New PhD Projects

New PhD Projects for 2017

Prospective students are encouraged to contact Supervisors to further discuss project details.

See our PhD page for information about applying for PhD candidature and scholarships.

New projects will be uploaded periodically.

Projects by Theme:

Cell Biology

Clinical Sciences

Genetics

Infection and Immunity

Population Health

Data Science

 

Project Descriptions:

Understanding the causes of craniofacial birth defects

Theme: Cell Biology
Project category: Laboratory-based research


Birth defects involving the face affect approximately 1% of all babies but the genes involved in most of these conditions are unknown. The olfactory receptors are a large group of genes involved with enabling a sense of smell but have never been linked to birth defects. We have identified an uncharacterised olfactory receptor, known as Olfr603, which is crucial for early embryonic development. Mice harbouring a mutant Olfr603 have midfacial clefting and severe brain abnormalities that model a group of conditions in humans known as frontonasal dysplasia. Analysis of gene expression changes in mutant mice demonstrate that Olfr603 signalling is required to regulate patterning of the cranial neural tube and differentiation of a wide range of neural and craniofacial derivatives. In parallel to these animal model studies we are using exome sequencing to identify genes for frontonasal dysplasia in humans. Examination of candidate genes from frontonasal dysplasia patients in our mouse models is highlighting novel mechanisms resulting in craniofacial birth defects. This project will involve a range of human genetics, molecular and developmental biology approaches to investigate human birth defects. Upon completion of this project, students will be in a strong position to participate in research into the genetic and developmental basis of human birth defects.

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Epigenetics and other stress-related biomarkers in mental health

Theme: Cell Biology
Project category: Laboratory-based research


Stress is a risk factor for a range of non-communicable diseases (NCDs), including cardiovascular disease, diabetes and depression, and can also contribute to cancer incidence and survival. Stress has been described as the 21st century health epidemic. It remains unclear however, how the timing, severity and accumulation of stress exposure can influence later physical and mental health, and what resilient factors can help buffer against the negative effects of stress. The uunderlying biological mechanisms driving these associations are also unclear.
This project will use data gathered from a large prospective study of over 2000 individuals, with detailed measures on recent stressful events, major lifetime traumas and childhood events (DSM diagnosed), as well as thorough medical, social and lifestyle information. Data on a range of stress-related biomarkers (inflammation, metabolic, magnetic resonance imaging) and genotyping is already available. Stored DNA samples will be used to measure telomere length and candidate gene DNA methylation levels. The student working on this project will learn advanced laboratory techniques and develop skills in the analysis of data gathered from a large cohort study. This project would suit a candidate with some experience in either molecular biology or epidemiology/biostatistics and an interest in mental health.

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The role of epigenetics in depression

Theme: Cell Biology
Project category: Laboratory-based research


Depression and anxiety are major public health problems with high prevalence rates worldwide and an increased risk of comorbidity and mortality. They are considered dimensional disorders whose severity is determined by multiple genes with small effects and complex interactions between genetic predisposition and environmental factors. Epigenetic mechanisms are thought to play a key role in depression and anxiety, but studies to date have been limited by small sample sizes and further investigation is required. This project, as part of a wider collaboration with a French research team, will make use of data gathered from the longitudinal population-based ESPRIT study of 1863 men and women. This study, currently in its fifteenth year, has gathered extensive biological, and clinical data, including diagnosis of past and current major depression disorder and anxiety disorder, as well as anxiety and depressive symptoms and medication use at each wave of follow-up. A DNA bank has also been constituted and a number of candidate-genes have been genotyped.
This PhD project will focus on the role of epigenetics in depression and anxiety, and will involve both laboratory and non-laboratory based (public health) research. The student will determine the degree of methylation of candidate-genes from blood and buccal derived DNA, and will determine whether these differ according to the presence and chronicity of psychiatric disorder. The student will also have access to all of the data which has already been gathered from the ESPRIT cohort, including the possibility of gene-epigenetic interactions.

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Utility of Epigenetics profile to refine diagnosis, prognosis and improve outcome in childhood blood cancers.
 

Theme: Cell Biology
Project category: Laboratory-based research


Leukaemias are the most common form of cancer in children. Despite intensive investigation, the primary cause(s) of disease remain unclear and a proportion of children still succumb to disease. The MCRI/RCH has one of the largest collections of archival patient-derived leukaemic bone marrow in existence internationally, with a complementary ongoing prospective collection of tumour and matched blood samples.
During the course of recently completed Masters and PhD projects, we identified a panel of DNA methylation markers and miRNAs that are common to childhood ALL and AML. More recently we have identified signatures with potential prognostic utility and for monitoring minimal residual disease in both childhood ALL and AML.
The aim of this project is to further investigate the utility of such markers in a large collection of additional ALL and AML samples with matched clinical data, in order to further explore the prognostic potential of DNA methylation in this group of diseases and to reveal novel insights into leakaemia pathobiology.

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Epigenetics as a mediator of gene: environment interactions underlying early life programming of cardiovascular and metabolic risk.

Theme: Cell Biology
Project category: Laboratory-based research


The world is experiencing an alarming rise in the incidence of cardiovascular disease, obesity and poor metabolic health. Mounting evidence suggests that the period in utero and early postnatally plays a critical role in programming these phenotypes. Both genetic and environmental factors contribute to complex disease risk and are also known to influence epigenetic profile. Thus, epigenetic variation has emerged as prime candidate for the early life programming of later CV and metabolic health. Epigenetic variants have great potential as biomarkers for monitoring ideas progression and may be reversible with appropriate intervention.

The overall aims of this project are to examine the association of epigenetic variation in early life (with a focus on DNA methylation), genetic variation and environmental exposures, with measures of adiposity and cardiovascular health in the unique Barwon Infant study of 1000 mothers and their children (www.barwoninfantstudy.org.au). BIS has a wealth of environmental measures and longitudinally sampled biospecimens with genome-wide genetic data already collected, enabling an unprecedented investigation of the role of genes, environment and epigenetics in conferring early life risk of cardio/metabolic health in humans.

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Understanding how stress impacts on health and disease

Theme: Cell Biology
Project category: Non-laboratory-based research


Stress is a risk factor for a range of non-communicable diseases (NCDs), including cardiovascular disease, diabetes and depression, and can also contribute to cancer incidence and survival. Stress has been described as the 21st century health epidemic. It remains unclear however, how the timing, severity and accumulation of stress exposure can influence later physical and mental health, and what resilient factors can help buffer against the negative effects of stress. The underlying biological mechanisms driving these associations are also unclear.
This project will use data already gathered from a large prospective study of over 2000 individuals, with detailed measures on recent stressful events, major lifetime traumas and childhood events (DSM diagnosed), as well as thorough medical, social and lifestyle information. A range of stress-related biomarkers (inflammation, metabolic, magnetic resonance imaging) have already been measured and genotyping has been completed. DNA methylation data is also available for a number of candidate genes. No further data collection is required. The candidate will learn advanced laboratory techniques and employ biostatistical approaches to analyse the extensive data generated. This project would suit a candidate with some experience in either epidemiology or biostatistics and an interest in mental health.

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Heart structure and mechanics in children with a single ventricle
 

Dr Vijay Rajagopal
Department of Mechanical Engineering
University of Melbourne
 

Theme: Clinical Sciences
Project category: Non-laboratory-based research


Each year, at least 30 children are born in Australia with a form of congenital heart disease that means only one of the two heart pumps (ventricles) is functionally viable. Currently, the best chance of survival comes with a series of three complex operations that result in a Fontan circulation, where a single ventricle pumps blood to the body, and the major veins are connected directly to the pulmonary arteries to supply lung blood flow. Although medium-term survival is improving, these patients have reduced exercise capacity and a significant risk of heart failure.

In this project, the student will analyse magnetic resonance imaging data acquired at the Royal Children's Hospital before and after exercise in children with a Fontan circulation. Three-dimensional models of the contracting heart and its chambers will be constructed from patient data in collaboration with the Deparment of Mechanical Engineering (University of Melbourne). Heart deformation will be assessed to quantify cardiac strain patterns, with the aim of improving clinical assessment of heart function and risk of complications in this complex disease.

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Modelling the cardiovascular birth transition in vulnerable infants

Theme: Clinical Sciences
Project category: Non-laboratory-based research


Birth is arguably the most crucial and most complex event of life. Immediately after birth, rapid and profound changes occur in the cardiovascular system to facilitate the shift from placental respiration to breathing with the lungs. However, premature birth, congenital heart disease and/or birth complications (such as fetal or newborn asphyxia) can cause problems with the birth transition that may have long lasting consequences for the child (e.g. brain damage, requirements for intensive care, greater long-term risk of cardiovascular disease). The precise nature of the perinatal cardiovascular complications, and how they might be treated better or avoided altogether, are very difficult to study in human babies due to ethical and practical constraints.

In this PhD project, the student will develop a state-of-the-art computational modelling platform for studying the birth transition and challenges encountered by vulnerable infants. A key benefit of a modelling approach is the lack of ethical constraints and great flexibility in studying the problem. The project will be integrated with world-leading work by our group on fetal modelling and experimental studies of the birth transition in lambs, and will benefit from our links with the neonatal intensive care unit at the Royal Children's Hospital.

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Modelling the cardiovascular system throughout childhood

Theme: Clinical Sciences
Project category: Non-laboratory-based research


It is increasingly being recognised that the precursors to adult cardiovascular disease begin in childhood. However, we currently have limited information about the normal development of the cardiovascular system during childhood and how this normal development is interrupted by problems such as congenital heart disease. One-dimensional modelling is a powerful tool for investigating the cardiovascular system but, surprisingly, no models of the growing circulation exist.

Based on existing state-of-the-art models of the adult and newborn cardiovascular systems, the student will develop methods for incorporating childhood growth and physiological development. The model will be validated against measurements in children. The resulting model will allow simulation of blood pressure and flow throughout the circulation of a representative normal child at any time during childhood. By perturbing parameters of the normal development model, new insights will be gained into problems faced by children with congenital heart disease and why some children have a high risk of developing cardiovascular disease as adults.

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Advanced MRI analysis of congenital heart disease

Theme: Clinical Sciences
Project category: Non-laboratory-based research


In many forms of congenital heart disease, disturbed blood flow patterns arise from abnormal vascular anatomy or heart function. This causes two fundamental and interrelated haemodynamic problems, 1) flow turbulence, which causes dissipation of fluid energy and harms endothelial cells that form the inner lining of vessel walls and 2) pressure losses, which increase workload on the heart, increase stress on vessel walls, and/or reduce or adversely redistribute blood flow to organs and tissues. These factors in turn lead to secondary cardiovascular diseases or complications. While routine clinical imaging techniques may in some cases detect turbulence or implicate pressure losses, they cannot accurately map and quantify them. Two recently described magnetic resonance imaging (MRI) techniques enable quantitative mapping of turbulence and relative pressure in 2 or 3 dimensions over time, promising unprecedented insights into disturbed flow patterns.

In this project, the student will develop and validate computational tools for calculating turbulence and relative pressure maps from 4D (i.e. 3D + time) phase-contrast MRI in patients with congenital heart disease. The key aim will be developing novel MRI-based measurements that provide added value to cardiologists who are treating cardiovascular disease in childhood.

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Foot biomechanics during gait in children with cerebral palsy

Theme: Clinical Sciences
Project category: Non-laboratory-based research


The goal of this project is to better understand the biomechanics of the foot in children with cerebral palsy, and the effect of a range of surgical operations often performed to improve foot function in children with cerebral palsy.
The project will involve the collection of kinematics, kinetics and pedobarographic data of children with cerebral palsy during gait before and after foot surgery.
The project will require the student to design innovative software to process bi-plane x-ray images to register the bones of the foot to the skin markers used to track foot movement. The system will be integrated in the clinical setting.
The project will also involve musculoskeletal modelling of the foot and the entire lower limb to calculate muscle and joint contact forces during the movement. One objective of the project is to predict the effect of foot surgery on foot function through virtual surgery of the musculoskeletal model. The predicted effect will be compared to the observed foot function post-surgery.

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The Impact of Infant Cardiac Surgery on Infants and Parents

Dr Candice Franich-Ray
Social & Mental Health Research
Clinical Sciences
E candice.franichray@rch.org.au

 

Theme: Clinical Sciences
Project category: Non-laboratory-based research


Congenital heart disease is a potentially serious abnormality affecting approximately 8 in every 1000 infants born in Australia. It occurs across the socio-economic spectrum with severity ranging from self-correcting minor defects to life threatening lesions requiring prolonged treatment and multiple surgical procedures. As mortality has reduced attention is increasingly focused on factors which influence child and family adaptation to living with a heart condition.

Data collection has already been completed for this study. Families completed a questionnaire and interview one month after their infant's discharge from hospital following cardiac surgery and a sub set of families were followed up one year later.

We are looking for a PhD student to join our team who would be interested in completing the data analysis. There is both qualitative and quantitative data at two time points available. The aims of the initial study were to examine the impact infant cardiac surgery on infants and parents and identify risk and protective factors in subsequent adjustment. This information is important as it can (i) contribute to the development of evidence based protocols for clinical management of infants with congenital heart disease and their families and (ii) inform therapeutic interventions aimed at reducing psychosocial morbidity in "at risk" children and their families.

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How do babies take their first breaths?

Dr Louise Owen
Neonatal Research
Clinical Sciences
E louise.owen@mcri.edu.au

Dr Prudence Pereira
Neonatal Research
Clinical Sciences
E prue.pereira@mcri.edu.au

Theme: Clinical Sciences
Project category: Non-laboratory-based research

Birth involves the successful transition from a fluid-filled fetal lung state to a lung that is aerated (air filled). This needs to occur quickly to allow other organs to start working. About 10% of term babies, and most preterm babies, do not aerate their lungs properly at birth. These babies often need help with their breathing. We do not yet fully understand how babies take their first breathes at birth and why some have problems. This observational study aims to describe how babies aerate their lungs at birth and develop normal breathing. It will use a new state-of-the-art lung imaging system developed at the MCRI to study newborn babies in the Delivery Room of the Royal Women’s Hospital. The successful candidate will then analyse the ventilation, aeration and filling characteristics of each imaged lung. This will help us determine whether the human lung starts breathing in the way we think it does. The successful candidate will have the potential to access additional resources and funding support through the NHMRC Preterm Infants Centre of Research Excellence.

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Inhaled Vaccines: Aerosol delivery of novel vaccines to the infant lung

Dr Paul Licciardi
Pneumococcal Research
Infection and Immunity
E paul.licciardi@mcri.edu.au

Theme: Clinical Sciences
Project category: Laboratory-based research

THE PROBLEM: The development of a safe and effective aerosol vaccine delivery platform that would be comparable to intravenous delivery has been a considerable challenge to the health care industry. Potentially, this represents a rapid response solution to pandemic disease outbreaks, especially in the developing world. Existing aerosol delivery systems struggle to maintain biomolecule stability and ensure retention of the structure as per regulatory requirements. Our team has developed a novel aerosol delivery system does not produce these disruptive processes, and we have shown that the nebuliser can efficiently deliver pulmonary vaccines in an adult sheep model.

THE PROJECT: The student will conduct studies to determine if vaccine delivery via the aerosol route will induce a strong mucosal immune response, within the lung, and a robust systemic immune response compared to alternative routes of delivery in an infant lamb model.

TECHNIQUES: The student will use immological assays such as ELISA and molecular assays to validate the immune responses. Students will work closely with a team of molecular biologists, clinicians (neonatologists) and engineers. Candidates with a strong background in Biomedical Science or Biomedical Engineering (interest in immunology) or other relevant engineering expertise is encouraged to apply.

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SMART Nappy: Novel low cost point-of-care diagnostics for premature babies

Theme: Clinical Sciences
Project category: Laboratory-based research

THE PROBLEM: Accurate, low-cost, point-of-care diagnostics for premature babies are severely lacking in resource-limited rural settings. This leads to poor monitoring and late diagnoses of high risk premature babies that could otherwise have a healthy start to life. This type of diagnostics will radically change the way health care is delivered by shifting the focus from a lab-based diagnostic paradigm to an onsite, real-time diagnosis.

THE PROJECT: To improve rural health care for newborns is to develop accurate, low-cost diagnostics for newborns that will be used to detect and enable proper clinical management of the disorders. These point-of-care diagnostics require only a drop of blood or urine and require no additional steps beyond applying the sample. This means that they can be utilized by minimally-trained individuals in communities or clinics in rural settings to allow better patient management.

TECHNIQUES: The student will use biochemical sensing methods to quantify the biomarkers. The techniques developed will be validated against gold standard methods of diagnosis. This project is a collaborative effort between Engineering, Chemistry and Clinical sciences. There may be an opportunity to develop clean room techniques related to nanofabrication. Candidates with a strong background in Biomedical Science or Biomedical Engineering (Chemistry or Biochemistry) or other relevant Chemical Engineering expertise is encouraged to apply.

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Extremely preterm birth and long-term mental health

Theme: Clinical Sciences
Project category: Non-laboratory-based research

We are seeking a PhD student to join our team on a project focussed on the mental health and psychosocial outcomes of young people who were born extremely prematurely. Extreme prematurity is a risk factor for a range of adverse outcomes, but very few studies have followed these children into adulthood. We are now following up a cohort of young people aged 25 who have been part of this study since they were born. There is also a large amount of longitudinal data, including previous mental health assessment and MRI data, giving plenty of scope for interested students to select a research question that fascinates them.

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Multimodal Neuroimaging of Children - Projects in Typical Brain Development Or ADHD

Mr Charles Malpas
Developmental Imaging
Clinical Sciences
E charles.malpas@mcri.edu.au

 
 

Theme: Clinical Sciences
Project category: Non-laboratory-based research

Projects are available on the NICAP dataset (Neuroimaging of the Children’s Attention Project). Using state-of–art methods for multi-modal MRI neuroimaging, with detailed neuropsychological data of a large sample of children with ADHD and healthy controls.

Projects are available in modeling how brain structure and function develops, or is different in children with ADHD. We seek students with a strong academic track record and interest/experience in neuroimaging analysis.

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Genetic bases of childhood speech sound disorders

Theme: Clinical Sciences
Project category: Non-laboratory-based research

Over half a million Australian children present with communication disorders annually, with life-long impacts on emotional health, social relationships, literacy attainment and employment. These conditions include severe and striking speech disorders such as stuttering and childhood apraxia of speech. Despite the burden of communication disorders, little is understood regarding their aetiology, preventing development of therapies targeting underlying pathways.

Through our recently awarded NHMRC CRE-SLANG, we are able to offer PhD stipends to examine the genetic bases of severe childhood speech sound disorder. In particular, we are looking to recruit PhD students from a speech pathology background who are passionate about detailed diagnostic phenotyping of children and families with a strong history of speech sound disorder. 

Two PhD scholarships of $35,000 per annum for 3 years are available for the successful candidates to pursue projects focused on the genetic bases of childhood speech sound disorders. There is some flexibility of the condition(s) studied (i.e., apraxia of speech, stuttering, etc) and the successful candidates will have some room to design aspects of their own project. The Institute also offers extensive student support, including travel and top-up scholarships that can be applied for internally. Candidates will be expected to apply for competitive external fellowships as part of the CRE-SLANG grant remit.

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Developing a diagnostic blood test for autism

Theme: Genetics
Project category: Laboratory-based research


Autism is a complex, heterogeneous neurodevelopmental disability with an early childhood onset and a lifelong course. The identification of biomarkers to define biologically homogeneous subgroups, predict risk, and aid the diagnosis of autism would greatly facilitate the management of this common disorder, which affects ~1% of the population.

This research project seeks to identify circulating RNA biomarkers that are dysregulated in autism and, using this information, aims to develop a diagnostic blood test for autism. In this way, the research seeks to overcome the current difficulties that exist around obtaining a diagnosis of autism and, by doing so, should help to facilitate intervention and thus improve outcomes for autistic children and their families. Students will develop a detailed understanding of autism, and skills in RNA biology, next generation sequencing, and bioinformatics.

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Determining the genetic basis of novel neurogenetic disorders

Theme: Genetics
Project category: Laboratory-based research


The identification and characterisation of genes underlying Mendelian disorders has been responsible for unprecedented advances in our understanding of human disease. Very recently, gene discovery has been driven by advances in genetic technologies, particularly the ability to routinely sequence entire genomes. This project will utilise clinical resources of the Victorian Clinical Genetics Services and modern molecular genetic and bioinformatic technologies to identify novel genes for neurogenetic disorders. In addition, the function of these genes will be investigated in cell and animal models to determine underlying disease pathogenesis. These studies have application in the field of personalised medicine, where the knowledge of an individual's genetic makeup can be utilised to predict disease development, influence decisions about lifestyle choices and tailor medical practice to the individual.

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Identifying the genetic causes of brain malformation in children

Theme: Genetics
Project category: Laboratory-based research


The human cortex is the surface of the brain that enables advanced intellectual function. It forms through a series of overlapping steps involving neuronal proliferation, migration and differentiation. Abnormal formation of the cortex causes a group of disorders known as malformations of cortical development (MCD), which can result in epilepsy, intellectual disability and cerebral palsy. There is considerable evidence that gene mutations cause MCD, but to date few of the genes involved have been identified. This project will utilise modern genomic technologies, including whole exome and genome sequencing, to identify the genetic basis of MCD in patients treated by the Children's Epilepsy Program at the Royal Children's hospital. The function of these genes will be investigated in cell and animal models to determine underlying disease pathogenesis.

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Understanding the pathogenesis of RAB39B-mediated Parkinson's disease

Doctor Gabrielle Wilson
Neurogenetic Research (BLC)
Genetics
E gabrielle.wilson@mcri.edu.au

 
  
 

Theme: Genetics
Project category: Laboratory-based research


The recent advances in our understanding of common and disabling neurodegenerative diseases such as Parkinson and Alzheimer disease has been the result of the identification and analysis of causative mutations in families, where a linkage-based approach can be utilised to identify disease associated genes. We have identified several families who demonstrate clinical features of early-onset parkinsonism. Modern genomic technologies have allowed us to identify the gene responsible, which represents a novel gene for Parkinson's disease. This project will characterise the gene and investigate pathogenic mechanisms underlying disease utilising molecular and cell biology techniques. Subsequent studies will utilise newly developed and unique iPSC and mouse models to perform preclinical studies to characterise the disease process and identify potential therapeutic targets.

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Understanding the genetic basis of Autism Spectrum disorder

Theme: Genetics
Project category: Laboratory-based research


Austism spectrum disorders (ASD) are common developmental disorders that manifest in childhood and affect ~1:100 individuals. ASD typically display complex inheritance but the genetic basis underpinning the disease remains largely unexplained. This project aims to understand the genetic basis of ASD by performing genetic linkage studies in large families with 2 or more affected children. Novel genes will be characterised to understand pathogenic mechanisms underlying disease utilising advanced molecular and cell biology techniques. Subsequent studies will utilise newly developed and unique iPSC models to perform preclinical studies to characterise the disease process and identify potential therapeutic targets. This project is multidisciplinary and involves close collaborations with clinical researchers and bioinformaticians. The outcomes will enable understanding of the molecular basis of ASD and identify potential therapeutic targets for management of the disorder.

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Drug development for prevention of deafness

Theme: Genetics
Project category: Laboratory-based research


THE PROBLEM: Acquired hearing loss is prevalent within our community. There are several clinical situations that can result in inadvertent damage of the cochlea and acquired hearing loss. These include treatment with platinum based chemotherapeutic drugs and (somewhat counter-intuitively) cochlear implantation with an electrode array. Previous research has revealed that in most cases of acquired hearing loss, it is death of sensory cells within the cochlea that results in the hearing loss. We are particularly interested in the molecular regulation of this auditory cell death (known as apoptosis). Inhibition of key molecules in the apoptosis cascade can prevent hearing loss. Our laboratory is developing a drug that does just this. The aims of this project are to develop further molecular evidence for our primary drug target, and to build the pre-clinical evidence of efficacy of our drug at preventing acquired hearing loss in a range of settings.

THE PROJECT: Our team has developed a chemical inhibitor of intrinsic apoptosis, and has generated preliminary evidence that this compound can block ototoxic drug-induced auditory cell death in vitro.

An opportunity exists for a Graduate Research Student (Masters or PhD) to further investigate the regulation of auditory apoptosis and the efficacy of our novel inhibitor of apoptosis for preventing acquired hearing loss. Initial studies will be carried out in vitro using organotypic cultures of the cochlea. There is potential to progress these studies to in vivo drug efficacy testing in mouse and guinea pig models of acquired hearing loss.

TECHNIQUES: The student will use a wide variety of molecular and auditory biology laboratory techniques including: auditory brainstem response testing, micro-dissection of the auditory system, histological analysis of cochleae, organotypic culture, and western blotting. The project would suit students from a range of disciplines including (but not limited to) genetics, biochemistry, pharmacology or neuroscience.

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Master regulator of chromosome compaction, DNA repair and gene expression, and impact on disease aetiology

Theme: Genetics
Project category: Laboratory-based research


In order for our genetic material to be faithfully segregated into two daughter cells, the DNA must compact 10,000 fold to visible X-shaped structures known as mitotic chromosomes. Proper compaction of DNA also underpins the regulation of DNA repair and global gene expression. A master regulator in these fundamentally important processes is the multi-subunit protein complex, condensin, for which an increasing number of cancers and diseases have now been linked to its defect.

The aims of this project are to understand how condensin and its affiliated components affect chromosome folding, DNA repair and global gene expression, using integrated proteomics, biochemistry and cell biology approaches. Specific techniques employed will include genome editing and conditional gene knockout, next gen sequencing, proteomics and live cell imaging. The knowledge gained will have major implications for understanding the underlying causes of a wide range of diseases.

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Epigenetic modifications of the human beta-globin locus: new therapeutic targets for haemoglobin disorders

Dr Bradley Mccoll
Cell & Gene Therapy
Genetics
E bradley.mccoll@mcri.edu.au

A/Professor Marnie Blewitt
Molecular Medicine
WEHI
E blewitt@wehi.edu.au

  
 

Theme: Genetics
Project category: Laboratory-based research


Haemoglobin disorders, such as sickle cell disease and beta-thalassaemia are the result of mutations in the adult beta-globin gene. When these disorders are co-inherited with hereditary persistence of fetal haemoglobin, (high levels of gamma-globin gene expression in adult life) the disease phenotype is much reduced. Therefore, understanding the mechanism of gamma-globin globin gene regulation through development has been the subject of intense investigation for many years. These studies led to an appreciation of the role of epigenetic modifications such as DNA methylation and histone acetylation in globin gene expression and regulation. As a result, considerable efforts have been focused on the pharmacologic induction of fetal haemoglobin (HbF) using epigenetic-specific agents. However, the role of individual epigenetic regulators in globin gene expression is not very well understood.

This study will investigate the potential impact of epigenetic regulators on globin gene expression. Functional genomic screening strategies will be performed using RNA interference (RNAi) or CRISPR/Cas9 genome editing to either suppress or knockout the expression of specific epigenetic regulators in erythroid cells modified to express fluorescent reporter genes under the control of the gamma-globin promoter. Flow cytometry, real-time PCR and western blot analysis will be used to monitor gene expression. Positive outcomes of such studies could pave the way for better treatment strategies for sickle cell anaemia and beta-thalassaemia patients by targeting epigenetic regulators to increase fetal globin expression.

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Understanding how beta-thalassaemia influence resistance to bacterial pathogens

Dr Bradley Mccoll
Cell & Gene Therapy
Genetics
E bradley.mccoll@mcri.edu.au

Dr Odilia Wijburg
Pneumococcal Research
Infection and Immunity
E odilia.wijburg@mcri.edu.au

 

Theme: Genetics
Project category: Laboratory-based research


Thalassaemia is one of the most common genetic disorders affecting haemoglobin synthesis. This results in severe anaemia that must be treated with regular blood transfusions every 3-4 weeks. As a consequence of the frequent blood transfusions and excessive iron absorption, thalassemia patients develop a state of iron overload resulting in damage and failure of the heart and/or liver. The second most frequent cause of mortality and morbidity in thalassemia patients are infections. In particular, ferrophilic Gram-negative bacteria such as Klebsiella pneumoniae and Yersinia enterocolitica, are reported in patients undergoing iron chelation therapy. Encapsulated bacteria, such as Streptococcus pneumoniae, cause serious infections in splenectomized patients. A large number of immune abnormalities have also been described, mostly due to iron overload and/or long-term receipt of multiple blood transfusions. In this project, we will use a mouse model for thalassemia to investigate the immune deficiencies that predispose to increased susceptibility to infection with bacterial pathogens S. pneumoniae, Salmonella typhimurium and/or K. pneumoniae. To further understand the biological and clinical significance of aberrant immune function in beta-thalassaemia, we will undertake a comprehensive evaluation of the molecular and cellular mechanisms responsible for aberrant innate immune effector functions in beta -thalassaemic mice and beta -thalassaemia patients. The work proposed in this project will generate a better understanding of the mechanism underlying aberrant immune function and provide novel insights into disease progression.

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A mixed methods exploration of the experiences of patients of the diagnostic flagships in the Australian Genomics Health Alliance

Dr Clara Gaff
Clinical Genetics Research (BLC)
Genetics

E clara.gaff@mcri.edu.au

Dr Belinda McClaren
Molecular Development
Cell Biology
E belinda.mcclaren@mcri.edu.au

Dr Amy Nisselle
Molecular Development
Cell Biology
E amy.nisselle@mcri.edu.au
 

Theme: Genetics
Project category: Non-laboratory-based research

The Australian Genomics Health Alliance (AGHA), funded by the NHMRC, brings together more than 50 partner organisations committed to integrating genomic medicine into healthcare across Australia (www.australiangenomics.org.au). The Alliance aims to shorten diagnosis times, enable early intervention and provide access to treatment for people with genetic disorders by the translation of genomic technology into clinical practice for patients and family benefit.

Within the Alliance, Program 4 is conducting research around education and training needs of the genomic workforce, as well as ethical and patient perspectives of the Alliance activities. The Program 4 working group consists of experts in genetics/genomics education, clinical practice, evaluation, mixed methods research, genetic counselling, social science, science communication and ethics.

An opportunity exists for a PhD scholar to undertake a project aimed at investigating the patient experience of participants of the diagnostic Flagships of Australian Genomics. This project would ideally suit a candidate with interest/experience in Genetic Counselling, Ethics, Psychology and/or Social Sciences. Desirable candidate attributes include: sensitivity to patients and families; an ability to work in a multidisciplinary team; an organised and inquiring mind; a flexible approach to data collection; and, strong written and verbal communication skills.

The project will utilise mixed methods (quantitative and qualitative). The candidate will work with the team to develop data collection tools including interview questions and surveys. These tools will be informed by existing literature, expert input and a small sample of initial interviews. Patients enrolled in the Flagships will be invited to participate in the project and may be interviewed or complete a survey to capture their experience and expectations. The outcomes from the project will inform future patient management in genomic medicine.

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Effect of congenital UDT on Gonocyte development

Dr Ruili Li
Surgical Research
Infection and Immunity
E ruili.li@mcri.edu.au

 

Theme: Infection and Immunity
Project category: Laboratory-based research

Undescended testis (UDT) is a major health problem, affecting over 2-4% of males at birth, and with a long-term risk of infertility (30-60%) and a 5-10 fold increase in testicular cancer in young men. Infertility and testicular cancer are likely caused by failed transformation of primitive sperm cells (gonocytes) into spermatogonial stem cells (SSC). Currently UDT surgery is recommended at 6-12 months, but it is not known whether this is the right time, as there is insufficient knowledge about early postnatal germ cell development. The project will analyse the effect of congenital UDT on gonocyte transformation using animal models and human biopsies. The study will involve the use of flow cytometry, organ culture immunohistochemistry, confocal microscopy, PCR and Western blotting.

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Animal model with undescended testes may provide the key to understanding cellular interactions necessary for testicular descent

Dr Ruili Li
Surgical Research
Infection and Immunity
E ruili.li@mcri.edu.au

 

Theme: Infection and Immunity
Project category: Laboratory-based research

Congenital undescended testes (UDT), or cryptorchidism, is extremely common, affecting 2-4% of boys. Surgery to pull the testes down is currently recommended at 6-12 months, aiming to prevent deranged postnatal germ cell maturation, secondary to high temperature that eventually causes cancer and infertility. The testis forms inside the abdomen near where the kidneys are. The genito-inguinal ligament, or 'gubernaculum', initially anchors the testis to the groin and then migrates through the abdominal wall and down into the scrotum, pulling the testis inside an extension of the peritoneal membrane, the processus vaginalis (PV). Gubernacular migration is controlled by androgens via the genitofemoral nerve (GFN), which releases calcitonin gene-related peptide (CGRP) to direct migration and control PV closure after descent. Our recent study has indicated that neorotrophins, such as CNTF and BDNF and their respective receptors, are expressed in the inguinoscrotal fat pad in response to androgen to masculinise each GFN. The project aims to examine interactions between the inguinal fat pad, the GFN and the gubernaculum, and the molecular signals that trigger gubernacular outgrowth from the abdominal wall, for migration to the scrotum. The study will involve the use of immunohistochemistry, confocal microscopy, tissue culture, PCR and Western blotting.

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Streptococcus pneumoniae: host and pathogen factors involved in pathogenesis and response to vaccination

Theme: Infection and Immunity
Project category: Laboratory-based research


Streptococcus pneumoniae (the pneumococcus) is a major cause of pneumonia and other severe infections worldwide. In addition to causing disease, the pneumococcus can also colonise the nasopharynx (nose and throat) of healthy individuals. This colonisation is most common in young children, is essential for pneumococcal transmission, and considered a precursor to disease. Our laboratory is interested identifying both the host and bacterial factors involved in pneumococcal carriage and disease, and investigating the ability of vaccines to interrupt these processes. Using a combination of clinical samples and in vitro and in vivo models, we will investigate pneumococcal pathogenesis and evaluate known risk factors of pneumococcal disease such as malnutrition and hypoxia. Gene expression studies (RNA-seq and RT-PCR) and whole genome sequencing will identify genes of interest. Candidate genes will be examined by mutagenesis and functional assays including in vivo models of pneumococcal disease. We will use in vivo models to assess strategies including vaccination to combat pneumococcal infections.

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Immune susceptibility to RSV during early life

Doctor Lien Anh Ha Do
Pneumococcal Research
Infection and Immunity
T +61393455554
E lienanhha.do@mcri.edu.au

Theme: Infection and Immunity
Project category: Laboratory-based research

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory infections among hospitalised children. This is particularly true for preterm infants, who have RSV hospitalisation rates 3 times higher than term infants, and are more likely to present with severe clinical features requiring admission to intensive care. Currently, there is no RSV vaccine (infant or maternal) available to protect these infants, despite a number of potential candidates in development. We are interested in the immunological basis of the increased susceptibility to severe RSV among preterm infants as they are especially vulnerable to infection and are the least likely to benefit from maternal vaccination strategies. This PhD project will involve the investigation of key immune susceptibility signatures associated with severe RSV disease in the first months of life as part of a birth cohort study design. As part of this project, the role of possible risk factors including vitamin D status and co-infections Streptococcus pneumoniae on inflammatory responses and development of severe disease will also be examined. We will take advantage of high-throughput technologies in immunology and molecular biology to examine clinical data and ex-vivo immunological data using techniques such as cell culture, flow cytometry, next-generation sequencing and functional assays.

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Risky behaviours in females aged 16-29 years : The Young Female Health Initiative Study

Professor John Wark
Medicine
Medicine
E jdwark@unimelb.edu.au

Doctor Asvini Subasinghe
Molecular Microbiology
Infection and Immunity
E asvini.subasinghe@mcri.edu.au

 
 

Theme: Infection and Immunity
Project category: Non-laboratory-based research


There is strong evidence to show that young adults exhibit a number of poor health behaviours such as alcohol use, smoking, lack of physical activity, and risky sexual behaviours. Researchers who have examined risky behaviour patterns have speculated that poor health behaviours established during emerging adulthood may persist into later stages of adulthood.
The Young Female Health Initiative (YFHI) and Safe-D studies are comprehensive female health studies conducted with 16-25 year old females. Students will have the opportunity to investigate the prevalence and determinants of risky behaviours in a representative sample of young Australian females as well as determining variations in these behaviours longitudinally using data collected from two year follow up visits. Findings from this study will be able to consolidate whether established risky behaviours may persist throughout adulthood and may suggest factors that influence these behaviours.

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Vitamin D status and mental health outcomes in females aged 16-25 participating in a randomized controlled trial

Professor John Wark
Medicine, Royal Melbourne Hospital
Bone and Mineral Medicine
E jdwark@unimelb.edu.au

Dr Asvini Subasinghe
Molecular Microbiology
Infection and Immunity
E asvini.subasinghe@mcri.edu.au

 

Theme: Infection and Immunity
Project category: Non-laboratory-based research


There is a large body of evidence supporting a relationship between Vitamin D and poor mental health. Students will have the unique opportunity to investigate the association between Vitamin D and several indices of mental health in females recruited into the intervention component of the Safe-D study (Part B). Participants with 25 OHD levels 25 to 75 nmol/L are randomized to one of three groups in 1:1:1 ratio: a mobile phone-based application designed to encourage safe sun exposure, vitamin D supplementation (1000 IU/day), and a control group. Data collection points are at baseline, 4 and 12 months post baseline with the major endpoints being at 4 months. A wide range of information is collected from participants throughout the course of this study including validated and self-reported information relating to mental health status and lifestyle behaviours. Students will have the fantastic opportunity to investigate a number of relationships between Vitamin D status and indices of mental health. There is also an opportunity to determine whether there are any temporal changes in these associations at 4 months and 12 months after baseline. Findings from this study will help provide an insight into the effects of improving vitamin D levels on several health outcomes, particularly mental health.

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Vitamin D status and musculoskeletal outcomes in females aged 16-25 participating in a randomized controlled trial

Professor John Wark
Bone and Mineral Medicine,
Royal Melbourne Hospital
E jdwark@unimelb.edu.au

Dr Asvini Subasinghe
Molecular Microbiology
Infection and Immunity
E asvini.subasinghe@mcri.edu.au

 

Theme: Infection and Immunity
Project category: Non-laboratory-based research


Low vitamin D levels are associated with an increased risk of numerous chronic health conditions, including poor musculoskeletal health and osteoporosis. However, few researchers have investigated these relationships in young females. We present a novel opportunity for students to investigate these associations in 16-25 year old females participating in a randomized clinical trial as part of the Safe-D study. Participants with 25 OHD levels 25 to 75 nmol/L are randomized to one of three groups in 1:1:1 ratio: a mobile phone-based application designed to encourage safe sun exposure, vitamin D supplementation (1000 IU/day), and a control group. Data from comprehensive surveys, blood tests, bone densitometry, body composition scans, and Leonardo mechanography tests are available on participants at baseline and at 12 months post baseline. Therefore, students will also have the opportunity to investigate these associations longitudinally. Findings from this study will help provide an insight into the effects of improving vitamin D levels on several health outcomes, particularly musculoskeletal health. Findings from this study will help provide an insight into the effects of improving vitamin D levels on musculoskeletal disorders. This project would suit a student interested in musculoskeletal health.

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Longitudinal analysis of health outcomes in 16-29 year old females : Young female health initiative study

Professor John Wark
Bone and Mineral Medicine,
Royal Melbourne Hospital
T 9342 7109
E jdwark@unimelb.edu.au

Dr Asvini Subasinghe
Molecular Microbiology
Infection and Immunity
E asvini.subasinghe@mcri.edu.au

 

Theme: Infection and Immunity
Project category: Non-laboratory-based research


The Young Female Health Initiative (YFHI) and Safe-D studies are comprehensive female health studies conducted with 16-29 year old females. Data are collected via online surveys and clinical site visits for the YFHI study at baseline and at 2 years post baseline. Survey data are available on the following health domains: general health and lifestyle behaviours, mental health, sexual and reproductive health, bone and joint health, cardiovascular and metabolic health, and dietary behaviours. Clinical data include fasting blood tests, anthropometric measurements, sexual health samples, bone mineral density, and body composition scans obtained through site visits. Students will have the novel opportunity to investigate a research question of interest in a representative sample of young Australian females as well as determining variations in health outcomes longitudinally using data collected from two year follow up visits. This project would suit a student interested in women's health.

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Longitudinal Study of Australian Children: PhD in Biostatistics

A/Professor Julie Simpson
School of Population and Global Health
University of Melbourne
E julieas@unimelb.edu.au

Theme: Data Science
Project category: Non-laboratory-based research

We seek expressions of interest from prospective students to undertake a methodological PhD in biostatistics. The proposed PhD project focuses on investigating the pitfalls and possibilities of multiple imputation, a widely used statistical method for handling missing data in medical research studies. In particular, the PhD student will both evaluate and develop methods for conducting sensitivity analyses to assess departures from assumptions regarding the mechanism leading to missing data. This is a very topical area of research in biostatistics. The PhD student will engage directly with the application of these methods in the Longitudinal Study of Australian Children, a nationally representative longitudinal study of 10,000 children managed by the Department of Social Services on behalf of the Australian Government.

The PhD will be conducted through the University of Melbourne and the successful candidate will be based at the Murdoch Children's Research Institute. The candidate will become a member of our missing data research group which includes Prof John Carlin, A/Prof Julie Simpson, A/Prof Katherine Lee, Dr Margarita Moreno-Betancur and Dr Cattram Nguyen. This research will also be supported by the broad research group of the Victorian Centre for Biostatistics (ViCBiostat). See the ViCBiostat website (www.vicbiostat.org.au/) for more information on our group’s research program on missing data and multiple imputation.

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 Analysis of gene regulations on gonocyte transformation into spermatogonial stem cells

Theme: Infection and Immunity
Project category: Laboratory-based research

Undescended testis (UDT) is a major health problem, affecting over 2-4% of males at birth. Boys with UDT face two major problems later in life (20-40 years of age) even after surgically correcting the testis position. One of the problems is infertility, in which 30-60% of males with cryptorchidism will be infertile; and the other is testicular cancer, where the risk of testicular cancer in cryptorchidism is 5-10 fold higher than for normal young men. Infertility and testicular cancer are likely caused by failed transformation of gonocytes (stem cells forming sperm) into spermatogonial stem cells (SSC). Currently UDT surgery is recommended at 6-12 months, but it is not known whether this is the right time as there is insufficient knowledge about early postnatal germ cell development. Our group have studied gonocyte transformation for many years with fully established foundations for the project.

We are seeking an enthusiastic and motivated PhD candidate with an Honours or Masters degree in a relevant science/biomed/medicine discipline. They must be keen to work in the laboratory setting with both disease models and human biopsies to join us as a team member of our research project.

This project is suitable for a PhD candidate who wishes to focus on analysis of the gene regulations in gonocyte transformation and the effect of congenital UDT on gonocyte transformation using various disease models and human UDT biopsies. The study will involve molecular biology, cell biology, histology and next generation sequencing.

A PhD scholarship of $25,000 per annum for 3 years is available for a candidate to pursue this project. The Institute also offers extensive student support, including travel and top-up scholarships that can be applied for internally.

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 Genetic bases of childhood speech sound disorders

Theme: Clinical Sciences
Project category: Non-laboratory-based research

Over half a million Australian children present with communication disorders annually, with life-long impacts on emotional health, social relationships, literacy attainment and employment. These conditions include severe and striking speech disorders such as stuttering and childhood apraxia of speech. Despite the burden of communication disorders, little is understood regarding their aetiology, preventing development of therapies targeting underlying pathways.

Through our recently awarded NHMRC CRE-SLANG, we are able to offer PhD stipends to examine the genetic bases of severe childhood speech sound disorder. In particular, we are looking to recruit PhD students from a speech pathology background who are passionate about detailed diagnostic phenotyping of children and families with a strong history of speech sound disorder. 

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Understanding the underlying dynamics, impact and health consequences of intimate partner violence for women and children

Theme: Population Health
Project category: Non-laboratory-based research

Globally, one in three women experience physical or sexual violence by intimate partners. Between the birth of a first child and that child turning one year of age, one if five women report experiences of emotional and/or physical violence by an intimate partner, translating to around 60,000 Australian families affected in this phase of life each year. Intimate partner violence damages the mental and physical health of women and children, and is a leading contributor to death and disability for women of childbearing age.

We are looking to recruit a PhD scholar to examine the underlying dynamics, impact and health consequences of exposure to intimate partner violence drawing on longitudinal data collected in a Victorian prospective cohort of over 1500 first time mothers and their children. The PhD scholar will be based in the Healthy Mothers Healthy Families group at MCRI, and will have opportunities to participate in capacity-building and peer mentoring activities of the newly established NHMRC Safer Families CRE.

A PhD scholarship of $26,300 per annum for 3 years is available for the successful candidate to pursue a project focused on understanding the dynamics of intimate partner violence and consequences for women and children. There is some flexibility regarding the focus of the research on maternal and/or child outcomes, and the successful candidate will have some room to design aspects of their own project. The Institute also offers extensive student support, including travel and top-up scholarships that can be applied for internally. Candidates will be expected to apply for competitive external fellowships. See here for more details.

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