1. Using children's genes in research
Dr Merle Spriggs
Ethics
Laboratory and Community Genetics
T 90905237
E merle.spriggs@mcri.edu.au
|
A/Professor Lynn Gillam
Ethics
Laboratory and Community Genetics
T 0417 536 785
E l.gillam@unimelb.edu.au
|
|
|
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, 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.
2. The ethics of surgically assigning sex to children
Dr Merle Spriggs
Ethics
Laboratory and Community Genetics
T 9090 5237
E merle.spriggs@mcri.edu.au
|
A/Professor Lynn Gillam
Ethics
Laboratory and Community Genetics
T 0417 536 785
E l.gillam@unimelb.edu.au
|
|
|
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.
3. Research, young people and the internet
Dr Merle Spriggs
Ethics
Laboratory and Community Genetics
T 9090 5237
E merle.spriggs@mcri.edu.au
|
A/Professor Lynn Gillam
Ethics
Laboratory and Community Genetics
T 0417 536 785
E l.gillam@unimelb.edu.au
|
|
|
Internet communities and personal webspaces are a rich source of qualitative data for health and social researchers. It is a particularly fertile source for those whose research areas involve children and young people. Although there is some guidance for conducting research online, there are no detailed or universally accepted ethics guidelines for research of homepages, blogs or webspaces such as MySpace. Questions that arises are – “If MySpace is a public webspace, can research be done without consent?†“If it is thought that consent should be obtained, how should it be obtained in this context?†Most teenagers use the internet without parental supervision and generally, researchers can use information that is in the public domain without obtaining consent. On the internet however, what is public and what is private is not so clear. Added to this, are the difficult issues around consent in research involving children and young people. In the context of research, children and young people are considered to be a vulnerable population requiring special protection such as consent from a parent or guardian. The immature judgment of some young people may also mean that a distinction between private and public is not meaningful. This project will investigate and analyse the ethical issues, especially consent issues in research involving internet spaces in which children or young people participate. The precise topic and the methods used can be negotiated with the supervisors
4. Establishing whether the gene polymorphism responsible for Crohns disease in the mouse has a role in promoting human inflammatory bowel disease.
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
|
|
|
The human inflammatory bowel diseases, 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 a new mouse model of Crohns disease by screening mice derived from an ENU mutagenesis screen at the Australian Phenomics Institute in Canberra. The Crohns disease mouse has a single point mutation, and mapping studies which will pin-point the gene responsible are almost complete. The aim of this project will be to characterize the gene mutation, develop a genotyping assay to detect it and to work out how a polymorphism in the affected gene causes inflammation-associated pathology. A further aim of this project is to determine if the affected mouse gene is also mutated in humans. In collaboration with A/Prof Ian van Driel (BIO21).
5. Genes which prevent cancer development: how gastrokine 2 (GKN2) acts as a tumour suppressor gene.
Dr Trevelyan Menheniott
Gastrointestinal Research in Inflammation and Pathology (GRIP)
Infection, Immunity and Environment
T 99366502
E treve.menheniott@mcri.edu.au
|
Professor Andrew Giraud
Gastrointestinal Research in Inflammation and Pathology (GRIP)
Infection, Immunity and Environment
T 83416446
E andrew.giraud@mcri.edu.au
|
|
|
Gastric cancer is the second biggest cause of cancer mortality in the world. It is caused mainly by 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 cancer development. Moreover, H. pylori infection, which promotes gastric ulceration, inflammation and cancer, 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.
6. The role of IL-11 in promoting the gastric cancer phenotype.
Dr Louise Judd
Gastrointestinal Research in Inflammation and Pathology (GRIP)
Infection, Immunity and Environment
T 99366501
E lmj@unimelb.edu.au
|
Dr Trevelyan Menheniott
Gastrointestinal Research in Inflammation and Pathology (GRIP)
Infection, Immunity and Environment
T 99366502
E treve.menheniott@mcri.edu.au
|
|
|
We have recently established that IL-11 is the most important cytokine driving gastric tumour development in our mouse model of gastric cancer, and importantly that increased expression is associated with human gastric adenocarcinoma development. 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.
7. Tumour associated macrophages and gastric 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
|
|
|
We know that tumour associated macrophages play a key role in promoting tumour growth in a number of different cancers, however very little is known of these cells in the development and progression of gastric cancer. Out lab is uniquely placed to study gastric cancer with a well characterized mouse model, the FF model that develops cancer dependent on the activation of the oncogenic transcription factor STAT3. In this model the presence of macrophages in the stomach is crucial for cancer development. Recently we have developed systems in the FF model to specifically reduce activation of STAT3 in macrophages. The aims of this project are twofold, the first is to analyse the phenotype of these macrophages in vitro to determine how crucial STAT signaling is to cell function and the second will examine the gastric tumour outcome in the FF mice that lack the ability to signal through STAT3 in macrophages.
8. 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 61-3-8341 6322
E paul.lockhart@mcri.edu.au
|
A/Professor Martin Delatycki
Genetic Health Research (Bruce Lefroy Centre)
Laboratory and Community Genetics
T 61-3-8341 6284
E martin.delatycki@ghsv.org.au
|
|
|
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 to characterise the phenotype of the mouse and determine the molecular function of the gene involved.
9. 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
|
|
|
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 neurons 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 performed a 2-hybrid screen and identified several proteins that interact with TorsinA. The aim of this project is to further characterise these interacting proteins and investigate their contribution to the disease phenotype. The project will involve a range of molecular and cellular techniques, initially utilising cellular models. In addition, we have established colonies of transgenic mice with specific defects in the TorsinA gene. These mice will allow us to identify the molecular pathways disrupted during disease and provide the means to develop and test novel therapeutic treatments.
10. 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
|
Professor KH Andy Choo
Chromosome and Chromatin Research
Laboratory and Community Genetics
T 83416306
E andy.choo@mcri.edu.au
|
|
|
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.
11. 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
|
Professor KH Andy Choo
Chromosome and Chromatin Research
Laboratory and Community Genetics
T 83416306
E andy.choo@mcri.edu.au
|
|
|
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.
12. Gene regulation studies of the Friedreich ataxia locus
Dr Joseph Sarsero
Genetic Health Research (Bruce Lefroy Centre)
Laboratory and Community Genetics
T 8341-6285
E joe.sarsero@mcri.edu.au
|
A/Professor Martin Delatycki
Genetic Health Research (Bruce Lefroy Centre)
Laboratory and Community Genetics
T 8341-6284
E martin.delatycki@ghsv.org.au
|
|
|
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. An understanding of FXN gene regulatory mechanisms may enable upregulation of FXN expression as a form of therapy for FRDA. Our laboratory has been undertaking the identification of long-range cis-acting regulatory elements controlling human FXN gene expression by: i) the targeted deletion of conserved non-coding sequences in an FXN-EGFP genomic reporter construct, and ii) the generation of nested deletions of DNA sequences upstream of the FXN gene fused to a reporter gene. This project will build on our current findings and further delineate regions involved in FXN gene regulation. The project will involve a range of molecular and cellular techniques.
13. Epigenetic factors in Friedreich ataxia
Dr Joseph Sarsero
Genetic Health Research (Bruce Lefroy Centre)
Laboratory and Community Genetics
T 8341-6285
E joe.sarsero@mcri.edu.au
|
A/Professor Martin Delatycki
Genetic Health Research (Bruce Lefroy Centre)
Laboratory and Community Genetics
T 8341-6284
E martin.delatycki@ghsv.org.au
|
|
|
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. Evidence suggests that the mutation may induce epigenetic changes and heterochromatin formation, thereby impeding gene transcription. This project will examine the correlation between the age of onset and severity of disease symptoms with the size of the GAA expansions, transcript levels, the amount of residual frataxin produced, and DNA methylation patterns. The project will involve a range of molecular and cellular techniques including PCR, real-time RT-PCR, western blot, lateral flow (dipstick) immunoassays and bisulfite sequencing. These studies are expected to contribute new insights into the mechanisms involved in mediating gene silencing in FRDA.
14. Folate supplementation, neurodevelopment and epigenetics
Dr Richard Saffery
T 8341 6341
E richard.saffery@mcri.edu.au
|
Dr David Godler
T 8341 6307
E david.godler@mcri.edu.au
|
|
|
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.
15. Epigenetics of mammalian germ and stem cell development
Dr Jeffrey Mann
Stem Cell Epigenetics
Laboratory and Community Genetics
T 9936 6516
E jeff.mann@mcri.edu.au
|
|
|
|
The health of reproductive stem cells can be measured by genetic integrity, that is, are there mutations in the DNA code which can lead to congenital abnormalities? Also, their health can be measured by epigenetic integrity, epigenetics being the overlying system of regulatory controls of genes or DNA sequence. Germ cells are unique in undergoing a large scale rebuilding of their epigenetic architecture, in preparation for their own unique developmental programme, and for the developmental programme of the fertilised egg. In doing so, mistakes can be made (epimutations), and these can be as severe in consequence as genetic mutations. The aim of our research is to find out more about how and why reproductive stem cells undergo this large scale rebuilding of epigenetic systems. Also, how mistakes are made in this process, and how these may affect the development of germ cells and embryos. Please contact Jeff Mann for further information on specific projects.
16. Identification of genes involved in disorders of sexual development
Professor Andrew Sinclair
Molecular Development
Early Development and Disease
T 83416424
E andrew.sinclair@mcri.edu.au
|
Dr Stefan White
Molecular Development
Early Development and Disease
T 83416426
E stefan.white@mcri.edu.au
|
|
|
Intersex disorders, 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 intersex cases but we have no explanation for the remaining 80%. DNA samples from >50 sex-reversed 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.
17. Identification and classification of elements regulating genes involved in gonadal differentiation
Professor Andrew Sinclair
Molecular Development
Early Development and Disease
T 83416424
E andrew.sinclair@mcri.edu.au
|
Dr Stefan White
Molecular Development
Early Development and Disease
T 83416426
E stefan.white@mcri.edu.au
|
Dr Thomas Ohnesorg
Molecular Development
Early Development and Disease
T 83416426
E thomas.ohnesorg@mcri.edu.au
|
|
Intersex disorders, 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. However, we understand relatively little of this regulatory network. Our research seeks to understand the molecular basis of testis and ovary development and how key genes are regulated. We are currently studying regulatory elements controlling a range of genes involved in gonadal 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.
18. 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
|
A/Professor Joe Smolich
Heart Research
Critical Care and Neurosciences
T 93454571
E joe.smolich@mcri.edu.au
|
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, genetics 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.
19. Dissecting Survival And Apoptosis Pathways In Myeloid Cells
A/Professor Paul Ekert
Cancer
Early Development and Disease
T 93455008
E paul.ekert@rch.org.au
|
Dr Anissa Jabbour
Cancer
Early Development and Disease
T 93455835
E anissa.jabbour@mcri.edu.au
|
|
|
Growth and survival of haemopoietic cells is regulated by growth factors such as Interleukin-3 (IL-3). When IL-3 is removed, dependent cells kill themselves by a mechanism that can be regulated by the Bcl-2 family of apoptosis regulators. The genes that regulate this process are likely to be important in the development of leukaemia since leukemic cells acquire the ability to survive and proliferate independently of growth factors. We have identified members of the Bcl-2 family that are required for apoptosis to occur in the absence of IL-3 and also genes that couple growth factor signalling to the survival of haemopoietic cells. Some of these genes do, as predicted, have important roles in myeloid leukaemia. The projects in the laboratory seek to determine how growth factors promote cell survival, and how the genes we have identified are regulated by growth factor signalling. The projects will provide students 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.
20. The role of saturated and unsaturated fatty acids in the development of childhood obesity, and subsequent risk of Type 2 diabetes.
Dr Matthew Sabin
Hormone Research
Early Development and Disease
T 93456986
E matthew.sabin@mcri.edu.au
|
Dr Vincenzo Russo
Hormone Research
Early Development and Disease
T 93457931
E vince.russo@mcri.edu.au
|
Professor George Werther
Hormone Research
Early Development and Disease
T 93455951
E george.werther@rch.org.au
|
|
Childhood obesity is increasing in prevalence and is associated with insulin resistance and Type 2 diabetes in susceptible individuals. At the MCRI, we have recently developed a major cross-theme research group (http://www.mcri.edu.au/projects/m-powr/default.asp) to investigate the questions of: which children are most at risk of developing obesity, and which are then most likely to develop co-morbidities?
Insulin resistance is known to be an important factor in the predisposition to future disease in obese individuals. The effect of different dietary factors on the development of insulin resistance in childhood is, however, extremely difficult to investigate in large populations of children, due to so many other confounding factors. We have therefore developed a unique juvenile pig model with which to assess dietary influences on adiposity/insulin resistance.
The first of these studies has recently been completed with pigs fed (from weaning) different dietary fats and sugar. All tissue samples and bloods have been obtained and samples are cryopreserved and ready for analysis. There will therefore be no delay in obtaining ethics/obtaining samples for this project.
Specifically, we hypothesise that juvenile pigs fed saturated fats will become centrally obese and insulin resistant, whilst pigs fed unsaturated fats will become generally obese and not insulin resistant. The role of increased sugar in the diet in these processes is unknown. Adipose tissue biopsies will be examined for the relative mRNA concentrations of Fatty Acid Synthase and Stearoyl CoA Desaturase (major enzymes controlling lipogenesis) and muscle samples will be analysed for factors important in insulin signalling. These data will demonstrate, along with the body composition data and measures of insulin sensitivity (already measured using DEXA and hyperinsulinaemic euglycaemic clamps respectively), how diets in early life impact upon future risk of obesity and Type 2 diabetes.
The successful applicant will be involved in the whole process from decision-making (e.g. choice of analyses), to undertaking laboratory work and assisting in the writing of publications & data presentation.
21. Growth Factor CheckPoints in Neuroblastoma Cells Tumorigenesis: Cellular and Molecular Mechanisms
Dr Vincenzo Russo
Hormone Research
Early Development and Disease
T 93457931
E vince.russo@mcri.edu.au
|
Professor George Werther
Hormone Research
Early Development and Disease
T 93455951
E george.werther@rch.org.au
|
|
|
Neuroblastoma is a common and devastating childhood cancer, highly invasive and resistant to treatment. Cells derived from these tumours are undifferentiated aggressive and disseminating. By modulating the growth factor environment of these cells we have discovered a number of critical genes involved in arrested differentiation, proliferation and motility of neuroblasts. The products of these genes control key cell cycle checkpoints, intracellular signaling and the activation of modulators of the extracellular matrix. We aim to dissect further these cellular and molecular mechanisms, particularly those related to the cell cycle and growth factor / cytokine signaling and reorganization of the extracellular matrix.
The methodological approach includes: cell cycle analysis by FACS; RNA extraction & molecular hybridisation (real time PCR and gene-array): functional gene analysis with validated siRNA: nuclear extracts and gel shift assay (EMSA); cell extracts, receptor activation and signaling pathway analysis (immunoblotting, phospho- protein, pathway inhibitors, etc): signaling-protein interactions using wild type and mutated signaling molecules. This project is designed for Ph.D. candidates (3 years), however part of these studies are suitable to be developed as Hons projects (1 year).
22. Major or minor birth defects? Hospitalisations as a measure of morbidity.
A/Professor Jane Halliday
Public Health Genetics
Laboratory and Community Genetics
T 83416260
E jane.halliday@mcri.edu.au
|
Ms Evelyne Muggli
Public Health Genetics
Laboratory and Community Genetics
T 83416291
E evi.muggli@mcri.edu.au
|
|
|
The project will utilise an administrative dataset to identify cases with one of two selected birth defects and follow their hospitalisation patterns over time. This will give us the opportunity to monitor the impact of these conditions over the course of the children’s lives. The results of this study will provide us with important information to inform health policy, better plan for services and direct future research on the clinical management of these children.
Two examples of birth defects to be studied:
• Hypospadias are among the most common birth defects of the male genitalia, involving an abnormally placed urinary opening. While hypospadias is generally considered a ‘mild’ birth defect, there are degrees of severity and the impact of this condition on the course of a child’s life is not well documented. The prevalence of hypospadias in male babies is 40 per10,000.
• Tetralogy of Fallot (TOF) is a congenital heart defect, involving three to four anatomical abnormalities. TOF is the most common cause of the cyanotic ‘blue baby’ syndrome. Total surgical repair is possible, but surgical success and long-term outcome vary and lifetime follow-up is necessary. TOF occurs in approximately 3-6 births per 10,000.
23. Helping broken bones heal
A/Professor Amanda Fosang
Arthritis and Rheumatology
Musculoskeletal Disorders
T 83416466
E amanda.fosang@mcri.edu.au
|
Dr Kumara Kaluarachchi
Arthritis and Rheumatology
Musculoskeletal Disorders
T 83416431
E kumara.kaluarachchi@mcri.edu.au
|
Ms Stephanie Gauci
Arthritis and Rheumatology
Musculoskeletal Disorders
T 83416431
E steph.gauci@mcri.edu.au
|
|
The cost of skeletal fractures to society is monumental and any improvement in the rate or extent of fracture healing will produce an enormous socioeconomic benefit. When bones fracture, blood from the bone and surrounding tissue forms a clot, which is invaded by fibroblasts and cartilage progenitor cells. The next phase of repair is the formation of a soft cartilage callus that stabilises the fractured bone. Gradually this soft callus is mineralised and the cartilage template is resorbed and replaced by woven bone, and finally by mature lamellar bone. This project will focus on the cartilage callus. Very little is known about how the callus is resorbed and replaced, yet without this process the bone cannot heal. We have developed a mutant mouse strain with a genetic defect in cartilage remodelling. The mice are unique in the world and are ideally suited to the study of callus formation and bone repair. The project will use an in vivo fracture model to identify mechanisms critically important for bone healing. The study aims to identify molecules and/or pathways that can be developed as therapies for improving the rate and quality of bone healing in fractures.
top of page
![The University of Melbourne [logo]](/template-assets-custom/images/custom_logo_crest_comb.gif){kind=logo}
