Please come to our Information Night on:
Thursday 16 September 2010
4.00pm – 6.00pm
Ella Latham Theatre, Royal Children’s Hospital
Biomedical Research PhD Projects in Child & Adolescent Health offered during 2010
Please note that the project list will be updated regularly with new projects and opportunities.
Please contact the supervisors directly to arrange an appointment as soon as possible to discuss the projects further.
- Food Allergy
- Food Allergy in School-Aged Children
- The role of Epigenetics in Paediatric Leukaemia development and outcome.
- Diagnostic procedures for imputation models in incomplete data analysis
- Parsing early onset depressive disorders in children and adolescents
- You are what your mothr ate? Epigenetic variation in newborn twins: effect of maternal diet and environment and underlying genetic make up
- Understanding neurodevelopmental outcomes of late preterm neonates using magnetic resonance imaging
- Understanding motor development in the very preterm child using diffusion magnetic resonance imaging
- The effects of prematurity on the visual system of children born preterm
- Understanding brain development of extremely preterm adolescents using diffusion magnetic resonance imaging
- Neuropathogenic mechanisms of mitochondrial dysfunction
- Determining cord blood stem cells with cardiac fate for the repair of congenital myocardial dysfunction
- Cardiac molecular signaling mechanisms in survival adaptation to hypoxia and post-operative stress recovery
- Cardiac molecular signaling mechanisms during the progression of heart failure
- Probiotic and Peanut Oral Immunotherapy (P-POIT) for the Treatment of Peanut Allergy
- Childhood Arthritis – the role of epigenetics in determining risk of disease
- Molecular characterisation of Bacterial Vaginosis
- Atopic disorders and children’s psychosocial wellbeing
- The molecular signalling pathways that cause osteoarthritis
- The contribution of protein misfolding (“unfolded protein response”) to inherited cartilage and bone disease
- TRPV4 and skeletal development
- Collagen VI and WARP interactions during neurological development
| A/Professor Katie Allen T +61 3 9345 5060 E |
Dr Nick Osborne T 90905260 E |
Peanut allergy has been reported to be increasing in industrialised countries. Children with IgE-mediated food allergies such as peanut allergy are at risk of life-threatening episodes of anaphylaxis. Along with obesity, atopy has been touted as the new epidemic of the 21st century. This project aims to examine the epidemiology of food allergy in a large cohort of Melbourne children. The primary goal will be to catalogue the prevalence of peanut allergy in the community and measure if there are modifiable factors that can alter this prevalence. As up to 20% of individuals develop tolerance to food allergy, a secondary focus of this project will be to elucidate what mechanisms promote tolerance to foods. Infants who are 12-month-old and pre-peanut ingestion will be recruited from the community at vaccination sessions in and across metropolitan Melbourne via council-led immunisation clinics. Skin prick test for food allergens will be administered and a questionnaire completed. Children with positive skin prick tests will be invited to attend the Royal Children’s Hospital to be offered an inpatient-based food challenge to confirm whether the infant has true peanut allergy. Other genetic and biochemical analyses will be undertaken as potential markers to predict allergy or development of tolerance.
2. Food Allergy in School-Aged Children
| A/Professor Katie Allen T 9345 5060 E |
Dr Nick Osborne T 90905260 E |
Childhood food allergy has become a major public health problem and the apparently rising incidence of food allergy is magnified by the devastating but extremely rare sudden death of a healthy child. There is considerable uncertainty surrounding the resolution of food allergy by adolescence. We know that some children with food allergy will grow out of it before adolescence. However the proportion that outgrows an allergy, and the factors that predict this, are not known. A second area of uncertainty concerns the paradox that while anaphylaxis related to food allergy is most prevalent in children under 5 years it poses a far greater risk of death to adolescents, accounting for two of every three anaphylaxis deaths. We aim to determine the prevalence of, and environmental risk factors for food allergy, and to characterise co-existing atopic manifestations (asthma, hayfever & eczema) in childhood and adolescence; and to identify knowledge about and attitudes to food allergy and anaphylaxis in both allergic and non-allergic school children during the transition from primary to secondary school. We also aim to examine amongst those school children aged 10-14 years identified with self-reported food allergy to assess the diagnostic positive predictive values of skin prick test for food allergy. This study has the potential to have a significant impact on public health policy regarding the prevention and management of allergy and anaphylaxis in schools.
3. The role of Epigenetics in Paediatric Leukaemia development and outcome.
| Dr Nicholas Wong T 8341 6205 E |
Dr Richard Saffery T 8341 6341 E |
| Dr Jeff Craig T 8341 6346 E |
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.
4. Diagnostic procedures for imputation models in incomplete data analysis
| Professor John Carlin T 93456363 E |
Dr Katherine Lee T 93456549 E |
Multiple imputation (MI) is an increasingly popular statistical method for managing incomplete data in the analysis of epidemiological studies. Analysis using MI requires the use of statistical models to obtain predicted or imputed values for missing observations, and the validity of the results depends on these models being sensible and providing a good fit to the data. As part of a larger research program on multiple imputation methods, this project will develop and evaluate new approaches to the diagnostic checking of imputation models. The development will be based primarily on the concept of posterior predictive checking, which essentially involves comparing the completed data (in the MI case including both observed and imputed values) to replicated complete datasets under the MI model. The project will emphasise a related practical approach to model checking within MI, involving comparison of the distribution of the observed and imputed values for each variable that is subject to missingness. We believe that more or less automatic graphical model-checking scans will be an important addition to existing and future packages that perform MI. Methods will be subject to evaluation using simulation studies and case study examples. The candidate will require a strong background in mathematical statistics and preferably some knowledge of epidemiology and health research.
5. Parsing early onset depressive disorders in children and adolescents
| A/Professor Alasdair Vance T 93454666 E |
Early onset depression in late childhood and early adolescence mainly comprises dysthymic disorder and major depressive disorder, alone and in combination. This project aims to investigate the cognitive difficulties and neural networks that underpin both these early onset depressive disorders. In addition, VBM structural imaging techniques will help us identify brain regional differences in grey and white matter volume that are associated with these disorders, alone and in combination. Key associations with depressive symptoms and suicidal ideation and/or attempts will be explored.
| Dr Jeff Craig T 83416346 E |
Dr Richard Saffery T 83416341 E |
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. Epigenetic factors modify gene structure and function without changing DNA sequence; they are reversible and can be influenced by the environment. 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 are being used in state-of-the-art methods to analyse epigenetic markers in the twins. We are also studying ‘identical’ (monozygotic) twins to assess epigenetic variation at birth independent of genetic variation and to pinpoint the genes associated with low birth weight, which is associated with predisposition to complex disease. Our study also includes fraternal (dizygotic) twins, which can help shed light on the role that dietary/lifestyle and genetic factors have on epigenetic variation of newborns. This project will involve analysis of DNA methylation and/or histone modification and will involve genome-wide microarray analysis. The student will be working in a supportive environment of ten researchers skilled in all the required techniques. Current PhD students have travelled overseas to present their work and published in high impact journals.
| Dr Deanne Thompson T 93454830 E |
Ms Jeanie Cheong T 83453771 E |
| Dr Peter Anderson T 93454830 E |
Neurodevelopment of late preterm infants born between 32 to 36 weeks' gestational age has not been extensively studied, even though there is evidence to suggest that such infants have neurobehavioural and educational difficulties in comparison to their term-born peers. The aim of this study (LaPrem) of late preterm infants is to compare quantitative MRI characteristics of late preterm and healthy term-born infants at term equivalent age. Volumetric analyses of brain tissues such as gray and white matter will be performed, as well as segmentation of the frontal, temporal, parietal and occipital lobes, cerebellum and hippocampus. Diffusion MRI will be used to obtain measures of microstructural integrity, and the connectivity of various white matter bundles will be estimated using advanced MRI processing techniques such as tractography. Comprehensive neurobehavioural assessments will also be performed on these infants in order to assess the consequences of late preterm birth.
| Dr Deanne Thompson T 93454830 E |
Ms Jeanie Cheong T 83453771 E |
| Dr Peter Anderson T 93454830 E |
Up to 50% of preterm infants born <30 weeks gestational age or <1250g birth weight display either severe motor deficits such as cerebral palsy, or milder forms of motor impairment known as developmental coordination disorder (DCD). Tractography is a diffusion MRI processing technique that can provide a virtual 3D representation of the white matter fibre tracts, such as the sensorimotor pathways. The aim of this study is to use tractography to assess the connectivity and microstructural integrity of the corticospinal tracts in 7 year old children born preterm from the Victorian Infant Brain Studies (VIBeS) cohort, compared with healthy term-born children. Perinatal causes and functional consequences for alterations to the corticospinal tracts will also be assessed.
9. The effects of prematurity on the visual system of children born preterm
| Dr Deanne Thompson T 93454830 E |
Dr Rod Hunt T 93456265 E |
| Dr Peter Anderson T 93454830 E |
One of the many potential difficulties very preterm infants born <30 weeks gestational age or <1250g birth weight face is disruption to visual development. The integrity of the visual pathways is able to be assessed using diffusion MRI. Specifically, tractography is a technique that can provide a 3D virtual representation of the visual tracts, and diffusion measures are able to estimate the axonal integrity and degree of myelination within the white matter tract. The aim of this study is to use diffusion MRI to assess the connectivity and integrity of the visual pathways of 7 year old children born preterm from the Victorian Infant Brain Studies (VIBeS) cohort, compared with healthy term-born children. Perinatal causes and functional consequences for alterations to the visual tracts will also be assessed.
| Dr Deanne Thompson T 93454830 E |
Professor Lex Doyle T 83453716 E |
| Ms Jeanie Cheong T 83453771 E |
Dr Peter Anderson T 93454830 E |
The Victorian Infant Collaborative Study (VICS) has been following the neurodevelopment of extremely preterm infants born in 1991-1992. This adolescent cohort is currently undergoing MRI scans. Opportunity exists for a student to investigate various neural networks that are commonly affected by prematurity, using diffusion-weighted neuroimaging techniques such as 3-D white matter tractography. Quantitative diffusion MRI techniques enable insight into the connectivity of white matter fibres, and microstructural integrity of axons and myelin.
11. Neuropathogenic mechanisms of mitochondrial dysfunction
| Dr Ann Frazier T 83416287 E |
A/Professor David Thorburn T 83416235 E |
Mitochondrial dysfunction causes a range of early-onset neurological conditions and contributes to neurodegenerative conditions such as Parkinson Disease. The mechanisms of neuronal damage are unknown, and the study of these at a cellular level may lead to improved treatment and greater understanding of the role of both nuclear- and mitochondrial-DNA mutations in both rare and common conditions. This project will focus on complex I deficiency, the most common mitochondrial respiratory chain defect. Multiple parameters will be addressed in both primary and established cell culture models, using techniques in fluorescent microscopy and cell biology, as well as biochemistry and molecular biology. Previous studies of these parameters have mostly focused on easily obtained tissue and cell samples from patients, yet these are not necessarily relevant for understanding the neuropathology of mitochondrial disease. Therefore, this project will use cell culture models that more closely reflect neuronal function to study possible mechanisms of neuronal damage. These include: 1. Primary neuronal and astrocyte cell cultures established from mouse models with complex I deficiency resulting from mutations in different nuclear encoded complex I subunits. 2. Patient fibroblast cell lines converted to relevant neuronal lineages using iPS cell technology.
| Dr Salvatore Pepe T 93454114 E |
Dr Ngaire Elwood T 93456398 E |
| Dr Christian Brizard T 93455200 E |
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.
| Dr Salvatore Pepe T 93454114 E |
Dr Michael Cheung T 93455714 E |
| Professor Igor Konstantinov T 93455200 E |
Dr Freya Sheeran T 93454762 E |
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.
14. Cardiac molecular signaling mechanisms during the progression of heart failure
| Dr Salvatore Pepe T 93454114 E |
Dr Freya Sheeran T 93454762 E |
| A/Professor Joe Smolich T 93454571 E |
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.
15. Probiotic and Peanut Oral Immunotherapy (P-POIT) for the Treatment of Peanut Allergy
| A/Professor Mimi Tang T 93455911 E |
Dr Paul Licciardi T 93455554 E |
Food allergy is a major public health problem of childhood. 5-8% of children have food allergy, and more than 1 in 70 have peanut allergy. Peanut allergy is of particular concern as a substantial proportion of reactions are life-threatening anaphylaxis, allergy is usually lifelong, and peanut is the most common cause of death due to food anaphylaxis. A promising new treatment approach is the combined administration of a probiotic adjuvant with peanut oral immunotherapy (P-POIT). Our pilot studies show that oral immunotherapy is safe when administered within a careful regimen, is well accepted, and shows preliminary evidence of efficacy with reduced peanut specific IgE and increased peanut specific IgG4. The probiotic Lactobacillus rhamnosus GG has immunomodulatory effects that are expected to enhance the tolerogenic potential of oral immunotherapy.
16. Childhood Arthritis – the role of epigenetics in determining risk of disease
| Dr Justine Ellis T 83416311 E |
Dr Jeff Craig T 83416346 E |
The factors that lead to development of arthritis in childhood (juvenile idiopathic arthritis - JIA), are currently largely unknown. However, this disease can have devastating effects, not only due to the pain and disability that is experienced, but also by affecting normal growth and development. It is believed that JIA is caused by a combination of genetic and environmental factors, and these are the focus of research within our CLARITY JIA Biobank. A potential risk factor yet to be considered in relation to JIA is that of epigenetic variation. In this project we will consider the question of whether differences in methylation occur across the genome when DNA from JIA patients and healthy control children are compared. We shall use data obtained from genome-wide methylation arrays to look for potential points of difference, then follow up this hypothesis-generating data by conducting in depth analyses if specific genes that appear differentially methylated. The project will potentially involve exposure to patient recruitment, biospecimen processing, cell isolation and sorting, DNA extraction, PCR, methylation analysis using the Sequenom MassARRAY system, bioinformatic and statistical approaches to data analysis.
17. Molecular characterisation of Bacterial Vaginosis
| A/Professor Sepehr Tabrizi T 83453672 E |
Dr Jimmy Twin T 83453679 E |
Bacterial Vaginosis (BV) is a condition due to imbalance in natural flora of vagina where native Lactobacillus spp. microflora of the human vagina is depleted, and replaced by an overgrowth of mixed bacteria. BV is a common condition, and studies have shown it affects 10-30% of women in countries such as the United Kingdom and United States. BV may cause symptoms of an abnormal vaginal discharge or odour. However, more than half the women with BV do not have any symptoms. In most women BV has no complications, but it can cause miscarriage, premature birth and pelvic infections, and can increase a woman’s risk of getting sexually transmitted infections. The current recommended treatment for BV is with antibiotics, either 7 days of metronidazole tablets by mouth or 7 days of a vaginal clindamycin cream. Studies have shown that these treatments cure 70-80% of women within a month; however, up to half experience subsequent episode of BV within 6 months of treatment. The etiology of why this imbalance to vaginal flora occurs is unknown. The Bacteria Associated/Related Vaginosis Ecology (BRAVE) study aims to understand what types of microorganisms are present in the vaginal discharge that occurs during BV. This includes bacteria, yeast and viruses. This will be carried out using modern molecular methods, such as quantitative PCR (qPCR) targeting known organisms associated with BV, and next-generation sequencing (NGS) to characterise the entire microbial ecology of select samples. In addition, small chemical compounds known as metabolites will be analysed with the aim of developing a more accurate diagnostic test and developing the basis of a systems biology approach to understanding BV and how it develops and progresses.
18. Atopic disorders and children’s psychosocial wellbeing
| Dr Nick Osborne T 90905260 E |
A/Professor Jan Nicholson T 93456650 E |
Allergy and atopic disorders, along with obesity has been touted as the new epidemic of the 21st century. A documented increase in psychosocial stress has also occurred in a similar timeframe. Children with IgE-mediated food allergies such as peanut allergy are at risk of life-threatening episodes of anaphylaxis. This project aims to examine the association of psychosocial factors with allergy and eczema in a large cohort of Australian children, the Longitudinal Study of Australian Children (LSAC). The primary goal will be to catalogue the prevalence psychological morbidity/risk factors among children, and parents of children with atopic disease in the community and measure if there are modifiable factors that can alter this prevalence. As up to 20% of individuals develop tolerance to food allergy, and a large proportion outgrow eczema, a secondary focus of this project will be to elucidate what mechanisms promote tolerance to foods or dissipation of eczema symptoms. A third line of enquiry would look at the effects of atopic disease on the metal health of children and parents. The data has been collected on two cohorts of over 4,000 children from 1999, aged between 0-1 years up to 8-9 years from a representative sample of the Australian population with strong spatial diversity. LSAC is an ongoing study with further data being collected at present.
19. The molecular signalling pathways that cause osteoarthritis
| Professor John Bateman T 83416422 E |
Dr Richard Wilson T 93456601 E |
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.
| Professor John Bateman T 83416422 E |
Dr Richard Wilson T 93456601 E |
| Mr Trevor Cameron T 93456602 E |
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.
21. TRPV4 and skeletal development
| Dr Shireen Lamande T 83416465 E |
Professor John Bateman T 83416422 E |
| Ms A Graham T 83416412 E |
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. We are developing a knockin mouse carrying a disease causing Trpv4 mutation and this project will also involve characterising the skeletal phenotype in this mouse model. We are also interested in understanding the signalling pathways downstream of Trpv4 activation that are altered by mutations and will identify candidate pathways using gene expression microarrays and identifying proteins that interact with Trpv4 and are important for its function.
22. Collagen VI and WARP interactions during neurological development
| Dr Shireen Lamande T 83416465 E |
Professor John Bateman T 83416422 E |
WARP is a recently identified extracellular matrix molecule with expression restricted to permanent cartilages and a distinct set of basement membranes in peripheral nerves, muscle, and the central nervous system vasculature. WARP knockout mice are healthy, viable, and fertile with no overt abnormalities; however, they have a significantly delayed response to acute painful stimulus and impaired fine motor coordination, suggesting compromised peripheral nerve function. WARP interacts with the extracellular matrix protein collagen VI and the collagen VI microfibrillar network is severely reduced and mislocalised in peripheral nerves of WARP knockout mice. Collagen VI is broadly distributed and mutations in humans cause muscular dystrophy. Other tissues such as cartilage, bone and tendons are also affected although these phenotypes have been poorly defined. Our data suggests that collagen VI may also be important in peripheral nerves and this project will define the role of collagen VI in the nervous system using collagen VI knockout mice, WARP knockout mice and collagen VI/WARP double knockout mice. This project will also characterise the phenotype in other tissues where collagen VI and WARP are coexpressed such as cartilage and skeletal muscle.