83416438
E catherine.satzke@mcri.edu.au
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Streptococcus pneumoniae (the pneumococcus) is the leading vaccine-preventable cause of serious infection in children, with up to 2 million deaths per year. Attachment to the host epithelium is the critical stage by which pneumococci colonise the nasopharynx and upper respiratory tract, leading to diseases such as pneumonia, meningitis and otitis media. For Indigenous Australian and other high-risk children, exposure to a substantial burden of pneumococci occurs during the first days of life, prior to any vaccination, and often determines their health status into adulthood. Simple strategies that prevent or reduce pneumococcal colonisation would have significant long-term benefits. Probiotics are live micro-organisms that confer a health benefit to the host. It is hypothesised that these could have a major role in the prevention or disruption of pneumococcal colonisation. In the gastrointestinal system, probiotics have been shown to restore the microflora balance that is disrupted during infection or inflammation. Probiotics may have a similar effect on pneumococcal colonisation of the nasopharynx, but this has not yet been tested. This study aims to develop an in vitro adherence model to examine the effect of probiotics on pneumococcal adhesion using quantitative adherence assays. This model will then be used to test a variety of probiotic strains (e.g. Lactobacillus rhamnosus GG) for activity against common colonising and invasive pneumococcal serotypes of clinical importance. The impact of probiotics on the prevention of, as well as the capacity to interfere with, established pneumococcal colonisation will be determined in several human respiratory cell lines
18. Identifying the molecular mechanisms underlying a common craniofacial disorder, Pierre Robin Sequence
Dr Peter Farlie
Craniofacial Research
Musculoskeletal Disorders
T 83416409
E peter.farlie@mcri.edu.au
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Professor John Bateman
Skeletal Biology and Disease
Musculoskeletal Disorders
T 83416422
E john.bateman@mcri.edu.au
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Pierre Robin Sequence (PRS) is a common craniofacial disorder consisting of small lower jaw, posteriorly placed tongue and cleft secondary palate. These defects lead to serious feeding and respiratory difficulties in infants. The underlying cause is thought to involve inadequate growth of the facial skeleton during embryonic stages. In several PRS patients, we have identified chromosomal translocations and microdeletions far upstream of SOX9, a gene encoding a transcription factor with known roles in the development of the craniofacial skeleton. We have hypothesised that in PRS patients, these chromosomal lesions remove DNA regulatory elements that normally act over a large genomic distance to drive SOX9 expression in craniofacial tissues. This Honours project will address the following questions: Where exactly do the regulatory elements exist in the genomic sequence upstream of SOX9? In which embryonic tissues do the elements drive SOX9 expression? Which signalling pathways and transcription factors converge on these elements to co-ordinate SOX9 expression? The project will involve cross-species genomic sequence analysis and construction and electroporation of GFP reporter plasmids into chicken embryos to enable tissue-specific expression to be visualised. This project has the potential to uncover the molecular mechanisms of a human disease, and will provide a solid grounding in developmental biology techniques.
19. Large-scale screen of genes controlling skeletal development
Dr Peter Farlie
Craniofacial Research
Musculoskeletal Disorders
T 83416409
E peter.farlie@mcri.edu.au
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Professor John Bateman
Skeletal Biology and Disease
Musculoskeletal Disorders
T 83416422
E john.bateman@mcri.edu.au
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Congenital defects of the skeleton are common and have a major impact on health and well being of affected children. Microarray RNA expression analysis of skeletal development is a powerful genome scale screening technology that is beginning to reveal essential pathways in skeletogenesis. However, a major limitation in this process is the functional analysis of identified candidate genes. To address this limitation in the analysis of our microarray data, we have developed a high-throughput screen to analyse the function of candidate genes in early skeletal development using avian retroviral delivery of expression and knockdown constructs. This screen will allow the student to rapidly analyse gene function in a whole animal model and will facilitate large-scale functional analysis of the genes controlling skeletal development and causing human skeletal defects and disease. Students will use cutting edge approaches to dissecting the genetic networks controlling complex developmental events during formation and growth of the craniofacial and limb skeletons. Experience gained in this project will allow students to initiate investigations into the mechanisms controlling development of any organ system.
20. Epigenetic factors in Friedreich ataxia
Dr Joseph Sarsero
Genetic Health Research (Bruce Lefroy Centre)
Laboratory and Community Genetics
T 83416285
E joe.sarsero@mcri.edu.au
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Dr Marguerite Evans-Galea
Genetic Health Research (Bruce Lefroy Centre)
Laboratory and Community Genetics
T 83416295
E marguerite.galea@mcri.edu.au
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A/Professor Martin Delatycki
Genetic Health Research (Bruce Lefroy Centre)
Laboratory and Community Genetics
T 83416284
E martin.delatycki@ghsv.org.au
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The neurodegenerative disease Friedreich ataxia (FRDA) is an autosomal recessive disorder characterised by neurodegeneration and cardiomyopathy. The presence of a GAA trinucleotide repeat expansion in the first intron of the FXN gene results in an insufficiency of the mitochondrial protein, frataxin. Current data indicates that the mutation may induce epigenetic changes and heterochromatin formation, thereby impeding gene transcription. Employing a range of molecular and cellular techniques (PCR, real-time RT-PCR, western blot, lateral flow immunoassays and bisulfite sequencing), this project will examine the correlation of the age of onset and severity of disease symptoms with the size of the GAA expansions, transcript levels, residual frataxin protein produced and DNA methylation patterns. These studies aim to contribute novel insight into the mechanisms involved in mediating FXN gene silencing in FRDA.
21. Evidence based paediatric bioethics in Australia:
A/Professor Lynn Gillam
Ethics
Laboratory and Community Genetics
T 90905203
E l.gillam@unimelb.edu.au
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Dr Craig Fry
Ethics
Laboratory and Community Genetics
T 90905216
E craig.fry@mcri.edu.au
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Paediatric bioethics is a new and developing field in Australia, and internationally. Whilst there are some useful theoretical analyses of child and adolescent capacity to consent, and the basis and limits to parents’ rights to make medical decisions for their children, there have been no attempts to test the applied utility of these theories across a range of health conditions and social contexts. Significant ethical dilemmas currently exist in relation to for example: child and adolescent decision-making on their own health and medical treatment; and in the case of adolescent alcohol and drug use and treatment. At the Children's Bioethics Centre we are establishing an integrated program of world-class research in paediatric bioethics, to inform policy, practice and education, and deliver enhanced outcomes in paediatric health. In this project we will: (1) Document current ethical challenges and dilemmas in paediatric health practice (service delivery and research) and policy in Australia; (2) Explore the attitudes, knowledge and practices of health professionals, children and adolescents, and families in relation to these ethical challenges; (3) Develop practical resources and decision-making strategies for addressing these ethical challenges. Students could work on one or a number of aspects of this project.
22. Ethical challenges in new public health research methods.
Dr Craig Fry
Ethics
Laboratory and Community Genetics
T 90905216
E craig.fry@mcri.edu.au
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A/Professor Lynn Gillam
Ethics
Laboratory and Community Genetics
T 90905203
E l.gillam@unimelb.edu.au
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Public health encompasses diverse settings, target groups, disciplines and skills in the quest to improve prevention, health promotion and health care. Success depends on innovative research and practice methods which often push the boundaries of knowledge and current ethical standards. Examples of new research methods currently being trialled in public health include: SMS messaging in health promotion research with difficult to access groups; Internet-based survey research and counselling; respondent driven sampling; brain imaging techniques to inform pharmacotherapy policy and treatments; photo/video research to engage specific target groups; and data linkage of health and other personal records. New health research methods like these give rise to important ethical questions, including: How do existing research ethics guidelines apply to these new forms of research participation? Do these new methods result in different outcomes for participants in relation to benefits and harms? Are existing definitions and guidelines around autonomy and consent applicable? Do new research methods like these alter participant confidentiality requirements and researcher responsibilities? What are the ethical limitations of methods innovation in health research with vulnerable populations? How can methods innovation be supported by ethical analysis? This project will: (1) document current ethical challenges encountered in new and emerging public health research methods; (2) explore the views, practices and needs of health researchers in relation to these ethical challenges; and (3) develop practical research ethics resources and guidelines to address identified needs. This will be the first mixed methods empirical study of ethical challenges in public health research in Australia and is also internationally unique.
23. Addiction and moral identity: Theoretical and empirical approaches
Dr Craig Fry
Ethics
Laboratory and Community Genetics
T 90905216
E craig.fry@mcri.edu.au
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A/Professor Lynn Gillam
Ethics
Laboratory and Community Genetics
T 90905203
E l.gillam@unimelb.edu.au
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Research in neuroscience and genetics is increasingly revealing the role of the brain in drug addiction, and the impact of drug use upon brain function, human decisions about drug use and behaviour related to drug use. Advances in this area potentially have widespread implications for public policy and the treatment of people who use drugs. Addiction neuroscience reinvigorates long-standing philosophical questions about free will, self-control, responsibility, and identity. Such issues are crucial for the practical translation of this new science and for ethical and effective public policies and practices in the addictions field. This project will examine the moral self-conception, practical identity, and values of people who currently use drugs and drug addicted persons. It will review philosophical accounts of responsible agency and self-control against the empirical data, and perceptions currently informing treatment. This project utilises a mixed methods approach incorporating literature review, focus groups, in-depth interviews, structured survey, and key informant interviews.
24. Developing lentiviral vectors for gene therapy of Friedreich ataxia
Dr Marguerite Evans-Galea
Genetic Health Research (Bruce Lefroy Centre)
Laboratory and Community Genetics
T 83416295
E marguerite.galea@mcri.edu.au
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Dr Joseph Sarsero
Genetic Health Research (Bruce Lefroy Centre)
Laboratory and Community Genetics
T 83416285
E joe.sarsero@mcri.edu.au
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A/Professor Martin Delatycki
Genetic Health Research (Bruce Lefroy Centre)
Laboratory and Community Genetics
T 83416284
E martin.delatycki@ghsv.org.au
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Friedreich ataxia (FRDA) is an autosomal recessive disorder characterised by neurodegeneration with many patients wheel-chair-dependent by the age of 20 years. Cardiomyopathy is the leading cause of death. A GAA trinucleotide repeat expansion in the first intron of the FXN gene results in reduced expression of the mitochondrial protein, frataxin. Toward the goal of therapeutic gene therapy, we aim to develop a series of lentiviral vectors to facilitate expression of a non-affected copy of the FXN gene. Molecular and cellular applications (cloning, PCR, lentiviral vector production, qPCR, protein expression assays, tissue culture and flow cytometry) will be used in this translational project and multiple target cells will be evaluated. The long-term goal will be to analyse the most promising vector(s) in vivo. Safe and efficacious FXN gene correction could provide a much-needed alternative FRDA treatment option in the clinic, but more excitingly, a potential cure.
25. Determining the age-related differences in binding partners of the anticoagulant Heparin.
Dr Vera Ignjatovic
Haematology Research
Critical Care and Neurosciences
T 99366520
E verai@unimelb.edu.au
|
Professor Paul Monagle
Haematology Research
Critical Care and Neurosciences
T 93455868
E paul.monagle@unimelb.edu.au
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Unfractionated Heparin (UFH) is the most commonly used anticoagulant medication in children. Over 15% of children admitted to a tertiary paediatric hospital are exposed to UFH during their inpatient care. Therefore, the interaction between UFH and the haemostatic system is of significant clinical importance. We have previously demonstrated clinically significant age-related differences in the anticoagulation effect of the UFH. These differences were hypothesized to be due to the age-specific differences in binding of this drug to plasma proteins. We have preliminary evidence to support this hypothesis. The focus of this project is to investigate these differences further by identifying the binding partners of UFH in plasma samples from neonates, children and adults. These results will contribute to improving our understanding of the action of UFH in neonates and children.
26. Establishing whether mutations in mouse genes which cause IBD also play a role in human Crohns disease and ulcerative colitis in childhood
Dr Louise Judd
Gastrointestinal Research in Inflammation and Pathology (GRIP)
Infection, Immunity and Environment
T 99366501
E lmj@unimelb.edu.au
|
Professor Andrew Giraud
Gastrointestinal Research in Inflammation and Pathology (GRIP)
Infection, Immunity and Environment
T 83416446
E andrew.giraud@mcri.edu.au
|
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The human IBD, Crohns disease and ulcerative colitis, are debilitating gut conditions which are becoming more prevalent in children, and increase the chance of development of colorectal cancer in adulthood. In order to better understand the genetic contribution to disease development, we are currently developing new mouse models of IBD by analysing mice from a sensitised ENU mutagenesis screen done in collaboration with the Australian Phenomics Institute in Canberra. Several promising models are currently being analysed. The aim of this project will be to characterize the gene mutations involved, develop genotyping assays to detect them, and to determine if the affected mouse genes are also mutated in human IBD. Techniques: Molecular and genetic analysis, Western blotting
27. How the cytokine IL-11 promotes gastric cancer development
Dr Louise Judd
Gastrointestinal Research in Inflammation and Pathology (GRIP)
Infection, Immunity and Environment
T 99366501
E lmj@unimelb.edu.au
|
Professor Andrew Giraud
Gastrointestinal Research in Inflammation and Pathology (GRIP)
Infection, Immunity and Environment
T 83416446
E andrew.giraud@mcri.edu.au
|
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We have recently established that IL-11 is the most important cytokine driving gastric cancer in a mouse model, and importantly that increased expression of IL-11 is associated with human stomach cancer development (Gastroenterology 136:967, 2009). This project will establish the gene targets for IL-11 in the stomach, which gastric cells synthesise IL-11, and how H. pylori infection induces IL-11 activation to promote stomach pathology. The pathological outcome of transgenic over-expression of IL-11 in the gastric and intestinal mucosae will also be assessed. Techniques: Broad range of protein and molecular analytical techniques; transgenic mouse phenotype analysis; immunohistochemistry
28. GREMLIN (GREM1): oncogenic target of cytokine signalling in cancer
Dr Louise Judd
Gastrointestinal Research in Inflammation and Pathology (GRIP)
Infection, Immunity and Environment
T 99366501
E lmj@unimelb.edu.au
|
Professor Andrew Giraud
Gastrointestinal Research in Inflammation and Pathology (GRIP)
Infection, Immunity and Environment
T 83416446
E andrew.giraud@mcri.edu.au
|
Dr Trevelyan Menheniott
Gastrointestinal Research in Inflammation and Pathology (GRIP)
Infection, Immunity and Environment
T 99366502
E treve.menheniott@mcri.edu.au
|
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GREM1 has been identified as part of a target gene signature for IL-11 signalling in gastric cancer by cDNA microarray. In order to better understand the role of GREM1 in promoting cancer, we have constructed a stable and inducible GREM1 expression system in the human gastric cancer cell line MKN28. This project will use this cell line to examine the outcome of forced GREM1 expression on cell proliferation, apoptosis and target gene expression, particularly BMP signaling proteins for which GREM1 acts as an inhibitor. Finally, a new GREM1-specific antibody will be used to examine the disposition of GREM1 in mouse and human gastric cancers and precancerous lesions in order to evaluate its role in adenocarcinoma development. Techniques: Broad range of protein and molecular analytical techniques; immunohistochemistry; cell culture.
29. Genes which prevent cancer development: gastrokine 2 as a tumour suppressor gene
Professor Andrew Giraud
Gastrointestinal Research in Inflammation and Pathology (GRIP)
Infection, Immunity and Environment
T 83416446
E andrew.giraud@mcri.edu.au
|
Dr Trevelyan Menheniott
Gastrointestinal Research in Inflammation and Pathology (GRIP)
Infection, Immunity and Environment
T 99366502
E treve.menheniott@mcri.edu.au
|
Dr Louise Judd
Gastrointestinal Research in Inflammation and Pathology (GRIP)
Infection, Immunity and Environment
T 99366501
E lmj@unimelb.edu.au
|
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Gastric cancer is the second biggest cause of cancer mortality in the world, particularly in East Asian countries. It is caused mainly after chronic infection by the bacterium H. pylori, and is promoted by chronic inflammation in childhood in susceptible individuals. We have established that the protein GKN2 is highly expressed by the mouse and human gastric mucosa, and that its expression is strongly suppressed in stomach cancer. Moreover, H.pylori infection produces a dramatic fall in GKN2 expression. We have also shown that this suppression can be reversed by using new experimental drugs. This project will use the GKN2 knockout mouse, cell lines transfected with GKN2 or mutant versions of the protein, GKN2 DNA probes and antibodies, and drugs that increase GKN2 expression, to evaluate how this protein can be manipulated to reverse tumour growth. Techniques: Broad range of protein and molecular analytical techniques; transgenic mouse phenotype analysis; immunohistochemistry; cell culture.
30. Genetic counselling intervention for family communication following sudden death due to an inherited condition
Dr Jan Hodgson
Genetics Education and Health Research
Laboratory and Community Genetics
T 83416308
E jan.hodgson@mcri.edu.au
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A/Professor Sylvia Metcalfe
Genetics Education and Health Research
Laboratory and Community Genetics
T 83416309
E sylvia.metcalfe@mcri.edu.au
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We are currently conducting a randomised controlled trial (RCT) of a genetic counselling intervention to facilitate communication to family members who are at risk of inheriting or developing a genetic condition. These family members may benefit from referral to genetics services. Some inherited conditions lead to sudden death in families where the genetic condition has not previously been identified. Autopsy findings may reveal that the cause of death has implications for family members. This project follows on from the RCT and will involve applying the genetic counselling intervention to this specific population of at-risk family members. Data collection will involve interviews with family members and referral audit.
31. Neuropathogenic mechanisms of mitochondrial dysfunction
Dr Ann Frazier
Mitochondrial & Metabolic Research
Laboratory and Community Genetics
T 83416287
E ann.frazier@mcri.edu.au
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A/Professor David Thorburn
Mitochondrial & Metabolic Research
Laboratory and Community Genetics
T 83416235
E david.thorburn@mcri.edu.au
|
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Mitochondrial dysfunction causes a range on early-onset neurological symptoms and contributes to neurodegenerative conditions such as Parkinson Disease. The mechanisms by which mitochondrial disease result in neuronal damage are unknown, therefore the study of these at a cellular level may lead to improved treatment and greater understanding of the role of nuclear- and mitochondrial-DNA mutations in both rare and common conditions. This project will focus on the most common mitochondrial energy production disorder, complex I deficiency, by establishing and characterising two cell culture models of complex I deficiency: 1) Neural cell cultures established from two mouse models of complex I deficiency resulting from mutations in two different nuclear encoded complex I subunits. 2) Olfactory stem cell cultures derived from nasal epithelial biopsies from patients with mtDNA mutations affecting complex I activity, or with Parkinson disease, which will be differentiated into neurons and glia. We will use techniques in microscopy, biochemistry and molecular biology to study the effects of these mutations, assessing parameters such as the mitochondrial membrane potential, reactive oxygen species, ATP production, apoptosis and cellular calcium dynamics. Such studies could highlight potential therapeutic approaches and allow us to monitor the effects of therapy.
32. Identifying TRPV4 interacting proteins using proteomics and pharmacology
Dr Shireen Lamande
Muscular Dystrophy
Musculoskeletal Disorders
T 83416465
E shireen.lamande@mcri.edu.au
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Professor Peter McIntyre
Muscular Dystrophy
Musculoskeletal Disorders
T 8344 5745
E pmci@unimelb.edu.au
|
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Mutations in the calcium channel TRPV4 cause defective skeletal development. Consistent with the disease phenotypes, TRPV4 is expressed in cartilage and bone cells, but it is also found in many other tissues including nerves and kidney and we don’t yet understand why mutations predominantly affect the skeleton. The mutant TRPV4 proteins are not glycosylated normally and appear to be relatively unstable, possibly due to misfolding. We would like to understand how TRPV4 is regulated and activated in cartilage cells by identifying proteins that interact with the intracellular N-terminal domain of TRPV4. This project will screen for interacting proteins by expressing Strep-tagged TRPV4 proteins in mammalian cells, using affinity pull-down approaches to recover TRPV4 and interacting proteins followed by mass spectrometry to identify the interacting proteins. The effect of co-expressing TRPV4 and its partner proteins will be studied using established ion-channel assays.
33. TRPV4 and skeletal development
Dr Shireen Lamande
Muscular Dystrophy
Musculoskeletal Disorders
T 83416465
E shireen.lamande@mcri.edu.au
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Professor John Bateman
Skeletal Biology and Disease
Musculoskeletal Disorders
T 83416422
E john.bateman@mcri.edu.au
|
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Mutations in the calcium channel TRPV4 cause defective skeletal development but very little is known about the temporal and spatial expression of TRPV4 during cartilage and bone development. This project will characterise TRPV4 mRNA and protein expression during skeletal development in the mouse using in situ hybridization and immunohistochemistry. We know that the Trpv4 knockout mouse has some abnormal skeletal features but to date only the knee joints have been studied and so another aspect of this project will involve detailed analyses of the skeleton in this mouse during development using histology and a range of imaging techniques.
34. Understanding the role of infectious agents in children with early onet Crohn's disease
Dr Carl Kirkwood
Enteric Viruses
Infection, Immunity and Environment
T 83416439
E Carl.kirkwood@mcri.edu.au
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Dr Josef Wagner
Enteric Viruses
Infection, Immunity and Environment
T 83416450
E josef.wagner@mcri.edu.au
|
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Crohn’s disease is a major cause of morbidity throughout the world. It is an incurable condition associated with chronic inflammation of the gastrointestinal tract of genetically susceptible individuals. Crohn’s disease usually begins in early adulthood and is treated with potent immunosuppressive medications, but often requires surgery. We have conducted preliminary studies designed to identify an infectious agent in gut biopsy tissue obtained from children with suspected Crohn’s disease. Using microarray and subtractive hybridisation techniques we have identified a candidate viral agent that we propose could initiate the gut damage and ongoing immune activation. This project will continue to utilise molecular techniques to genetically characterise the viral agent in children with Crohn’s disease and develop specific PCR detection assays to determine the prevalence of the virus in clinical specimens collected from children at disease onset.
35. mRNA surveillance in human disease: How cells detect and degrade deleterious mutant mRNA (nonsense-mediated mRNA decay)
Professor John Bateman
Skeletal Biology and Disease
Musculoskeletal Disorders
T 83416422
E john.bateman@mcri.edu.au
|
Dr Shireen Lamande
Muscular Dystrophy
Musculoskeletal Disorders
T 83416465
E shireen.lamande@mcri.edu.au
|
|
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Cells have several critical quality control processes to reduce the impact of mutations on cell function. We are studying nonsense-mediated decay (NMD), a mRNA quality mechanism that degrades mRNA containing premature stop codons. Since mutations that introduce premature stop codons account for one-third of inherited disorders, NMD is of immense importance in many diseases as well as normal development [see Hum Mol Genet. 8:1893 (1999); Am J Hum Genet 82:786 (2008)]. Our studies will explore the molecular basis of NMD by the production of mutations in reporter gene constructs we have developed to measure NMD in vitro by transfection of cells and determination of mRNA levels by PCR and primer extension assays. The project will characterise the mRNA sequences that specify NMD in different cell types and determine role of known and novel RNA binding proteins using electromobility shift assays. These trans-acting proteins will be identified by proteomics (electrophoresis and mass spectrometry) and their role in NMD tested by suppression of expression using RNA interference.
36. The molecular signalling pathways that cause osteoarthritis
Professor John Bateman
Skeletal Biology and Disease
Musculoskeletal Disorders
T 83416422
E john.bateman@mcri.edu.au
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Dr Richard Wilson
Skeletal Biology and Disease
Musculoskeletal Disorders
T 93456601
E richardwilson.m@mcri.edu.au
|
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Degeneration of articular cartilage is the central pathological feature of osteoarthritis (OA) and it is this progressive erosion of cartilage that leads to joint failure and necessitates joint replacement surgery. We have a major research program determining the molecular events in the initiation and progression of cartilage breakdown. Using microarray analysis to look at gene expression changes and proteomic approaches we have determined new osteoarthritis candidate genes. Several research projects are available in this program exploring the detailed biology of these genes and the signalling pathways that result in the onset and progression of OA. These studies will involve the study of the biological function of these genes in cultured cartilage and bone cells, and how both over-expression and expression knockdown by RNAi affects cellular signalling and cell phenotype in vitro. This will compared with the changes found in osteoarthritic tissues. The projects will use of a wide range of molecular biology, biochemical, cell biology and proteomic techniques.
37. The contribution of protein misfolding (“unfolded protein responseâ€) to inherited cartilage and bone disease
Professor John Bateman
Skeletal Biology and Disease
Musculoskeletal Disorders
T 83416422
E john.bateman@mcri.edu.au
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Dr Richard Wilson
Skeletal Biology and Disease
Musculoskeletal Disorders
T 93456601
E richardwilson.m@mcri.edu.au
|
|
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Inherited musculoskeletal disorders are a significant disease burden and although many mutations have been defined, our knowledge on the molecular mechanisms that cause them, and ultimately how these mechanisms could be manipulated, is only just beginning to be explored. Many of the gene mutations result in the production of mutant protein that is compromised in its ability to form the correct 3-D folded functional structures. Recent research has shown that these unfolded proteins can cause cellular stress and activate intracellular signalling pathways that have profound effects on cell gene expression that may contribute to cellular pathology (see Bateman et al.,Nature Reviews Genetics 2009 Mar;10(3):173-83). The proposed studies will explore the molecular signalling pathways using in vitro and transgenic mouse models and a range of immunohistochemical, biochemical, molecular methods and proteomic analysis (2D-electrophoresis and mass spectrometry) skills. In addition, our studies will explore the use of new therapeutic agents to overcome protein misfolding and cell stress, as a proof-of-principle that some of these diseases can be effectively treated.
38. Characaterisation of viral agents responsible for acute diarrhoea in children
Dr Carl Kirkwood
Enteric Viruses
Infection, Immunity and Environment
T 83416439
E Carl.kirkwood@mcri.edu.au
|
Professor Ruth Bishop
Enteric Viruses
Infection, Immunity and Environment
T 93455062
E r.bishop@mcri.edu.au
|
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Diarrhoea is responsible for over 2 million deaths worldwide, primarily in children under 5 years of age. A diverse group of pathogens including viruses, bacteria and parasites can cause diarrhoea, with rotavirus, and norovirus the chief viral agents identified. However, up to 30% of diarrhoeal cases are of unknown etiology, suggesting a role for novel or unknown agents. We have conducted preliminary studies using a mass-mini sequencing approach to explore the viral communities present in children with undiagnosed diarrhoea. Using this approach we have detected known enteric viruses as well as novel viruses including bocavirus and picobirnaviruses. The role of these emerging viruses is unclear in the era of mass rotavirus vaccination. In this research project we propose to further explore to the role of both known and novel viruses. Molecular techniques will be used to genetically characterise these viruses, and specific RT-PCR assays will be utilised used to determine the prevalence of these agents in clinical specimens collected from children with diarrhoea.
39. Characterisation of the role of PArkin Co-Regulated Gene (PACRG) in neurodegenerative disease
Dr Paul Lockhart
Genetic Health Research (Bruce Lefroy Centre)
Laboratory and Community Genetics
T 83416322
E paul.lockhart@mcri.edu.au
|
Dr Juliet Taylor
Genetic Health Research (Bruce Lefroy Centre)
Laboratory and Community Genetics
T 83416295
E juliet.taylor@mcri.edu.au
|
|
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Parkinson’s disease (PD) is a common progressive neurodegenerative disorder that is a major cause of morbidity and mortality. Mutations in the parkin gene are the most common cause of early onset-PD, and altered parkin function is a risk factor for several different neurodegenerative diseases. We have recently shown that Parkin Co-Regulated Gene (PACRG) shares a bi-directional promoter with parkin and the two proteins interact. We hypothesise that this interaction facilitates the degradation of misfolded and toxic proteins within the brain. Failure or compromise of the function of either parkin or PACRG results in the accumulation of toxic proteins and results in the development of neurodegenerative disease. This project will determine the function of PACRG, with a particular focus on its role in the brain. This will be achieved through a range of approaches including gene expression studies, protein analysis and the characterisation of cell and animal models.
40. Characterisation of a novel gene and mouse model of ciliary dyskinesia
Dr Paul Lockhart
Genetic Health Research (Bruce Lefroy Centre)
Laboratory and Community Genetics
T 83416322
E paul.lockhart@mcri.edu.au
|
Miss Gabrielle Wilson
Genetic Health Research (Bruce Lefroy Centre)
Laboratory and Community Genetics
T 83416295
E gabrielle.wilson@mcri.edu.au
|
|
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Cilia are evolutionarily conserved microtubule-based hair-like organelles that project from nearly all mammalian cell types. Although they perform remarkably diverse functions they share a similar basic structure, consisting of a basal body, axoneme and ciliary membrane. Defects in cilial function have classically being associated with human phenotypes such as neural tube and patterning defects, male infertility and sinusitis. However, recent studies have broadened the range of associated syndromes and phenotypes to include obesity, diabetes and hypertension. There is limited understanding of the genes and proteins involved in the formation and function of cilia, but recent studies have taken advantage of mice models to study the pathogenesis of ciliary dysfunction in vivo. We have identified a novel mouse model characterised by male infertility and hydrocephalus (enlarged ventricles within the brain). We have identified the defective gene and have preliminary data suggesting it is a key protein required for the functioning of motile cilia. This project will utilise a range of molecular and cellular techniques, including the development of cell and animal models, to investigate the role of the protein and potential contribution to human cases of hydrocephalus.
41. Determining of the molecular basis of childhood dystonia
Dr Paul Lockhart
Genetic Health Research (Bruce Lefroy Centre)
Laboratory and Community Genetics
T 83416322
E paul.lockhart@mcri.edu.au
|
Dr Kirstee Martin
Genetic Health Research (Bruce Lefroy Centre)
Laboratory and Community Genetics
T 83416286
E kirstee.martin@mcri.edu.au
|
Dr Paul Lockhart
Genetic Health Research (Bruce Lefroy Centre)
Laboratory and Community Genetics
T 83416322
E paul.lockhart@mcri.edu.au
|
Dr Paul Lockhart
Genetic Health Research (Bruce Lefroy Centre)
Laboratory and Community Genetics
T 83416322
E paul.lockhart@mcri.edu.au
|
Dystonia is a common movement disorder which is characterised by involuntary sustained muscle contractions and abnormal movement. The condition affects approximately 1 in 5000 people, but remains poorly understood with limited treatment options. Mutation of the TorsinA gene causes dominant early-onset general torsion dystonia, the most common heritable form of the disease. TorsinA is highly expressed in a subset of neuron within the brain, particularly the basal ganglia and associated motor circuits. Although the normal function of TorsinA is currently unknown we have preliminary data suggesting the protein functions as a chaperone and transports substrates within the neuron. We have identified several proteins that interact with TorsinA. The aim of this project is to further characterise these interacting proteins using a range of molecular and cellular techniques and investigate their contribution to the disease phenotype. In addition, we have established mouse models and human patient-derived cell lines specific defects in the TorsinA gene. These will allow us to identify the molecular pathways disrupted during disease and provide the means to develop and test novel therapeutic treatments.
42. Cardiac molecular signaling mechanisms during the progression of heart failure
Dr Salvatore Pepe
Heart Research
Critical Care and Neurosciences
T 93454114
E salvatore.pepe@mcri.edu.au
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A/Professor Joe Smolich
Paediatric Intensive Care
Critical Care and Neurosciences
T 93454571
E joe.smolich@mcri.edu.au
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Professor Dan Penny
Heart Research
Critical Care and Neurosciences
T 93455922
E dan.penny@rch.org.au
|
|
Congenital and acquired myocardial disorders, despite diverse etiology, commonly involve a reduced capacity to manage oxygen and nitrogen free radical metabolism. Chronic augmented oxidative stress, particularly in fetal and neonatal development, not only leads to post-translational structural modification of proteins, but also impacts gene transcription, ultimately with consequences to structural, metabolic and functional remodeling during adaptive and maladaptive heart failure. These pathological changes remain to be well defined in the developing heart at molecular and cellular level in order for potential therapeutic targets to be identified. Students ideally should have a background in at least one of the following: biochemistry, immunology or pharmacology. Studies will explore novel molecular signaling pathways (intracellular/mitochondrial/nuclear) using unique in vitro and ex vivo models and a range of immunohistochemical, biochemical, molecular, genetic and cell biology methods.
43. Cardiac molecular signaling mechanisms in survival adaptation to hypoxia and post-operative stress recovery
Dr Salvatore Pepe
Heart Research
Critical Care and Neurosciences
T 93454114
E salvatore.pepe@mcri.edu.au
|
Dr Michael Cheung
Heart Research
Critical Care and Neurosciences
T 93455714
E michael.cheung@rch.org.au
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Professor Igor Konstantinov
Heart Research
Critical Care and Neurosciences
T 93455200
E igor.konstantinov@rch.org.au
|
|
Many congenital heart disorders, involve chronic hypoxic conditions due to one or more cardiovascular structural defects which compromise normal cardiopulmonary blood flow and thus blood reoxygenation. During heart surgery cardioplegic heart arrest and cardiopulmonary bypass impose additional inflammatory and ischemia-reperfusion stress. Ischemic preconditioning (IPC) activates a powerful innate protection via brief intermittent periods of coronary artery ischemia-reperfusion prior to a sustained period of ischemia, thus reducing post-ischemic injury. In animal and human models of ischemia-reperfusion injury, a simple stimulus known as remote ischemic preconditioning (RIPC) has been shown to reduce post-ischemic tissue damage and inflammation. RIPC can be invoked by causing IPC at a site remote from the heart, ie using a pressure cuff to intermittently occlude and reperfuse blood vessels in limbs. In numerous cell types mitochondria have been recognised to be central to IPC where multiple signalling pathways appear to converge to regulate metabolic function. However the molecular and cellular mechanisms that underly the cardioprotection induced by RIPC remain to be defined. Thus, our current goals are to define these intracellular/ mitochondrial/ nuclear signaling pathways using animal models and cell-based studies. New understanding of RIPC will identify specific targets to harness more potent cardioprotective effects in our clinical setting. Students should have a background in one or more of the following: biochemistry, immunology, genetics, physiology, pharmacology.
44. Determining cord blood stem cells with cardiac fate for the repair of congenital myocardial dysfunction
Dr Salvatore Pepe
Heart Research
Critical Care and Neurosciences
T 93454114
E salvatore.pepe@mcri.edu.au
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Ms Faten Zaibak
Cord Blood Stem Cell Research
Early Development and Disease
T 99366523
E faten.zaibak@mcri.edu.au
|
Dr Ngaire Elwood
Cord Blood Bank
Early Development and Disease
T 93456398
E ngaire.elwood@mcri.edu.au
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Dr Christian Brizard
Heart Research
Critical Care and Neurosciences
T 93455200
E christian.brizard@rch.org.au
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As the heart has recently been found to be capable of self renewal, the current work is aimed at acquiring a basic understanding of the growth and differentiation of cardiac progenitor cells. Cord blood, obtained from the placenta and umbilical cord, contains cells called unrestricted somatic stem cells (USSC) that are capable of forming many different tissues including the heart. Related genetic transcriptional signaling, immune and endocrine regulatory factors that are involved in determining what drives cardiac cell fate will be studied to develop models of myocardial cell recruitment for potential treatment of congenital heart disorders which currently only have palliative surgical treatment options. Beyond cord cell line manipulation and characterization, our goals are projected to facilitate the iterative development of experimental surgical models, working with surgeons and clinicians. Students ideally should have a background in one or more areas such as immunology, genetics, biochemistry or pharmacology, and will predominantly utilise genetic, molecular and cellular techniques.
45. Understanding the immunological properties of cord blood derived-multilineage stem cells
Ms Faten Zaibak
Cord Blood Stem Cell Research
Early Development and Disease
T 99366523
E faten.zaibak@mcri.edu.au
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Dr Ngaire Elwood
Cord Blood Bank
Early Development and Disease
T 93456398
E ngaire.elwood@mcri.edu.au
|
|
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Cord blood, obtained from the placenta and umbilical cord, contains cells called unrestricted somatic stem cells (USSC) that are capable of forming many different tissues in the body. Towards cell therapy with USSC we have recently shown that USSC suppress T cell proliferation. This suggests that USSC are immunosuppressive and therefore may be useful for reducing graft versus host disease. We also have some preliminary evidence that one of the key pathways bone marrow mesenchymal stem cells (MSC) use to mediate immunosuppression is absent in USSC.
46. Cellular basis of skeletal muscle hypertrohy
Dr Jason White
Muscular Dystrophy
Musculoskeletal Disorders
T 83416418
E jason.white@mcri.edu.au
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Dr Shireen Lamande
Muscular Dystrophy
Musculoskeletal Disorders
T 83416465
E shireen.lamande@mcri.edu.au
|
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Skeletal muscle hypertrophy is an increase in muscle mass without any change to myofiber number, and is the result of myofibers with a larger cross-sectional area (CSA). Hypertrophy can be the result of environmental stimuli, such as load-bearing exercise, or genetic factors such as that observed in the callipyge genotype in sheep. Growth of post-natal skeletal muscle occurs primarily through accumulation of myonuclei and cytoplasm from mitotic cells. The source of mitotic cells involved in post-natal skeletal muscle hypertrophy is thought to be the endogenous population of muscle precursor cells or satellite cells. These cells can be extracted in primary culture and induced to proliferate where they are termed myoblasts. Myoblasts can be induced to withdraw from the cell cycle, differentiate and fuse together to form multi-nucleate syncitia termed myotubes. We have a number of projects will utilise myogenic cell lines to investigate the function of specific genes identified as being involved in the hypertrophy phenotype. The ultimate aim of these projects is the manipulation of gene expression in musclular dystrophy to ameliorate the progressive loss of skeletal mass and function.
47. Formation of endoderm progenitor/stem cells from cord blood – towards regenerative therapies for lung, liver, pancreas, gut and thymus
Dr Caitlin Filby
Cord Blood Stem Cell Research
Early Development and Disease
T 6522
E caitlin.filby@mcri.edu.au
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Ms Faten Zaibak
Cord Blood Stem Cell Research
Early Development and Disease
T 99366523
E faten.zaibak@mcri.edu.au
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Dr Ngaire Elwood
Cord Blood Bank
Early Development and Disease
T 93456398
E ngaire.elwood@mcri.edu.au
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Adult stem cells from cord blood are a valuable alternative to embryonic stem cells for potential regenerative medicine applications. This project aims to use novel small molecules and other differentiating cell culture techniques to drive cord blood-derived adult stem cells towards endoderm progenitor/stem cells that can give rise to cells of the endoderm (such as the lung, liver, pancreas, gut and thymus). These endodermal cells will then be directed to form organ-specific progenitor cells that will be useful for the treatment of a wide range of diseases, including Cystic Fibrosis. Techniques involved in this project include cord blood stem cell propagation and differentiation, real-time PCR, antibody staining, western blotting, fluorescent activated cell sorting.
48. Epigenetic regulation of telomere chromatin in embryonic stem cells
Dr Lee Wong
Chromosome and Chromatin Research
Laboratory and Community Genetics
T 83416240
E lee.wong@mcri.edu.au
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Professor KH Andy Choo
Chromosome and Chromatin Research
Laboratory and Community Genetics
T 83416306
E andy.choo@mcri.edu.au
|
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There is currently a huge interest in understanding how embryonic stem (ES) cell pluripotency is controlled, and what (epigenetic) changes occur at the chromatin level during differentiation. However, until the present study, no one has investigated the chromatin status of the telomere in pluripotent and differentiating ES cells. In our study, we have found that the telomere chromatin of the pluripotent ES cells is unique compared to that of the differentiating ES cells. Specifically we show enrichment of histone variant H3.3 and ATRX (alpha thalassemia mental retardation) at the telomeric chromatin in mouse ES cells. The study involving RNAi-depletion of H3.3 and ATRX that results in impairment of the telomere structure also confirms that H3.3 and ATRX are essential for the maintenance of telomeric integrity in these cells. This project involves the investigation of the roles of H3.3 and ATRX, and their interacting partner as a ‘reprogramming cue’ for the maintenance of prolonged telomere-self renewal in pluripotent ES cells.
49. Epigenetic determinants of neocentromere and centromere chromatin
Dr Lee Wong
Chromosome and Chromatin Research
Laboratory and Community Genetics
T 83416240
E lee.wong@mcri.edu.au
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Professor KH Andy Choo
Chromosome and Chromatin Research
Laboratory and Community Genetics
T 83416306
E andy.choo@mcri.edu.au
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This project aims to study the role of genetic and epigenetic factors in regulating the structural and functional integrity of chromosomes and chromatin. We will use normal centromeres, neocentromeres (a new class of centromere devoid of alpha-satellite repetitive DNA first discovered by us), and human artificial chromosomes to investigate how different chromatin-modifying proteins (including constitutive centromere proteins, histone variants, boundary element insulator and DNA repair checkpoint proteins) and non-coding RNA components (such as various classes of centromeric alpha-satellite transcripts and retrolements) are organised at the centromere regions. The organisation will be defined at the linear chromatin level using chromatin immunoprecipitation and microarray analysis. The knowledge gained will be fundamental to our understanding of how genetic and epigenetic factors regulate centromere hierarchical assembly and its function in the maintenance of mitotic activity.
50. ATRX is a key chromatin regulator at the telomere in cancer cells
Dr Lee Wong
Chromosome and Chromatin Research
Laboratory and Community Genetics
T 83416240
E lee.wong@mcri.edu.au
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Professor KH Andy Choo
Chromosome and Chromatin Research
Laboratory and Community Genetics
T 83416306
E andy.choo@mcri.edu.au
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ATRX (alpha thalassemia mental retardation) belongs to the SWI2/SNF2 family of chromatin remodelling proteins. It contains a PHD-like zinc finger at the N-terminus and a ATPase/helicase domain at its C-terminus. Mutations in the ATRX gene are associated with X-linked mental retardation (XLMR) often accompanied by alpha-thalassaemia (ATRX syndrome). Although ATRX has been postulated to be a transcriptional regulator, its precise roles remain undefined. We demonstrate ATRX localization at the telomeres in mouse embryonic stem (ES) cells in synchrony with the incorporation of histone variant H3.3 during telomere replication. We also detect increased ATRX telomere signal in ALT cancer cells (cells that maintain telomere length by Alternate Telomere Maintenance pathway). This project involves the study of the function of ATRX, through its interaction with H3.3, in the modulation of telomere-length renewal in cancers.
51. Hearing loss: identifying the genetic causes underlying childhood and adult deafness
A/Professor Henrik Dahl
Genetic Hearing Research
Early Development and Disease
T 83416253
E henrik.dahl@mcri.edu.au
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Dr Shehnaaz Manji
Genetic Hearing Research
Early Development and Disease
T 83416254
E shehnaaz.manji@mcri.edu.au
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Hearing loss affects 1:400 young people and many more adults and elderly people. The major objective of our research is to identify and understand the underlying causes of deafness in children and adults. Research in the hearing field has to a large extent advanced through the use of animal models. We have identified mouse strains with recessively inherited deafness, the most common form of inherited deafness in humans. These mice provide a new, unique and valuable resource for studying the contribution of genetic and environmental factors to hearing loss. We are identifying “deafness†genes by genetic and molecular studies in our mouse strains. Candidate genes are identified through database analysis, bioinformatics and DNA sequencing. The study of the function and expression of novel “deafness†genes is critical for our understanding of ear development and function. Expression of a “deafness†gene is analysed by in-situ and immunohistochemical techniques in mice as well as by biochemical methods in tissue culture cells. These studies are followed by screening for mutations in humans using novel techniques such as high resolution melt DNA profiling. These studies are providing much needed insights into the mechanisms leading to hearing loss in humans and will provide a foundation for developing new strategies for delaying, preventing or treating genetic deafness, including age-related hearing loss.
52. Understanding age-related differences in the structure of coagulation proteins and their interaction with anticoagulants
Dr Vera Ignjatovic
Haematology Research
Critical Care and Neurosciences
T 99366520
E verai@unimelb.edu.au
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Professor Paul Monagle
Haematology Research
Critical Care and Neurosciences
T 93455868
E paul.monagle@unimelb.edu.au
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Haemostatic system of children evolves with age, with marked physiological differences in the concentration of most haemostatic proteins, a concept known as Developmental Haemostasis. We have previously observed that these quantitative differences in haemostatic proteins do not explain all of the age-related differences in the effect of anticoagulants, suggesting the role for qualitative differences. Studies performed in our laboratory confirmed that fibrinogen isolated from neonatal and child plasma is qualitatively different to that isolated from adult plasma. In addition, we have demonstrated clinically significant age-related differences in the anticoagulation effect of the anticoagulant Heparin, hypothesized to be due to the age-specific differences in binding of this drug to coagulation as well as other plasma proteins. Using state of the art proteomic methodology, this proposal will build on our current and previous work and contribute significantly towards developing treatment strategies for children based on sound experimental evidence. This proposal will be the first attempt to: 1: Determine the extent of age-related differences in structure and binding kinetics of key coagulation proteins in humans (Fibrinogen, Antithrombin, and Thrombin); 2: Investigate the age-related differences in the interaction of haemostatic proteins with clinically relevant anticoagulants.
53. Uptake of prenatal screening tests for Down syndrome: ‘Chance or Choice’
Dr Sharon Lewis
Public Health Genetics
Laboratory and Community Genetics
T 83416279
E sharon.lewis@mcri.edu.au
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Dr Alice Jaques
Public Health Genetics
Laboratory and Community Genetics
T 83416291
E alice.jaques@mcri.edu.au
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A/Professor Jane Halliday
Public Health Genetics
Laboratory and Community Genetics
T 83416260
E janehalliday.h@mcri.edu.au
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Prenatal screening tests for Down syndrome should be offered to all pregnant women; however, approximately 20% of Victorian pregnant women do not have screening. We would like to determine whether this is by chance (not offered screening) or choice (choose not to have screening). Pregnant women attending antenatal care at the Royal Women’s Hospital will be asked to complete a short questionnaire about what prenatal tests they were offered (if any), whether they had a test and, their reasons for this decision. This type of research has been done in the past, but current information is needed to help plan future new screening strategies. The project will involve the development and administration of the questionnaire to the pregnant women as well as the analysis and interpretation of the data.
54. Formation of the Neuromuscular Synapse in the Cremaster Muscle
Professor John Hutson
Surgical Research
Infection, Immunity and Environment
T 93455805
E john.hutson@rch.org.au
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Dr Adam Balic
Surgical Research
Infection, Immunity and Environment
T 93454116
E adam.balic@hotmail.com
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Undescended testis is common (5% of boys) and 1-2% of male births require surgical repositioning of the testes, at considerable expense to society and trauma for patients and family. The organ responsible for testicular descent is called the gubernaculum. The gubernaculum consists of a mesenchymal cord which is attached to the testis and an unique muscle, known as the Cremaster muscle. Recently we have shown that during fetal development there is a delay in the formation of secondary myotubes. Unlike the case in primary myotube formation, the formation of secondary myotubes is known to require innervation. Functional innervation requires the formation of neuromuscular synapse. This project will examine the formation of the neuromuscular synapse in the Cremaster muscle and relate this muscles unique development and function.
55. Mechanisms Underlying the Normal Formation of the Gubernaculum/Scotal Interface
Professor John Hutson
Surgical Research
Infection, Immunity and Environment
T 93455805
E john.hutson@rch.org.au
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Dr Adam Balic
Surgical Research
Infection, Immunity and Environment
T 93454116
E adam.balic@hotmail.com
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Cryptorchidism or undescended testis is common (5% of boys) and 1-2% of male births require surgical repositioning of the testes, at considerable expense to society and trauma for patients and family. The organ responsible for testicular descent is called the gubernaculum. The gubernaculum consists of a mesenchymal cord which is attached to the testis and an unique muscle, known as the Cremaster muscle. Recently we have shown in a rodent model cryptorchidism, that the failure of the gubernaculum to descend normally is associated with a defect in tissue remodelling at the time of birth. Normally the tip of the gubernaculum becomes attached to the future scrotum by a sheet of collagen rich fibroblasts. This fibroblastic sheet forms within the inguinal fat pad shortly after birth. In our rodent model of cryptorchidism this stucture forms in an aberant location. This project will examin the formation of this connective tissue stucture, determine its composion and the regulatory mechanisms responsible for correct gubernacular attachment.
56. Novel mechanisms of chromosome and genome regulation and disease aetiology
Dr Damien Hudson
Chromosome and Chromatin Research
Laboratory and Community Genetics
T 83416300
E damien.hudson@mcri.edu.au
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Professor KH Andy Choo
Chromosome and Chromatin Research
Laboratory and Community Genetics
T 83416306
E andy.choo@mcri.edu.au
|
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In order for our genetic material to be faithfully segregated into two daughter cells, the chromosomes must compact nearly 10,000 fold. Prior to this event chromosomes are an amorphous mass of DNA, but upon compaction they form visible X-shaped structures known as mitotic chromosomes. A key component in this process is a multi subunit complex termed condensin. The aims of this project are to understand how condensin directs chromosome condensation and to find which components condensin interacts using gene knockout technology, and integrated proteomics and biochemistry. Furthermore we aim to look at the non-mitotic roles of condensin where a growing body of evidence suggests condensin has key roles in gene regulation and DNA repair. Critically malfunction of condensin is associated with human disease including cancer and immune deficiency. We expect to find novel interactors contributing to chromosome structure and to understand the mechanism of action of condensin and how it might contribute to disease.
57. Epigenetic regulation of centromeres and neocentromeres
Dr Owen Marshall
Chromosome and Chromatin Research
Laboratory and Community Genetics
T 83416300
E owen.marshall@mcri.edu.au
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Professor KH Andy Choo
Chromosome and Chromatin Research
Laboratory and Community Genetics
T 83416306
E andy.choo@mcri.edu.au
|
|
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The process of cell division, where the sister chromatids of each chromosome are drawn to opposite cell poles, is one of the most fundamental and yet complex cellular functions. Central to this process is the centromere, a complex structure formed from DNA and proteins that attaches to the microtubules of the cell machinery and governs the ordered segregation of chromatids. As might be expected of a structure with such an important function, the position of the centromere on any given chromosome is normally static and unchanging, embedded in vast tracts of repetitive DNA. However, in an extraordinary example of sudden epigenetic change, new centromeres (or neocentromeres) can very occasionally form on any part of a chromosome, deactivating the original centromere. This project aims to investigate whether the repositioned neocentromere can be deactivated and the old centromere re-activated. We will use a human repositioned centromere on chromosome 4 and target core centromere proteins to the inactive centromere in an attempt to reactivate it. The project will also further characterise the recently-formed neocentromere on this chromosome using FISH and chromatin immunoprecipitation (ChIP). The results of this study will be crucial to understanding how centromeres are formed, regulated and, ultimately, deactivated -- and as such have implications for cancer research and the process of speciation.
58. Stem cells and gene therapy: Targeted integration of functional genomic loci
Dr Jim Vadolas
Cell & Gene Therapy
Laboratory and Community Genetics
T 83416233
E jim.vadolas@mcri.edu.au
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Dr Heidi Peters
Clinical Services
GHSV / VCGS (Clinical / Diagnostic)
T 83416257
E heidi.peters@mcri.edu.au
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One of the major obstacles to successful gene therapy is the random integration of the therapeutic transgene, which is associated with insertional mutagenesis and oncogenesis. Using specific elements derived from adeno-associated virus (AAV) our research group has developed a novel strategy to enhance the delivery, and site-specific integration of large DNA molecules into the human genome. We have recently shown that we can enhance the delivery, and facilitate the site-specific integration of the entire human ß-globin locus. This project will investigate the site-specific integration of functional genomic loci into stem cells. Reporter gene expression and fluorescence in situ hybridisation will be used to monitor targeted integration and tissue-specific expression. In vitro differentiation will be used to assess the capacity of modified stem cells to differentiate along multiple lineages. We propose that this non-viral gene therapy strategy may be used in conjunction with patient-derived stem cells to facilitate persistent and stable transgene expression while avoiding the risks associated with random integration.
59. RNAi therapy: Applications in ß-thalassaemia
Dr Jim Vadolas
Cell & Gene Therapy
Laboratory and Community Genetics
T 83416233
E jim.vadolas@mcri.edu.au
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Dr Heidi Peters
Clinical Services
GHSV / VCGS (Clinical / Diagnostic)
T 83416257
E heidi.peters@mcri.edu.au
|
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Severe ß-thalassaemia (ß-thalassaemia major) is an inherited haemoglobinopathy arising from mutated ß-globin genes, resulting in reduced ß-globin chain synthesis. Much of the pathology of this disease is due to excess a-globin chains forming toxic insoluble precipitates in erythroid cells resulting in cell death, ineffective erythropoiesis and severe anaemia. Decreased a-globin chain synthesis leads to milder symptoms, exemplified by individuals who co-inherit a- and ß-thalassaemia. Therefore, a possible therapeutic strategy in the treatment of ß-thalassemia could include targeted reduction of a-globin chains to mimic co-inheritance of a/ß-thalassemia. RNA interference (RNAi) is an innovative new strategy for modulating gene expression and this pathway can potentially be exploited to mediate reductions in a-globin. Our group has identified key regions in the a-globin mRNA sequence which can be targeted with high efficiency using short-interfering RNA (siRNA) to mediate significant reductions in a-globin expression. We have also successfully demonstrated that RNAi-mediated reduction of a-globin results in phenotypic improvements in ß-thalassaemic cells. This project aims to develop strategies for targeted delivery of siRNA into erythroid progenitor cells. Initial studies will be conducted in vitro and will involve culture of both cell lines and primary cells. Further studies will also be conducted in vivo using our unique humanised ß-thalassaemia mouse models and patient-derived cells.
60. Determining the link between GM-CSF signaling and Bcl-2 family proteins
Dr Gabriela Brumatti
Cancer
Early Development and Disease
T 93455834
E gabriela.brumatti@mcri.edu.au
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A/Professor Paul Ekert
Cancer
Early Development and Disease
T 93455008
E paul.ekert@rch.org.au
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Our laboratory is interested in the molecular mechanisms by which growth factors, such as GM-CSF can signal diverse outcomes including cell survival, proliferation and differentiation. It has long been known that the withdrawal of growth factors such as GM-CSF from dependent cells induced apoptosis or cell death, in a manner that is inhibitable by Bcl-2. The implication is that GM-CSF signaling regulates the activity of Bcl-2 family members. In this project, you will learn to use established techniques to generate myeloid cell lines that are GM-CSF dependent from haematopoietic stem cells that lack the genes for each of the Bcl-2 family members. In this way you will establish which genes are required for the normal response to GM-CSF deprivation. The methodologies for this project are well established in the laboratory and you will be exposed to a wide range of common and broadly applicable techniques, including basic molecular and cell biology, clonal assays and flow cytometry.
61. Defining the role of p53 for Interleukin-3 (IL-3) in myeloid progenitor cells
Dr Anissa Jabbour
Cancer
Early Development and Disease
T 93455835
E anissa.jabbour@mcri.edu.au
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A/Professor Paul Ekert
Cancer
Early Development and Disease
T 93455008
E paul.ekert@rch.org.au
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The tumour suppressor p53 is mutated in 30% of leukaemia and 60% of all cancers. Its role is predominantly to sense DNA damage and mediate either cell cycle arrest to allow time for DNA repair or to promote cell death. Using a model of Interleukin-3 (IL-3) withdrawal in myeloid progenitor cells, we had found that Puma, a Bcl-2 family member (which are key regulators of the apoptotic response), is required for normal cell death to proceed. Puma is regulated at the transcriptional level by p53, but IL-3 withdrawal was largely thought to be a p53 independent process. Surprisingly, we found that p53-/- myeloid cells were protected from IL-3 withdrawal mediated cell death. As p53 may be important in the development of leukaemia since leukemic cells acquire the ability to survive and proliferate independently of growth factors, we now seek to analyse further the role of p53 and Puma in IL-3 signalling. The project will aim to determine how growth factors promote cell survival, and how growth factor signalling regulates these genes. The project will provide a student with opportunities to master a wide range of cell biological and molecular biological techniques, including PCR, cloning, tissue culture, flow cytometry, confocal microscopy, Western blotting and co-immunoprecipitation. In addition, students will learn about gene expression techniques and gene discovery, as they address the importance of various genes in the biology of tumours such as leukaemia.
62. Investigations into chromosome instability and human disease predisposition
Dr Paul Kalitsis
Chromosome and Chromatin Research
Laboratory and Community Genetics
T 83416300
E paul.kalitsis@mcri.edu.au
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Professor KH Andy Choo
Chromosome and Chromatin Research
Laboratory and Community Genetics
T 83416306
E andy.choo@mcri.edu.au
|
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Approximately 10 quadrillion cell divisions occur in the lifetime of a human. Each divisional event requires the accurate distribution of the newly-replicated chromosomes to the daughter cells. Any faults occurring during this process can cause an imbalance in chromosome number and lead to clinical conditions such as Down syndrome, pregnancy loss, infertility, and cancer. Our laboratory investigates the cellular and molecular mechanisms that are responsible for such chromosome imbalances. One project involves the use of a fluorescent protein chromosome instability mutant screening assay in mouse embryonic stem cells to identify genes and environmental agents that contribute to chromosome missegregation events. Another project uses affinity purification and mass spec/proteomic techniques to identify novel chromatin protein components using known essential chromosome proteins as affinity baits. We anticipate finding many new genes/proteins whose functions will be further studied using techniques such as RNAi gene knockdown and gene knockout in cells and mice. These studies are expected to contribute important new insight into key mechanisms regulating chromosome stability and their potential role in causing the plethora of known chromosome-related human diseases.
63. Can neural stem cells repair Hirschsprung’s Disease?
Dr Don Newgreen
Embryology
Early Development and Disease
T 83416276
E don.newgreen@mcri.edu.au
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Dr Heather Young
Embryology
Early Development and Disease
T 83440007
E h.young@unimelb.edu.au
|
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The nervous system lying in the wall of the gastro-intestinal tract is crucial for its functions, such as peristalsis, nutrient uptake and water balance. In early embryonic stages, nerve precursor cells (neural crest stem cells) migrate from the brainstem to the oesophagus and stomach then they migrate along the small intestine and then the colon to form the gut nerve cells. In the relatively common and serious birth defect Hirschsprung’s Disease this migration is faulty, leaving the last part of the colon without nerves and hence without normal functions. Novel proposals aim to rectify this disease by allowing neural crest stem cells to migrate into the part of the gut affected by Hirschsprung’s disease. However, this tactic is hampered by a lack of understanding of the normal migratory process. This project will fill gaps in our knowledge of this important developmental process, using advanced techniques such as gene electroporation, cross-species grafting, cell tracking, time-lapse movies and immunohistochemistry. For recent reviews (pdfs), email the above address.
64. Project 1. Stem cell transplantation for the treatment of MMA
Dr Heidi Peters
Clinical Services
GHSV / VCGS (Clinical / Diagnostic)
T 83416257
E heidi.peters@mcri.edu.au
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Dr Nicole Buck
Cell & Gene Therapy
Laboratory and Community Genetics
T 83416236
E nicole.buck@mcri.edu.au
|
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Methylmalonic aciduria is an autosomal recessive inborn error of organic acid metabolism, affecting approximately 1/140,000 children. The condition results from a functional defect in the enzyme methylmalonyl CoA mutase. This project aims to investigate the degree to which a transplanted immature liver cell line can reduce disease and biochemical phenotypes observed in a mouse model with an intermediate phenotype for the human disorder MMA. We have established colonies of transgenic mice which will be transplanted and then characterised biochemically and phenotypically. Tissues will be examined for the presence and level of EGFP expression using fluorescent microscopy, RT-PCR of mRNA, western blot and flow cytometry. The activity of the transplanted cells will also be confirmed by specific liver enzyme assays and measurement of metabolite levels by mass-spectrometry. This project will lead on to extending the work to examine methods of increasing the level of production of MMA enzyme from the cell line. This would involve the use of both viral gene therapy techniques and non viral methods prior to transplantation.
65. Project 2. Pharmacological upregulation of MUT for the treatment of MMA
Dr Heidi Peters
Clinical Services
GHSV / VCGS (Clinical / Diagnostic)
T 83416257
E heidi.peters@mcri.edu.au
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Dr Nicole Buck
Cell & Gene Therapy
Laboratory and Community Genetics
T 83416236
E nicole.buck@mcri.edu.au
|
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Methylmalonic aciduria (MMA) is an autosomal recessive inborn error of the propionate metabolic pathway. One form of this disease is caused by mutations in methylmalonyl-CoA mutase gene (MUT) resulting in reduced levels of enzyme activity. The pharmacological up-regulation of residual mutase activity is one approach to advance treatment strategies for these patients. The aim of the project is to create a cellular assay system to identify potential compounds which increase the amount of methylmalonyl-CoA mutase activity. The work will then be translated into a mouse model. These mice will allow us develop and test novel therapeutic treatments for MMA. The work will involve the acquisition of a broad range of molecular and cellular biological techniques including tissue culture, flow cytomtery and enzymology.
66. How do cancer cells move in tissues?
Dr Don Newgreen
Embryology
Early Development and Disease
T 83416276
E don.newgreen@mcri.edu.au
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Dr Vincenzo Russo
Hormone Research
Early Development and Disease
T 93457931
E vince.russo@mcri.edu.au
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The conversion of stationary cells into migratory and invasive cells underlies many dramatic alterations of embryonic form during normal development. Genetically and molecularly similar events occur pathologically during carcinoma invasion: the difference being that these events are uncontrolled in the cancerous state. Most of our knowledge of cell migratory or invasive behaviour comes from experiments in a tissue culture dish. This project will examine the ability of neural crest-derived cancer cells to move in a real tissue environment by transplanting neuroblastoma cell lines into tissues of bird embryos which are known to support normal neural crest cell movement. These cells are labelled with Green Fluorescent protein, and sub-lines have mutations that affect cell movement in tissue culture. This project allows the consequences of these mutations to be tested in more realistic tissue context. This intra-embryonic transplantation technique has already revealed that cancerous cells can display surprising properties. For recent reviews (pdfs), email the above address.
67. Identification of novel Wilms tumor 1 (WT1) gene mutations in cancer.
Dr Elizabeth Algar
Cancer
Early Development and Disease
T 93456579
E elizabeth.algar@rch.org.au
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Dr Lin Rigby
Cancer
Early Development and Disease
T 93454360
E lin.rigby@mcri.edu.au
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A/Professor Paul Ekert
Cancer
Early Development and Disease
T 93455008
E paul.ekert@rch.org.au
|
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The Wilms tumor gene (WT1) is expressed in many different forms of human cancer. Mutations in the WT1 coding region predispose to the childhood kidney cancer, Wilms tumor, and are also found in acute myeloid leukaemia (AML) where they are associated with a poor response to chemotherapy. WT1 is a complex gene and numerous alternatively spliced transcripts, antisense transcripts and imprinted transcripts are expressed from the locus. This project will involve searching and characterising new mutations within novel WT1 transcripts and identifying methylation abnormalities in the WT1 locus in patients with Wilms tumor and acute myeloid leukaemia. Methods to be used will include high resolution melting for mutation screening, methylation-sensitive MLPA and methylation sensitive southern blotting, in addition to basic techniques in molecular genetics.
68. Investigating the role of altered methylation in schizophrenia
Dr Richard Saffery
Developmental Epigenetics
Early Development and Disease
T 83416341
E richard.saffery@mcri.edu.au
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Dr Jeff Craig
Developmental Epigenetics
Early Development and Disease
T 83416346
E jeff.craig@mcri.edu.au
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Despite the relatively high prevalence (approaching 1%) and devastating social and financial impact, there is presently no “objective†biological test to screen for Schizophrenia risk. The identification of SZ biomarkers is a crucial step towards improving current diagnosis, developing new presymptomatic treatments, identifying high-risk individuals and disease subgroups, and assessing the efficacy of preventative interventions at a rate that is not currently possible. In addition, the identification of brain-specific biomarkers of SZ has the potential to reveal valuable insights into the development of this disorder.
We have data demonstrating that, SZ cases have lower serum folate level than controls with altered epigenetic modification of specific genes in the prefrontal cortex compared to disease free brains.
We now aim to further characterise specific epigenetic biomarkers of SZ in post-mortem brain samples, to identify peripheral epigenetic biomarkers of SZ in blood; and to characterise the downstream functional consequences of this altered methylation profile.
69. Epigenetics and the interaction between folate and vitamin D metabolism at the fetomaternal interface
Dr Richard Saffery
Developmental Epigenetics
Early Development and Disease
T 83416341
E richard.saffery@mcri.edu.au
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Dr Jeff Craig
Developmental Epigenetics
Early Development and Disease
T 83416346
E jeff.craig@mcri.edu.au
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Dr Adam Balic
Surgical Research
Infection, Immunity and Environment
T 93454116
E adam.balic@hotmail.com
|
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The fetomaternal interface (placenta: decidua) represents a major site of accumulation of active vitamin D. However the exact role of this remains to be elucidated but may involve immune modulation, regulation of cell division, and/or maximal transfer of VitD to the developing fetus.
Recent data have demonstrated a role of epigenetic modification generally (and DNA methylation specifically) in the regulation of genes involved vitamin D metabolic enzymes that control vitamin D bioavailability and action. As one-carbon donors derived from maternal dietary folate are critical for the establishment of DNA methylation, we believe that sub-optimal circulating levels of vitamin D and folate may act cooperatively to alter vitamin D bioavailability in the developing pregnancy.
70. Is there an association between altered epigenetic profile in first trimester placenta with adverse pregnancy outcome?
Dr Richard Saffery
Developmental Epigenetics
Early Development and Disease
T 83416341
E richard.saffery@mcri.edu.au
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A/Professor Jane Halliday
Public Health Genetics
Laboratory and Community Genetics
T 83416260
E janehalliday.h@mcri.edu.au
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Dr Jeff Craig
Developmental Epigenetics
Early Development and Disease
T 83416346
E jeff.craig@mcri.edu.au
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The developing pregnancy is faced with substantial challenges, including a complete dependence on the placental ‘buffer’ for nutritional requirements, protection from adverse circulating maternal factors (such as cortisol), and isolation from the maternal immune system. Placental insufficiency has been linked to adverse outcomes of pregnancy loss, Intrauterine Growth Restriction (IUGR), premature delivery, and/or pre eclampsia. We have generated novel data for the specific epigenetic (DNA methylation-induced) silencing of several different metabolic pathway genes as part of human placentation. Given the demonstrated interplay between various environmental/dietary factors and altered epigenetic profile, we believe that disruption of this methylation in early development may play an important role in the aetiology of such conditions.
This project will examine DNA methylation profile of CVS and amniotic fluid samples taken as part of routine prenatal diagnostic procedures. Using routinely collected perinatal data on all births, it will be possible to determine if there is an association of aberrant epigenetic profile with adverse pregnancy outcome. This will then be matched with linked birth outcome data, to examine the association of aberrant epigenetic profile and adverse pregnancy outcome.
71. The role of Epigenetics in Paediatric Leukaemia development and outcome.
Dr Jeff Craig
Developmental Epigenetics
Early Development and Disease
T 83416346
E jeff.craig@mcri.edu.au
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Dr Nicholas Wong
Developmental Epigenetics
Early Development and Disease
T 83416205
E nick.wong@mcri.edu.au
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Dr Richard Saffery
Developmental Epigenetics
Early Development and Disease
T 83416341
E richard.saffery@mcri.edu.au
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Leukaemia is the most common form of cancer in children, accounting for over 30% of newly diagnosed cases. Most cases involved specific genomic rearrangements (translocations). However, these are neither sufficient nor absolutely necessary for disease development. Despite the fact that ~80% of cases are successfully treated by chemotherapy, the underlying causes of childhood leukaemia remain unclear and cannot be explained by genetic or environmental factors alone. Epigenetics is an emerging field examining the modulation of gene expression in the absence of underlying genetic change. We believe disruption of epigenetic profile could play a major role in the aetiology of paediatric leukaemia in conjunction chromosome translocations. This project will catalogue epigenetic changes at gene promoters from archived matched leukaemia and remission bone marrow samples in an attempt to identify changes in associated with development or outcome of specific leukaemia subtypes.
72. Folate supplementation, neurodevelopment and epigenetics
Dr Richard Saffery
Developmental Epigenetics
Early Development and Disease
T 83416341
E richard.saffery@mcri.edu.au
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Dr David Godler
Chromosome and Chromatin Research
Laboratory and Community Genetics
T 83416240
E david.godler@mcri.edu.au
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DNA methylation has been implicated in chromatin condensation, regulation of global transcriptional activity and nuclear organization. Folate is a principal methyl donor in the majority of biochemical reactions, and is an indirect substrate for S-adenosyl-L-methionine (SAM). Although folate deficiency can cause genome-wide DNA hypomethylation through depletion of SAM; limited folate intake has been also shown to induce silencing of many tumour suppressor genes, attributed to regional hypermethylation. To date the molecular relationship between these two paradoxical phenomena is unknown, however it indicates presence of a finely tuned regulatory mechanism of site-specific epigenetic changes affected by folic acid supplementation – a mechanism that is evident from our preliminary findings. Furthermore, there is ample evidence to suggest that these disturbances result in aberrant gene expression associated with abnormal neurodevelopment. This project aims to study the epigenetic bases behind the neurodevelopmental defects associated with folate over or under supplementation in a mouse model, with a longer-term view to extend the study to humans.
73. DEVELOPMENT OF THE HUMAN PLASMA PROTEOME
Dr Vera Ignjatovic
Haematology Research
Critical Care and Neurosciences
T (03)99366520
E verai@unimelb.edu.au
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Professor Paul Monagle
Haematology Research
Critical Care and Neurosciences
T (03)93455161
E paul.monagle@rch.org.au
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Major diseases such as cardiovascular disease, cancer and diabetes and their related mortality increase with age and are the major causes of death in the Australian population, as well as world-wide. As an example, cardiovascular disease related mortality for children is 3% compared with 40% for adults. This data indicates that children are in some way protected from serious disease outcomes. We want to improve the understanding of the mechanisms of this protection by focusing on the age-related differences in the plasma proteome. This has not been investigated to date and is what makes our study novel and highly clinically significant. With an increase in number of elderly Australians, the total burden of major diseases (cardiovascular, cancer, diabetes) is likely to increase significantly over the coming decades. Successful completion of this project will improve our understanding of the differences between children and adults, in particular the age of onset and proteins likely to be involved and will therefore increase the potential for prevention and decrease in burden of these age-related events in Australia and world-wide. The proposed study is only possible because of our ability to combine state of the art proteomic methodology with access to adequate samples from neonates, children and adults. The overall objective of this proposal is to determine the age-specific differences of the human plasma proteome in the healthy population in order to understand the implications of these differences in disease processes.
74. Epigenetic variation in newborn twins: effect of maternal diet and environment and underlying genetic make up.
Dr Jeff Craig
Developmental Epigenetics
Early Development and Disease
T 83416346
E jeff.craig@mcri.edu.au
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Dr Richard Saffery
Developmental Epigenetics
Early Development and Disease
T 83416341
E richard.saffery@mcri.edu.au
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Many chronic diseases have an environmental component, and can be influenced even by the environment experienced in the womb. We are searching for the factors that, during pregnancy, influence the epigenetic profile of the fetus and with this, the health of the individual at birth and in later life. We have established a cohort of mothers and their newborn twins and have collected maternal blood and various tissues (including cords, cord blood and placenta) from newborns. Maternal nutrition and other environmental factors will be measured in mothers and we will use state-of-the-art methods to analyse epigenetic markers in the twins. We are studying dizygotic twins to investigate the role dietary/lifestyle and genetic factors have on epigenetic variation of newborns. We are also studying monozygotic twins to investigate the extent to which the intra-uterine micro-environment induces the kinds of epigenetic change that have been shown to be associated with increased disease risk. This project will involve analysis of DNA methylation and will techniques such as locus-specific and genome-wide microarray analysis. The student will be working in a supportive environment of fifteen researchers skilled in all the required techniques.
75. Copy Number Variation of candidate genes in myopia
Dr Stefan White
Molecular Development
Early Development and Disease
T 83416426
E stefan.white@mcri.edu.au
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A/Professor Paul Baird
T 99298613
E pnb@unimelb.edu.au
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Candidate genes for susceptibility to myopia will be screened with Multiplex Ligation-dependent Probe Amplification (MLPA). This technique allows the detection of gene copy number in individuals, to ascertain if people who have myopia have zero copies, one copy, two copies, or three or more copies of a particular gene. Copy number is an exciting new aspect to genetic analysis, and it will allow us to investigate genes that are key players in myopia in a new light.
76. Analysis of candidate sex-determining genes in an avian model
Dr Craig Smith
Molecular Development
Early Development and Disease
T 83416353
E craig.smith@mcri.edu.au
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Professor Andrew Sinclair
Molecular Development
Early Development and Disease
T 83416424
E andrew.sinclair@mcri.edu.au
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Sex determination is a fundamental and fascinating developmental process common to all animals. In humans and other vertebrates, sex determination results in the differentiation of either testes or ovaries during embryogenesis. Mutations in the sex-determining pathway can lead to gonadal abnormalities, ambiguous genitalia and /or sex reversal at birth. Our research seeks to understand the molecular and cellular basis of human sex determination, and how mutations in key genes can lead to these abnormalities. While most groups studying sex determination and gonadal sex differentiation use the mouse embryo as a model system, we have been utilising the chicken embryo. The chicken embryo has a number of experimental advantages over traditional mammalian models. Fertile eggs are readily available and, because embryogenesis occurs outside the maternal body, gonadal development is very accessible to experimental manipulation. Furthermore, draft sequence of the chicken genome is now available. The chicken embryo therefore represents a powerful model for the analysis of sex determination and gonadal development. Our lab is a world leader using this organism model to study sex determination (recently published in Nature; Smith CA, et al., 2009). This project will analyse candidate sex-determining genes and cellular processes underlying gonadal differentiation in this model system. Both molecular and cell biology-based methods will be used to functionally analyse key candidate genes that we have already identified. Techniques include expression analysis (PCR, in situ hybridisation, immunofluorescence, etc.), cell and organ culture, and manipulation of candidate genes using expression-plasmids and avian retroviruses, and RNA interference technology.
77. Analysis of genes responsible for male germ cell development and germ cell tumours
Dr Patrick Western
Molecular Development
Early Development and Disease
T 83416353
E patrick.western@mcri.edu.au
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Professor Andrew Sinclair
Molecular Development
Early Development and Disease
T 83416424
E andrew.sinclair@mcri.edu.au
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Germ cells mediate passage of all genetic information to the offspring and lay the foundation for embryonic development. To achieve this the germ line must differentiate into highly specialised cells while maintaining complete developmental potency. Primordial germ cells are derived from the pluripotent epiblast and share features with embryonic stem cells, including the expression of core genes that regulate developmental potency. In mice, at embryonic day 12.5, the male germ line is specified from the primordial germ cells. These early male germ cells ultimately differentiate into the various components of the male germ cell lineage required for sperm production. However, occasionally differentiation of male germ cells fails, and the male germ cells retain undifferentiated fetal germ cell characteristics and establish tumours, which exhibit aberrant control of cell cycle and pluripotency. Over the past five years we have studied the molecular regulation of male germ cell specification and differentiation with particular focus on the control of cell cycle and pluripotency (Western et. al. 2005 Stem Cells 23:1436-1442; Maldonando-Saldivia et. al. 2007 Stem Cells 25:19-28; Western et. al. 2008 Stem Cells 26:339-347; van den Bergen et. al. 2009 Biology of Reproduction 81:362-70; Western 2009 International Journal of Developmental Biology 53:393-409). Our work shows that male germ line differentiation involves the suppression of pluripotency both at the transcriptional and post-transcriptional levels. Central to this differentiation process is the strict regulation of germ cell mitotic arrest, which is associated with activation of key regulatory components such as retinoblastoma, and cell cycle inhibitors p27 and p15. Using molecular techniques, such as micro-array screening of gene and micro-RNA expression, we have identified genes/micro-RNAs that are specifically regulated during the specification and early differentiation of male germ cells. These data are being used to further explore male germ cell differentiation and the regulation of germ cell tumour initiation and development in mice. Genes identified in the mouse system will then be analysed for mutations or aberrant expression in germ cells tumours of patients with testicular cancer. Our work involves the use of a wide range of state of the art molecular and genetic tools such as analysis of gene knock-outs, flow cytometry, organ/tissue culture, immuno-fluorescence, confocal microscopy, quantitative real time PCR.
78. Genes involved in Disorders of Sex Development: identification and regulation
Dr Stefan White
Molecular Development
Early Development and Disease
T 83416426
E stefan.white@mcri.edu.au
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Dr Thomas Ohnesorg
Molecular Development
Early Development and Disease
T 83416426
E thomas.ohnesorg@mcri.edu.au
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Professor Andrew Sinclair
Molecular Development
Early Development and Disease
T 83416424
E andrew.sinclair@mcri.edu.au
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Disorders of Sex Development (DSD), ranging in severity from genital abnormalities to complete sex reversal, are surprisingly common and as such represent a major paediatric concern. The cause of these problems is most often the failure of the complex network of genes that regulate development of testes or ovaries. Our research seeks to understand the molecular basis of testis and ovary development and how mutations in key genes can lead to abnormalities. Mutations in known genes explain 20% of DSD patients but we have no explanation for the remaining 80%. DNA samples from a large number of DSD patients with gonadal dysgenesis (XX males and XY females) have been collected, and we are currently applying a range of powerful methodologies to look for mutations in these patients. These techniques include screening for deletions and duplications using high-density microarrays and multiplex ligation-dependent probe amplification, and identifying sequence changes using high-throughput deep sequencing and DNA denaturation analysis. We are also currently studying regulatory elements controlling a range of genes involved in gonad differentiation. Methods that are being applied include DNaseI hypersensitivity analysis, Chromatin Immunoprecipitation and reporter assays. Other methods involved include cell culture, quantitative PCR and expression analysis.
79. Analysing synovial fluids from children with juvenile arthritis
A/Professor Amanda Fosang
Arthritis and Rheumatology
Musculoskeletal Disorders
T 83416466
E amanda.fosang@mcri.edu.au
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Ms Karena Last
Arthritis and Rheumatology
Musculoskeletal Disorders
T 83416431
E karena.last@mcri.edu.au
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Children with juvenile idiopathic arthritis (JIA) live with inflamed, swollen and painful joints. For some, the disease leads to permanent disability. There is no cure. Treatment of JIA is focused on pain relief, suppressing inflammation and musculoskeletal rehabilitation. There are no treatments for, nor routine analyses of the damage done to joint cartilage during JIA. Because it has no blood supply, cartilage has a poor capacity for self-repair and extensive damage to cartilage and joints can be irreparable.
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