Lab based projects

Laboratory based Honours and Masters Projects offered in 2018.

Projects listed below are ordered by Research Theme. Projects are available as Honours, and when available marked as Masters above the project description. If a project is offered as Masters only it is clearly marked as such.

Non-Laboratory based Research Projects are found here.

Download a pdf copy of the 2018 Honours/Masters Handbook here.

Students are encouraged to directly contact Supervisors to further discuss the project, including providing a CV and academic transcripts to help the Supervisor determine if they are a suitable candidate.

Students should confirm their interest in the project with the Supervisor before nominating the project in their University application. Ensure the correct number corresponding to the project title is nominated for Department of Paediatrics in HATS.


 

 

Projects by Theme:

 

Cell Biology

1. Effect of ACTN3 on corticosteroid response in Duchenne muscular dystrophy
2. Examining the evolutionary role of alpha-actinin-3 in adaptive thermogenesis
3. Examining the effect of alpha-actinin-3 deficiency in skeletal muscle injury
4. Modelling childhood leukaemias using human pluripotent stem cells
5. Engineering artificial bone marrow
6. In vitro models of type 1 diabetes
7. How to transfer neural precursor cells to the aneural colon for cell therapy for the birth defect Hirschsprung disease
8. How to increase numbers of neural precursor cells in vitro for cell therapy for the birth defect Hirschsprung disease

Clinical Sciences

9. Haemostatic system in Fontan patients with liver dysfunction
10. Characterisation of the specificity and activity of bio-engineered antibodies in children
11. Investigation of the in vitro effect of the antiplatelet drug Tirofiban in children
12. Investigation of the age-specific changes in Blood Microparticles

13. Modulating fibrosis and myocardial injury in Muscular Dystrophy

Genetics

14. Tuberous sclerosis and epilepsy: using resected tissue to understand pathogenesis
15. Using cerebral organoids for the study of tuberous sclerosis complex
16. Functional characterisation of a novel gene linked to autism spectrum disorder
17. Understanding RAB39B-mediated Parkinson's disease
18. Solving Rare Diseases via the Australian Genomics Mitochondrial Disease Flagship
19. Characterisation of the parkin protein and how it causes Parkinson disease 
20. Human Stem Cell Models of Mitochondrial Disease
21. Brain cells in a dish: strategies for novel therapeutics in the CDKL5 disorder
22. HDAC6 inhibitors as a treatment for Rett syndrome: Resolving neuronal trafficking deficits

Infection & Immunity

23. Developing a new treatment for stomach cancer
24. Analysis of gene regulations on gonocyte transformation into spermatogonial stem cells
25. The immune response to infection in early cystic fibrosis
26. Targeting stem cells as a new treatment for stomach cancer 
27. Bacterial gene expression in pneumococcal pneumonia
28. Synergistic interactions between Streptococcus pneumoniae and respiratory viruses on bacterial pathogenesis

29. Bacterial factors for pneumococcal transmission
30. Examination of cross-neutralising immunity following HPV vaccination in Fiji
31. Molecular Epidemiology of Severe Respiratory Syncytial Virus Infections in Children under 2 years of age
32. Immunomodulatory effects of Vitamin D on the host response to bacterial and viral infections
33. Inhaled RSV therapeutics: Aerosol delivery of novel therapies to the infant lung 
34. Molecular mediators of gene: environment interactions underlying early life programming of cardiovascular and metabolic risk

Population Health 

35. The early origins of autism: a focus on epigenetic differences within identical twin pairs 

36. The application of a novel dried blood spot collection device for future diagnostic applications 

 

Project Descriptions:

Cell biology

1. Effect of ACTN3 on corticosteroid response in Duchenne muscular dystrophy

Dr Jane Seto
Neuromuscular Research
Cell Biology
jane.seto@mcri.edu.au

 

Available as Masters Project: No

Duchenne muscular dystrophy (DMD) is the most common, inherited childhood muscle disease and affects 1 in 3500 boys. Most patients succumb to the disease in their 20's due to cardiac and respiratory failure. DMD is caused by the loss of a critical skeletal muscle protein, dystrophin, and results in recurrent muscle damage. There is currently no cure for DMD, but corticosteroids are effective in reducing inflammation and slowing disease progression. Long term corticosteroid use however causes weight gain and muscle loss, which creates additional health problems for patients with DMD.

ACTN3 is known as "the gene for speed" and is associated with muscle strength and power. Approximately 1 in 5 people worldwide do not produce the ACTN3 gene product, alpha-actinin-3, in their muscles and have slightly lower muscle strength (within normal human variation) than people who have alpha-actinin-3. Interestingly, we found that muscles lacking alpha-actinin-3 are partially protected from damage in mouse models of DMD and ACTN3.

Recently, we also found that healthy mice lacking alpha-actinin-3 do not suffer as much corticosteroid-induced muscle loss. Our aim now is to determine if the presence or absence of alpha-actinin-3 will influence how muscles respond to corticosteroids using mouse models of DMD. This research will provide valuable preclinical data to identify DMD patients who may experience greater muscle loss with corticosteroid treatment, and may otherwise respond better to other classes of anti-inflammatory drugs that carry fewer side effects.

This project will involve animal handling and laboratory-based techniques such as molecular biology, immunohistochemistry, western blotting and muscle physiology to examine the structural, metabolic and signaling changes in skeletal muscle.

Back to Project List

2. Examining the evolutionary role of alpha-actinin-3 in adaptive thermogenesis

Dr Jane Seto
Neuromuscular Research
Cell Biology
jane.seto@mcri.edu.au

 

Available as Masters Project: Yes

Alpha-Actinin-3 is a skeletal muscle protein expressed primarily in fast-glycolytic fibres. It is responsible for maintaining sarcomeric integrity by cross-linking other muscle proteins, such as skeletal actin. We identified a common null polymorphism (R577X) in human alpha-actinin-3. An estimated 1.5 billion people worldwide are homozygous for the X-allele which results in the complete absence of the alpha-actinin-3 gene and protein. While alpha-actinin-3 deficiency does not cause disease, the 577 X-allele has undergone strong recent positive selection, following the migration of modern humans out of Africa. This data suggests that the absence of alpha -actinin-3 is evolutionary advantageous, however the mechanism of this positive selection has not been determined.

We have developed an alpha-actinin-3 knockout mouse (Actn3 KO) mimics the human muscle phenotype and provides a useful model to assess the role of alpha-actinin-3. Recently alpha-actinin-3 has been identified in Brown Adipose Tissue (BAT), a key heat producing organ, known to influence cold adaptation. While much is known about the role of alpha-actinin-3 in skeletal muscle, we have only just begun to understand its function in BAT.

Using the Actn3 KO mouse, this project will study the role of alpha-actinin-3, in both skeletal muscle and BAT in response to cold stimuli. The project will involve animal handling and laboratory-based techniques such as immunohistochemistry, western blotting and quantitative real-time PCR (RT-qPCR) to further study the role of alpha-actinin-3 in adaptive thermogenesis.


Back to Project List
 

3. Examining the effect of alpha-actinin-3 deficiency in skeletal muscle injury

Dr Jane Seto
Neuromuscular Research
Cell Biology
jane.seto@mcri.edu.au

 
 

Available as Masters Project: Yes

We have identified a common genetic variant in the alpha-actinin-3 (ACTN3 R577X) gene that results in absence of the fast muscle fibre protein, in ~20% of the world's population. This equates to ~1.5 billion people worldwide being completely deficient in alpha -actinin-3. Loss of alpha -actinin-3 does not cause disease but its absence significantly influences muscle function in both the general population and elite athletes by altering the muscles structure and metabolism.


We have developed a model of alpha -actinin-3 deficiency in mice (Actn3 KO). The Actn3 knockout (KO) mouse model mimics much of what we seen in humans. Actn3 KO mice run further on a treadmill, are able to train more efficiently and have an altered metabolic profile, due to a shift in the muscle to a more oxidative phenotype. Our data, generated over the last 8 years, provides strong evidence that alpha -actinin-3 influences normal variation in skeletal muscle function.


This project aims to determine how alpha -actinin-3 deficiency influences the muscles response to damage and its ability to regenerate following acute injury. We will use notexin to induce targeted muscle damage in both Actn3 WT and KO mice and examine the molecular and histological changes over time. The project will involve animal handling and laboratory-based techniques such as immunohistochemistry, western blotting and quantitative real-time PCR (RT-qPCR) to further study the role of alpha-actinin-3 in muscle damage/regeneration.


Back to Project List
 

4. Modelling childhood leukaemias using human pluripotent stem cells

Ms Elizabeth Ng
Blood Cell Development & Disease
Cell Biology
T +61399366014
E elizabeth.ng@mcri.edu.au

 

Available as Masters Project: Yes

Although the prognosis of childhood leukaemia has improved, there are still children with types of leukaemias for whom survival remains poor. A particular group with difficult to treat leukaemia are those who develop the disease in infancy. In a high proportion of these children, their leukaemic cells have a specific genetic abnormality that involves the abnormal fusion of the MLL1 (KMT2A) gene to variety of other partner genes. There has been significant progress using mouse models to increase our understanding of the manner in which MLL fusion proteins activate genes and drive cancer. However, progress is limited by the lack of robust human cell systems to study these childhood leukaemias and to use as a screening platform for potential therapeutic agents.

We have developed methods to differentiate human pluripotent stem cells (PSCs) into blood cells that resemble precursors of haematopoietic stem cells, the cell type that sustains blood formation throughout life (Ng et al, Nat Biotechnology 2016). Using this system, we can generate precursors of all the blood lineages, including cell types in which MLL mutations are first thought to arise. This capacity places us in a position to model the development of blood cells and to understand how MLL fusion genes cause childhood leukaemia. This endeavour will greatly expand our possibilities for understanding disease mechanisms and for studying the potential of new therapeutics in human cells.

In this project, MLL fusion genes will be put into the hPSCs and the effects on differentiation and cell growth will be studied. We will also determine the susceptibility of oncogene expressing cells to anti-cancer drugs


Back to Project List
 

5. Engineering artificial bone marrow

Ms Elizabeth Ng
Blood Cell Development & Disease
Cell Biology
T +61399366014
E elizabeth.ng@mcri.edu.au

 

Available as Masters Project: Yes

Haematopoietic stem cells give rise to all of the various cell types found in the blood, including those belonging to erythroid (red cells), myeloid and lymphoid (immune cells) lineages. In bone marrow failure syndromes, HSCs are lost, eventually resulting in the collapse of the blood system, a scenario that is sometimes fatal. The generation of haematopoietic stem cells (HSCs) from the in vitro differentiation of human pluripotent stem cells would benefit individuals with bone marrow failure who lack a perfectly matched HSC donor. However, the generation of HSCs in vitro has proved elusive, reflecting a failure to generate the correct cells and/or to provide a suitable stem cell niche. We have improved pluripotent stem cell differentiation methods to yield cells that are transcriptionally similar to 'preHSCs' that develop during early human embryogenesis .However, these cells still require further maturation to become therapeutically useful HSCs.

In adults, HSCs reside in the bone marrow, where they interact with a variety of endothelial and stromal cells. In this project we will generate an artificial human bone marrow-like microenvironment into which we can seed pluripotent stem cell-derived 'preHSCs' and determine whether this enables further maturation to yield true HSCs.Reconstruction of an artificial bone marrow will require the generation cell types such as cartilage precursors, macrophage like osteoclasts and vascular and haematopoietic components.

This project will involve generating the above cell types and combining them to generate an artificial bone marrow like culture system


Back to Project List
 

6. In vitro models of type 1 diabetes

Ms Elizabeth Ng
Blood Cell Development & Disease
Cell Biology
T +61399366014
E elizabeth.ng@mcri.edu.au

 

Available as Masters Project: Yes

Type 1 diabetes is a condition in which the immune system destroys the body's cells that produce insulin, the hormone controlling the level of glucose in the blood stream. Because of this, individuals with Type 1 diabetes must assiduously monitor their blood glucose levels and inject insulin 3-4 times per day. This condition affects around 110,000 Australians and, as yet, neither cause nor cure has been identified. In this project, we will use stem cell models to investigate mechanisms underlying type 1 diabetes, with particular emphasis on the interaction between cells of the immune system and insulin producing beta cells.

Beta cells reside in pancreatic islets, small clusters of endocrine cells that secrete hormones directly into the blood stream. In type 1 diabetes, residual islets can contain a mixture of different immune cells, including effector cells such as CD4 and CD8 T-cells and NK cells, as well as antigen presenting cells like macrophages, dendritic cells and B-cells. We have developed methods for generating many of these different cell types from human pluripotent stem cells. We also have protocols for deriving insulin producing beta cells from the same pluripotent stem cell lines, providing an opportunity to directly observe interactions between beta cells and cells of the immune system.

This project will involve generating combinations of the above cell types and observing their direct interactions using time lapse microscopy.


Back to Project List
 

7. How to transfer neural precursor cells to the aneural colon for cell therapy for the birth defect Hirschsprung disease.

 

Mr Lincon Stamp
Embryology
Cell Biology
T +61383416301
E lincon.stamp@mcri.edu.au

 

Available as Masters Project: Yes

The gut's own nervous system, the enteric nervous system (ENS), arises early in development from migratory precursor cells. In Hirschsprung disease, the distal-most colon is not colonised by these cells and so it fails to develop an ENS. This means the colon cannot function once the baby is born. The current treatment for this fatal birth defect is to surgically remove the non-functional part of the baby's colon, and join the upstream functional colon to the rectum. This saves the patient's life but loss of distal colon results in poor quality of life. Recently the notion has been presented that the ENS of the distal colon could be repopulated with ENS precursor cells at neonatal stages, so avoiding surgical colon removal. The two crucial questions are: 1) How to obtain the appropriate cells in appropriate numbers, and 2) How to transfer these cells into the distal colon. This project focuses on the second question, using firstly an animal model, the avian embryo, and secondly, pig colon tissue obtained at surgery. The avian model is chosen because the tissue maturity of the late stage embryonic avian colon resembles that of a human neonate, and because avian ENS precursor cells are readily obtainable. The pig model closely resembles human tissue in structure and size. Labelled ENS precursor cells will be seeded and grown on a polymer membrane which will then be wrapped onto the outer surface of the colon. The ability of the ENS precursor cells to penetrate the colon tissue will be assayed to test the practical efficacy of this method of cell transfer.


Back to Project List
 

8. How to increase numbers of neural precursor cells in vitro for cell therapy for the birth defect Hirschsprung disease.

Mr Lincon Stamp
Embryology
Cell Biology
T +61383416301
E lincon.stamp@mcri.edu.au

 

Available as Masters Project: Yes

The gut's own nervous system, the enteric nervous system (ENS), arises early in development from migratory precursor cells. In Hirschsprung disease, the distal-most colon is not colonised by these cells and so it fails to develop an ENS. This means the colon cannot function once the baby is born. The current treatment for this fatal birth defect is to surgically remove the non-functional part of the baby's colon, and join the upstream functional colon to the rectum. This saves the patient's life but loss of distal colon results in poor quality of life. Recently the notion has been presented that the ENS of the distal colon could be repopulated with ENS precursor cells at neonatal stages, so avoiding surgical colon removal. The two crucial questions are: 1) How to obtain the appropriate cells in appropriate numbers, and 2) How to transfer these cells into the distal colon. This project focuses on the first question, using firstly real embryonic ENS precursor cells from an animal model, the avian embryo, since these are easily and cheaply obtained. A second source will be human ENS precursor-like cells induced from human pluripotent cells. Both these cell types will be exposed to growth factor and small molecule regimes to inhibit cell differentiation and promote cell proliferation, the regimes being based on known effectors of normal ENS development. This project will increase our ability to produce ENS precursor cells in large numbers for proposed therapeutic use.


Back to Project List
 

Clinical Sciences

9. Haemostatic system in Fontan patients with liver dysfunction

Ms Chantal Attard
Haematology Research
Clinical Sciences
T +61399366551
E chantal.attard@mcri.edu.au

 

Professor Paul Monagle
Haematology Research
Clinical Sciences
T +61393455161
E paul.monagle@mcri.edu.au

 

Available as Masters Project: Yes

 

The Fontan procedure is the last of a series of operations offered to children with a single functioning ventricle. It is widely accepted that patients with a Fontan are at an increased risk of thrombosis due to a number of factors associated with their surgical procedure. These include: abnormalities in blood flow, endothelial dysfunction, as well as inherent abnormalities to the coagulation system. Furthermore, it is now recognised that liver dysfunction is common in this population, particularly due to increased systemic pressure.

The impact of liver dysfunction on the coagulation system of Fontan patients has never been investigated. Considering that the liver plays an essential role in the production of coagulation proteins, the impact of abnormalities in liver function may play a significant role in the dysregulation of the coagulation system that lead to thrombotic complications in this patient population.

This will be a detailed, laboratory-based clinical study investigating the blood clotting system in Fontan patients with liver disease.

Note: Samples and clinically relevant data for this study have been collected and the primary role of the Honours student will be to complete the laboratory testing and correlate the results to the known clinical outcomes.


Back to Project List
 

10. Characterisation of the specificity and activity of bio-engineered antibodies in children

A/Professor Christoph Hagemeyer
Australian Centre for Blood Diseases, Monash University
T (03) 990 30122
E Christoph.Hagemeyer@monash.edu

 

Available as Masters Project: No

This is a collaborative project between the Haematology Research laboratory at the Murdoch Children's Research Institute and the NanoBiotechnology laboratory at the Australian Centre for Blood Diseases.

The project will utilise recently developed antibody fusion molecules and targeted nanoparticles for the sensitive detection and safe treatment of thrombosis. These specifically modified recombinant antibodies can deliver imaging tracer and a therapeutic payload with high precision and reduced adverse effects; this is achieved by using novel bio-enzymatic conjugation methods allowing site-specific modification without affecting antibody function.

Specific state of the art antibodies targeting activated platelets and fibrin have previously been made and extensively characterised by A/Prof Hagemeyer at the ACBD. Whilst the specificity and activity of these antibodies have been tested in animal models of human disease and on human tissue ex vivo there are currently no data on the specificity and effect of these antibodies in blood samples obtained from children.

The fact, that the blood clotting system changes with age, concept known as Developmental haemostasis, has been proven conclusively. The Haematology Research Team at MCRI leads the World in this field with both laboratory and clinical research. Our studies have demonstrated age specific differences in concentration, function and structure of key haemostatic proteins and their response to anticoagulants. We have also shown differences in platelet phenotype and response to agonists, as well as differences in the mechanism of thrombin generation and clot structure in neonates and children compared with adults.

Considering these key age-specific differences in the blood clotting system, it is crucial to investigate the specificity and activity of existing bio-engineered antibodies in blood samples obtained from children; with a view of their possible use for disease detection and treatment in children affected by thrombosis and potentially the biotechnological generation of new, unique antibodies more specially tailored for children.

 


Back to Project List
 

11. Investigation of the in vitro effect of the antiplatelet drug Tirofiban in children

Ms Mara Galli
Haematology Research
Clinical Sciences
E mara.galli@mcri.edu.au

 

Professor Paul Monagle
Haematology Research
Clinical Sciences
T +61393455161
E paul.monagle@mcri.edu.au

 

Available as Masters Project: Yes

Tirofiban (Aggrastat) is an antiplatelet drug that functions by inhibiting the glycoprotein IIb/IIIa platelet receptor. This synthetic non-peptide inhibitor is specifically responsible for blocking the interaction between fibrinogen and the GP IIb/IIIa receptor on the platelet surface, and hence preventing platelet aggregation.

Despite its current use in hospitalised children, the safety and efficacy of Tirofiban have never been established in this especially vulnerable population. In fact, to date, there has not been a single study of Tirofiban in children, with all evidence arising from adult studies.
Considering that:
1. Bleeding is the most common adverse reaction associated with the use of Tirofiban.
2. Antiplatelet therapy is not routinely monitored in children at the Royal children's Hospital (RCH).
3. There are fundamental differences in platelet phenotype and response to agonists that exist between children and adults (Yip et al 2013; Yip et al 2015).

It is imperative to understand the effect of Tirofiban on platelets from children. This study will utilise flow cytometry, as a robust and sensitive tool for measurement of platelet function, to determine the differences in the in vitro effect of Tirofiban in infants, children and adults.

This first ever study of Tirofiban effect on platelets from children of different ages will provide essential data that will guide future use of this drug in hospitalised children. The results of this study will directly inform clinical practice at the RCH, and will be used by clinicians nationally and internationally.


Back to Project List
 

12. Investigation of the age-specific changes in Blood Microparticles

Ms Mara Galli
Haematology Research
Clinical Sciences
E mara.galli@mcri.edu.au

 

Available as Masters Project: Yes


Cellular Microparticles are heterogenous membrane vesicles of that are shed by almost all cells in response to cellular activation and apoptosis. The process of microparticle formation is a physiological phenomenon. However, increase in microparticle formation has been associated with inflammatory and autoimmune diseases, atherosclerosis, as well as malignancies.

Microparticles vary in size from 100 - 1000 nm and express antigens specific to their parental cells. The complexity of surface receptors in addition to the content of cytokines, signaling proteins, mRNA, and microRNA confirms the role of microparticles in exchange of biological signals and information.

Blood microparticles arise from the cellular components of blood, as well as the endothelial lining of blood vessels. Each of these individual populations of microparticles (i.e. platelet microparticles, endothelial microparticles) have been studied in the setting of disease.

While studies in adults demonstrate that platelet microparticles constitute 70-90% of the microparticles in the bloodstream, this has never been investigated in children. In addition, to date, there have been no investigations of the age-specific differences in the composition of the blood microparticles. Question such as: "Do particular microparticles dominate early in life and does this change during the process of ageing?" is yet to be answered.

Characterization of the age-related differences in the microparticles of the healthy population will provide new insights into normal growth and development and in our understanding of developmental biology. Given that the incidence of majority of diseases (i.e. diabetes, thrombosis, cardiovascular disease, cancer) increase with age, these results will provide the basis for understanding the age of onset of these diseases, as well as identification of potential biomarkers and therapeutic targets. This has the potential to impact on high frequency, high importance disease of adults.


Back to Project List
 

13. Modulating fibrosis and myocardial injury in Muscular Dystrophy

Doctor Adam Piers
Heart Research
Clinical Sciences
T +61399366458
E adam.piers@mcri.edu.au

 

Assoc. Prof Jason White
Musculoskeletal Research
Cell Biology
T +61399366020
E jason.white@mcri.edu.au

 

Available as Masters Project: Yes


Duchenne muscular dystrophy (DMD) is an X-linked muscle-wasting condition that affects approximately 1 in 3600 boys. It is caused by a mutation in the dystrophin gene, which results in the complete absence of the dystrophin protein. The absence of dystrophin significantly weakens the connection between the muscle cytoskeleton and extracellular matrix, leading to mechanical instability of the sarcolemma, inflammation, necrosis, and the replacement of muscle tissue with fat and fibrotic tissue. This deterioration is most obvious in skeletal muscle, initially affecting the limbs, before spreading to respiratory muscles and heart by the second decade of life. Currently there is no cure or effective therapy to prevent DMD from progressing to premature death.


The skeletal muscle pathology is currently treated using glucocorticoid drugs. However the management of cardiac dysfunction is more commonly addressed after heart symptoms first present. The current standard of care in the management of cardiac dysfunction involves the use of angiotensin-converting-enzyme (ACE) inhibitors and ß-adrenoreceptor blockers, an approach arising from heart failure management in adults, but with relatively limited study in DMD children.

Recent work has proposed the involvement of mitochondria-dependent cell death and irreversible opening of the mitochondrial permeability transition pore (MPTP) in the pathogenesis of the dystrophic myopathies. Early enhanced opening of the MPTP increases the susceptibility of dystrophin-deficient muscle to stress-induced cell injury. The genetic ablation of the MPTP-sensitizing protein cyclophilin-D has been reported to reduce fibrosis in dystrophic muscle, and improve muscle function in mouse models of muscular dystrophy, i.e., mdx mouse. This study aims to test whether pharmacological targeting of the MPTP ameliorates the cardiac pathology in mdx mice. The work will inform whether the clinical use of perindopril in DMD patients may be augmented by the inclusion of an additional class of drugs that directly target muscle cell death via MPTP control.


Back to Project List
 

Genetics

14. Tuberous sclerosis and epilepsy: using resected tissue to understand pathogenesis

Doctor Sarah Stephenson
Neurogenetic Research (BLC)
Genetics
T +61399366563
E sarah.stephenson@mcri.edu.au

 

Doctor Joseph Yang
Neuroscience Research
Clinical Sciences
E joseph.yang@mcri.edu.au

 

Dr Kay Richardson
Florey Institute of Neuroscience and Mental Health
T 61390356398
E kay.richards@florey.edu.au

 

Available as Masters Project: Yes

Tuberous sclerosis complex (TSC) is a multisystem disorder leading to benign tumours in multiple organs including the skin, kidneys, heart, lungs and brain. The most significant clinical features of TSC are neurological, with epileptic seizures being the most common and severe, particularly when they occur in early childhood. Seizures from TSC are often drug-resistant and incomplete control, especially during early childhood, is associated with adverse developmental consequences including
intellectual disability and autism.

The seizures of TSC originate in dysplastic lesions known as cortical tubers. Tubers are well circumscribed and usually confined to a single gyrus, often extending into the subcortical white matter. They are characterised by disorganised cortical lamination and abnormal cells including dysmorphic neurons and balloon or giant cells. Our recent experience with modelling tuber microstructure using ultra-high field (16.4 Tesla) ex vivo diffusion MRI acquired from the resected tuber specimens also plausibly demonstrated localisation of dyslaminated cortex and dysmorphic neurons in the tuber centre.

This suggests that it is the tuber centre that is likely to contain the highest density of dysmorphic neurons. We have qualitative data from visual analysis of tubers using routine histopathological techniques to support this, however neither we nor any other group have systematically tested this hypothesis by quantitative analysis of the density of dysmorphic neurons in various regions of a tuber. In this project, the candidate will use immunostaining and stereological techniques to determine the gradient density of dysmorphic neurons in resected tuber tissues. These histology findings will be overlayed with our ultra-high field ex vivo diffusion MRI data to create a 3D reconstruction of tubers.


Back to Project List
 

15. Using cerebral organoids for the study of tuberous sclerosis complex 

Doctor Sarah Stephenson
Neurogenetic Research (BLC)
Genetics
T +61399366563
E sarah.stephenson@mcri.edu.au

 

Available as Masters Project: Yes

Tuberous sclerosis (TSC) is a multi-system disorder leading to benign tumours in several organs including the skin, kidney, heart, lung and brain. The most significant clinical sequelae of TSC are neurological, with epileptic seizures being the most common and severe, particularly when they occur in early childhood. The seizures are often resistant to treatment with drugs and arise in abnormal brain regions called tubers. If the seizures are not suppressed or otherwise managed, especially during early childhood, they are often associated with adverse developmental consequences including intellectual disability and autism.

The ability to model neurological disorders utilising cerebral organoids represents an invaluable tool for both delineating disease processes and investigating the fundamental mechanisms required for normal human brain development. Tubers are three-dimensional structures characterised by markedly disturbed cortical layering and morphologically abnormal cell types. Little is known about the molecular mechanisms leading to tuber development or the mechanism of seizure generation.

We are currently developing iPSC-derived cerebral organoid models to investigate the aetiology of tuber formation and resultant epilepsy. In this project the candidate will utilise molecular and cellular techniques including stem cell culturing, differentiation, immunostaining and advanced microscopy to analyse organoid models of TSC.


Back to Project List
 

16. Functional characterisation of a novel gene linked to autism spectrum disorder

 

Available as Masters Project: Yes

Autism Spectrum Disorder (ASD) is a complex and highly heritable neurodevelopmental disorder defined by deficits in social communication and repetitive behaviours with restricted interests. Over 300,000 Australians have ASD and the annual national economic cost is ~$9.7 billion. Whilst there have been many studies that have identified variants which are predicted to predispose to ASD, the challenge is to unravel which variants are truly contributing to the phenotype and the mechanisms by which they do so. Therefore a key requirement for understanding disease pathogenesis is the development of models that recapitulate the disease enabling key insights into basic underlying mechanisms. To this effort, we have already recruited 6 extended families, which consist of grandparents, parents, children, aunts, uncles and cousins. We have performed high throughput genetic screens on 1 family and have identified a candidate mutation and gene that segregates with the disorder.

This project will focus on characterising the function of the gene at a molecular level to understand how it contributes to ASD. Techniques will include differentiation of stem cells into neuron and glial cells and manipulating the cells using various drug treatments to determine ASD pathogenesis. Specific techniques will include tissue culture, real time PCR, western blot and enzyme activity assays. 


Back to Project List
 

17. Understanding RAB39B-mediated Parkinson's disease

Available as Masters Project: Yes

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 recently identified RAB39B as a novel gene for Parkinson's disease and we are currently investigating how RAB39B may be involved in the development of Parkinson's disease.
.
This project will characterise the gene and investigate pathogenic mechanisms underlying disease utilising molecular and cell biology techniques. Studies will utilise newly developed and unique induced pluripotent stem cells (iPSC) and mouse models to perform pre-clinical studies to characterise the disease process and identify potential therapeutic targets. Specific techniques will include tissue culture, real time PCR analysis, western Blot analysis, confocal microscopy.


Back to Project List
 

18. Solving Rare Diseases via the Australian Genomics Mitochondrial Disease Flagship

Available as Masters Project: Yes
 

A "rare disease" affects fewer than 1/2000 people but there are over 7000 rare diseases that collectively affect 5% to 10% of the population, many of whom suffer life-threatening diseases or lifelong chronic disease. Rare diseases are thus a major public health problem and affected families have often faced a long diagnostic odyssey in attempting to achieve a diagnosis. Australian Genomics is a collaboration of over 40 Australian centres seeking to translate new genomic technologies into improved outcomes for rare diseases and cancer. Mitochondrial (mito) diseases are one of the first flagship projects. They are the most common group of inherited metabolic disorders and highly complex since they comprise almost 300 different genetic disorders with a wide range of clinical phenotypes and types of inheritance.

In previous studies we have used whole exome sequencing or whole genome sequencing to achieve diagnostic yields of over 60% in retrospective cohorts, identifying over a dozen novel disease genes. This project will focus on a prospective national cohort of paediatric patients who fit entry criteria for having probable mitochondrial disease. Recruitment commenced in early 2017, with half the cohort having whole genome and half whole exome sequencing over a 2-year period. Some patients will have sequence variants identified that have been previously shown to cause disease, which are straightforward to classify. Others will have novel sequence variants identified in known disease genes or in candidate disease genes not previously linked to disease. The project will use a range of bioinformatic, molecular, biochemical, immunochemical and cell biology approaches to investigate causality of novel variants. This will contribute to obtaining definitive diagnoses in previously unsolvable cases, understanding pathogenic mechanisms of disease and developing methods that can be applied to understanding the genetics of a wide range of other rare diseases.


Back to Project List
 

19. Characterisation of the parkin protein and how it causes Parkinson disease 

Doctor Sarah Stephenson
Neurogenetic Research (BLC)
Genetics
T +61399366563
E sarah.stephenson@mcri.edu.au

 
 

Available as Masters Project: Yes

Parkinson's disease (PD) is a neurodegenerative disorder with a complex aetiology and progression. Mutations in the parkin gene are the most common cause of early onset-PD. Pathologically PD is characterised by loss of dopamine producing neurons and Lewy bodies composed of aggregated of alpha-synuclein. We hypothesise that parkin plays a key role in eliminating toxic proteins such as alpha-synuclein from within the brain. Failure of parkin function results in the accumulation of toxic proteins and results in the development of PD. We are interested in how parkin functions with its co-regulated gene PACRG in protein turnover and neuron function. We have recently aged and a number of unique mouse models that are dysregulated for parkin/PACRG/alpha-synuclein in the laboratory. These will be characterised for markers of altered neuropathology, biochemistry and correlated with behaviour data already obtained.


Back to Project List
 

 

20. Human Stem Cell Models of Mitochondrial Disease

Available as Masters Project: Yes

Mitochondria are our cellular power plants that burn sugars, fats and proteins to generate energy. Each week in Australia a child is born with a mitochondrial disorder. Many of these children die in the first years of life and most suffer from severe disease, particularly affecting their brain and/or heart. Access to these tissues from patients is limited, making it difficult to assess the impact on mitochondrial and other pathways contributing to disease pathology. This project is part of a 5-year NHMRC-funded study to develop and characterize human stem cell models for over 20 genes in which knockout-type mutations cause inherited disorders of mitochondrial energy generation.


The overall aims are:


1) Assemble a representative panel of cellular models of OXPHOS disease in human Embryonic Stem Cells (hESCs) and human Induced Pluripotent Stem Cells (iPSCs) that can be used to study phenotypic rescue of novel defects, pathogenicity and treatment approaches.


2) Characterize pathogenic pathways in the most relevant cell lineages by assessing the impact of OXPHOS defects on the mitochondrial and cellular proteome of cardiomyocytes and neural cells generated from hESCs or iPSCs, as well as the impact on mitochondrial function and cellular physiology.


3) Define the impact of targeted therapeutic strategies in these models on the cellular proteome and other markers of cellular homeostasis.


The research project will thus involve generation of hESCs with CRISPR/Cas9 mediated gene disruption, or iPCs from mitochondrial disease patient fibroblasts, followed by confirmation of the impact on the targeted gene and pathway. Selected cell lines will then be differentiated to cardiomyocyte and/or neural lineages to enable comparison (with control cells) of the impact of the gene knockout on various aspects of mitochondrial and cellular function. These may include respiration, ATP synthesis, reactive oxygen species, mitochondrial membrane potential, redox balance, cellular stress response and quantitative proteomics. 


Back to Project List
 

21. Brain cells in a dish: strategies for novel therapeutics in the CDKL5 disorder

Dr Cas Simons
The University of Queensland
E c.simons@uq.edu.au

 

Available as Masters Project: No

The CDKL5 disorder is a rare X-linked neurodevelopmental disorder characterised by severe intellectual disability and seizures which appear in the first few months of life. There is no treatment for this devastating disorder and little is known about the biology of CDKL5 disorder.


The proposed research project will address the large knowledge gap on CDKL5 by examining if there is functional overlap between CDKL5 and MeCP2 (the gene responsible for Rett syndrome, which causes health problems that have a strong clinical overlap with the CDKL5 disorder) in regulating microtubule dynamics. Microtubules are the 'train tracks' that nerve cells use to deliver critical cargo to nerve connections called synapses. Any problems in the regulation of microtubules will impair nerve function. We have previously shown that microtubule dynamics are affected in Rett syndrome caused by mutations in MECP2.


Specifically, we plan to use cutting edge technologies developed by researchers at the MCRI that enable us to convert skin cells from patients with Rett syndrome and the CDKL5 disorder to develop a 'disease in a dish' model. We have already created induced pluripotent stem cells (iPSC) from patient fibroblasts with pathogenic CDKL5 variants, and have generated isogenic iPSC controls for each CDKL5 cell line using CRISPR-Cas9 gene correction. We will then differentiate iPSC into neurons and capture the overall gene profile in differentiated neurons carrying the CDKL5 mutations using RNA-seq. This will provide a global perspective of gene expression changes in response to CDKL5 mutations. Similar methodology has provided novel insights into gene regulation in a mouse model of RTT carrying Mecp2 mutations [32] and in the frontal cortex of the human Rett syndrome brain [33]. We will determine the validity of our candidate genes by high-throughput quantitative reverse transcriptase polymerase chain reaction. 

 


Back to Project List
 

22. HDAC6 inhibitors as a treatment for Rett syndrome: Resolving neuronal trafficking deficits

Dr Wendy Gold
Kids Research Institute, Westmead Children's Hospital
E wendy.gold@health.nsw.gov.au

 

Available as Masters Project: No


Rett syndrome is an incurable progressive genetic disease that causes girls to develop catastrophic severe motor, cognitive, neurological, and behavioural abnormalities. It is an X-linked genetic disorder most commonly caused by de novo mutations in the methyl-CpG-binding (MECP2) gene, which encodes a key transcriptional regulator protein, and affects about 1:9000 female births.
MeCP2-deficient neurons have a defective cytoskeletal architecture that compromises the trafficking of synaptic components such as mitochondria along the microtubule network. We have strong evidence that mitochondrial function and movement is disrupted in MeCP2-deficient fibroblasts. We are currently generating MECP2 mutant human neuronal cells. These will be generated from induced pluripotent stem (iPS) cells generated from Rett syndrome patients and differentiated into a neuronal lineage. From these cells we will assess mitochondrial activity (respiration, enzyme activity and ATP content) in MECP2-deficinet neuronal cells. We hypothesize that correcting this cytoskeletal defect could underlie a therapeutic solution for Rett syndrome. Our research has identified histone deacetylase 6 (HDAC6), an enzyme that post-translationally modifies microtubules, to be upregulated in MeCP2-deficient cells. As HDAC6 is a key regulator of the stability of the microtubule network it is a strong target for therapeutic intervention. Our laboratory has exciting preliminary data showing that inhibitors of HDAC6 can ameliorate the effects of MECP2 mutations in patient fibroblast cell lines and in a mouse model of Rett syndrome. We will determine the expression levels of key proteins known to be involved in Rett syndrome, and determine whether HDAC6 inhibition restores expression of these key targets. From the MECP2-deficinet neuronal cells we will also determine whether there are off-target effects of HDAC6 inhibition on mitochondrial function using a new class of drugs currently under investigation. If there are side-effects of these drugs, it may have relevance to their translation into clinical trials. 


Back to Project List
 

Infection and Immunity

23. Developing a new treatment for stomach cancer

Doctor Sohinee Sarkar
Mucosal Immunology
Infection and Immunity
E sohinee.sarkar@mcri.edu.au

 

Available as Masters Project: Yes


Infection with the cancer-causing bacteria Helicobacter pylori starts in childhood and lasts for life. This infection causes a chronic inflammation (gastritis) that can result in stomach cancer, globally the 3rd leading cause of cancer-related death. We have identified a genetic variant (a polymorphism) that increases the susceptibility of some people to this cancer. Individuals who have this polymorphism are five times more likely to get stomach cancer when infected with H. pylori, and this gene is highly expressed in cancer biopsies. Drugs against this gene target are already clinically available, meaning this discovery has the potential for a completely new treatment for stomach cancer. Stomach cancers arise as a result of severe inflammation driven by H. pylori mediated activation of the immune system, so this effect is likely due to genetic regulation of the immune cell response to bacterial stimulation.
AIMS: Key questions to be addressed by this project include 1) how this gene (and its polymorphism) make some people susceptible to stomach cancer and 2) whether drugs can protect against this cancer.
APPROACH: Human cell lines will be genetically modified with the latest genome editing technology and then stimulated with H. pylori. The immune response will then be quantified by measuring the cytokine response by ELISA. This will show how this gene affects the inflammatory response of human cells to these cancer-causing bacteria. Drugs that target this gene will also be tested in these assays, in order to identify candidates that might be used for the prevention or treatment of cancer.

Back to Project List

24. Analysis of gene regulations on gonocyte transformation into spermatogonial stem cells

Doctor Ruili Li
Surgical Research
Infection and Immunity
T +61399366757
E ruili.li@mcri.edu.au

 

Available as Masters Project: Yes

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 (neonatal germ cells) 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 aim of the project is to understand the molecular mechanism and regulation of early postnatal germ cell development/transformation of gonocytes into spermatogonial stem cells to provide possible clues for optimal timing of surgery for UDT to prevent infertility and testicular cancer.This project will focus on analysis of the gene regulations in gonocyte transformation and the effect of congenital UDT on gonocyte transformation using animal models and human UDT biopsies. The study will involve molecular biology, cell biology, histology. 


Back to Project List

25. The immune response to infection in early cystic fibrosis

Available as Masters Project: Yes

Cystic fibrosis (CF) is an inherited disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The commonest cause of death in CF is respiratory failure as a consequence of bronchiectasis (airway destruction). Disease begins in early life and is characterised by a diminished lung function that is related to infection with opportunistic pathogens, airway inflammation and structural changes. However, mucosal immunity in the early CF lung is not well studies and mechanisms of specific immune events that occur early in CF lungs are poorly understood. Immune factors that modify inflammation in the CF lung are likely to play a critical role in determining disease progression.

1) Characterise the mucosal immune response in the lungs of children with cystic fibrosis during the early stages of disease
2) Examine how this immune response changes with pathogenic infection

Bronchoalveolar lavage (BAL) cells and fluid from children less than 6 years of age will be analysed. The types of immune cells present in their lungs will be determined by flow cytometry. Existing immunity in BAL fluid from CF lungs will be measured by ELISA. The immune response of the BAL cells to infection will be measured by stimulating BAL cells in culture with pathogenic bacteria. The results will be related back to the clinical and infection status of the patient.

The immune response elicited to lung infections plays a critical role in modifying inflammation in the CF lung. Characterisation of this mucosal immune response will identify potential therapeutic targets via which inflammatory responses can be modified, with the potential of significantly impacting the extent and quality of life for patients suffering from CF.


Back to Project List
 

26. Targeting stem cells as a new treatment for stomach cancer 

Available as Masters Project: Yes

Stomach cancer has the 3rd highest mortality rate of all cancers worldwide and results largely from chronic inflammation caused by the bacterium, Helicobacter (H.) pylori. Current treatments, based on antibiotic eradication of H. pylori, have become progressively less effective, sparking efforts to find new ways to combat stomach cancer. Using a range of mouse genetic, cell/molecular and in vivo lineage mapping tools, this project will investigate the role of a recently discovered gastric epithelial 'reserve stem cell' population in the origins of stomach cancer, define molecular and/or H. pylori-related inflammatory signals that reprogram these cells into stomach-specific cancer stem cells (CSC) to give rise to tumour lineages, or premalignant precursor lesions, and establish translational rationale for targeting these cells to restrain or block disease progression.

Recent progress in cancer biology has been achieved by studies of CSC. The clinical potential of CSC in stomach cancer has been recognised but, until now, remains unexploited for therapy. Outcomes of this project will contribute to our understanding of (i) gastric reserve stem cells as inflammation-inducible CSC, (ii) how these cells impact cancer progression and (iii) how they might be targeted therapeutically to prevent disease. This information will help to inform novel approaches for stomach cancer prevention and treatment. This project would suit an ambitious and highly motivated individual who is keen to develop advanced skills in advanced cell/molecular biology and in using mouse genetic models of human disease. 


Back to Project List
 

27. Bacterial gene expression in pneumococcal pneumonia

Available as Masters Project: No

Streptococcus pneumoniae is the most common cause of community-acquired pneumonia, which is a leading killer of young children worldwide, and can also colonise the upper respiratory tract of healthy children. Our laboratory is interested in identifying genes involved in pneumonia pathogenesis, particularly those that are differentially expressed in disease vs colonisation. These genes could be candidates for novel prevention strategies and improved diagnostics for pneumococcal pneumonia. Using a combination of clinical samples collected from healthy children and pneumonia patients as well as in vitro assays, this project will examine pathogen gene expression and genomics using a variety of molecular methods.


Back to Project List
 

28. Synergistic interactions between Streptococcus pneumoniae and respiratory viruses on bacterial pathogenesis

Doctor Salvatore Manna
Pneumococcal Research
Infection and Immunity
T +61399366773
E sam.manna@mcri.edu.au

 

Available as Masters Project: No

Co-infections with influenza virus and bacterial pathogens (e.g. Streptococcus pneumoniae) can lead to severe respiratory infections. Clinical evidence suggests that a similar synergy exists between S. pneumoniae (the pneumococcus) and other viruses that are more commonly major causes of respiratory infection and hospitalisation of young infants. Using in vivo models, this project will investigate the how respiratory viruses such as influenza, can 1) augment various aspects of pneumococcal pathogenesis and 2) how prevention strategies targeting one pathogen can indirectly impact the other.


Back to Project List
 

29. Bacterial factors for pneumococcal transmission

Doctor Salvatore Manna
Pneumococcal Research
Infection and Immunity
T +61399366773
E sam.manna@mcri.edu.au

 

Available as Masters Project: No

Streptococcus pneumoniae (the pneumococcus) is a leading killer of children worldwide. Transmission between hosts is a key step of pathogenesis and also underpins herd protection. Despite this importance, little is known about the bacterial factors that mediate transmission. This project will use mutagenesis (targeted, and transposon mutagenesis with next-gen sequencing) to identify the bacterial factors, and to assess their importance in our established in vivo transmission model.


Back to Project List
 

30. Examination of cross-neutralising immunity following HPV vaccination in Fiji

Mr Zheng Quan Toh
Pneumococcal Research
Infection and Immunity
T +61393455554
E zheng.quantoh@mcri.edu.au

 

Available as Masters Project: Yes


Cervical cancer is the fourth most common cancer in women worldwide, caused by infections with the human papillomavirus (HPV), with highest rates in low- and middle-income countries. Most cases (70%) are due to oncogenic HPV types 16 and 18 which are included in the two widely used prophylactic HPV vaccines, 2vHPV (Cervarix, GSK Biologicals) or 4vHPV (Gardasil, Merck) given as a 3-dose schedule over six months. Three other oncogenic HPV types 31, 33 and 45, represent an additional 15% of cervical cancer cases. For countries using 2vHPV or 4vHPV, cross-neutralising antibodies to non-vaccine types HPV31/33/45 are important as it may provide broader protection against a wider range of oncogenic HPV types. We have recently completed a study examining immunity in Fijian girls who received 1, 2 or 3 doses of 4vHPV six years earlier as well after a booster dose of 2vHPV. This Honours project aims to specifically examine cross-neutralising immunity in blood following 4vHPV using a combination of approaches, including HPV neutralisation assays and cellular immune assays. This is the first such study to examine the persistence of cross-neutralising antibodies following HPV vaccination.


Back to Project List
 

31. Molecular Epidemiology of Severe Respiratory Syncytial Virus Infections in Children under 2 years of age

Doctor Danielle Wurzel
Respiratory Diseases
Infection and Immunity
E danielle.wurzel@mcri.edu.au

 

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

 

Available as Masters Project: Yes

Respiratory syncytial virus (RSV) is the most common cause of acute lower respiratory tract infections in young children. It is a major reason for hospitalisation worldwide and a leading cause of infant mortality particularly in low-resource settings. Whilst most children are infected with RSV in the first two years of life, it is unclear why some children develop more severe disease whilst others develop only mild symptoms. This may be due to host factors such as the immune response or characteristics of the virus e.g. specific variations in the virus genome. The aim of this study is to identify the major risk factors of severe RSV infection in young children with a specific focus on the genetic characteristics of the RSV strains circulating in Australia.

Back to Project List
 

32. Immunomodulatory effects of Vitamin D on the host response to bacterial and viral infections

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

 

Available as Masters Project: Yes


Infections with the Streptococcus pneumoniae and Respiratory Syncytial Virus are a major cause of morbidity and mortality in children less than 5 years of age. In particular, bacterial-viral co-infections cause substantial more inflammation and disease. The host response to infection involves activation of both innate and adaptive immunity both in the mucosal tissue as well systemically. Vitamin D has been shown to have a variety of biological effects including beneficial effects on the immune system. These include modulation of cytokine production, T-lymphocyte function and inflammatory responses, suggesting that Vitamin D may have an important function in the control of bacterial and viral infections. This project aims to characterise the effects of Vitamin D on immune cell populations in response to bacterial and/or viral co-infection. This study will use a variety of techniques including human immune cell culture and stimulation, flow cytometry and cytokine assays


Back to Project List
 

33. Inhaled RSV therapeutics: Aerosol delivery of novel therapies to the infant lung 

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

 

Available as Masters Project: Yes

Respiratory syncytial virus (RSV) is the most common cause of acute lower respiratory infection in young children <5 years. There is no RSV vaccine currently available. The only preventive treatment available is passive protection with Palivizumab, an RSV specific monoclonal antibody (mAb). However, this is costly, at A$7,500 per course and requires repeated injections throughout the RSV transmission season. Developing safe and effective methods of therapeutic administration to protect infants at the highest risk of respiratory illness from RSV has been challenging, and advances are urgently needed. Aerosol delivery of a RSV mAb to the deep lung may be the most effective method, to protect infants from RSV. 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 biomolecules in sheep models. This project aims to explore a novel strategy for RSV therapeutic delivery. We will test whether using a novel method of delivery for Palivizumab, a respiratory syncytial virus (RSV) specific mAb, will effectively prevent and reduce severe RSV infections in neonatal lambs. The student will conduct studies to determine if therapeutic mAb delivery via the aerosol route will be effective to prevent RSV disease in an infectious infant lamb model. The student will use clinical measurements, viral assays, immological assays and molecular assays to validate the responses.  Students will work closely with a team of molecular biologists, clinicians and engineers.

34. Molecular mediators of gene: environment interactions underlying early life programming of cardiovascular and metabolic risk 

Available as Masters Project: Yes


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 change 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.

Population Health

35. The early origins of autism: a focus on epigenetic differences within identical twin pairs 

Doctor Yuk Loke
Environmental & Genetic Epidemiology Research
Population Health
T +61399366263
E jane.loke@mcri.edu.au

 

Available as Masters Project: No

Autism is a complex and heterogeneous neurodevelopmental disability that impacts social communication and behaviour. Currently, behaviour-based assessment is needed for diagnosis, along with clinical assessments. Despite international effort and funding, progress has been slow towards finding its biological basis. It is likely to originate before birth in most cases but is often not diagnosed until at least 2-3 years of age.

An increasing number of genetic abnormalities are being found in some children with autism, but none are sufficiently common or specific to act as diagnostic tests. There is an increasing understanding that most human disease results from genetic and environmental interactions, the latter arising very early in life. Epigenetics, the molecular "switches" that turn genes on or off, are helping us to understand how environment might mediate changes to gene expression that result in predisposition to disease. Importantly, it may be possible to change the epigenetic "switches." Identical twins are ideal for studying epigenetics because they are otherwise genetically identical. In this project we bring together expertise in epigenetics and clinical care. No-one has previously taken this approach.

In our definitive study we want to discover genes that have a different epigenetic state in autism to improve our understanding of causative mechanisms and identify potential biomarkers for risk. This is also the latest in a series of similar projects we have offered, each one leading to a successful Honours thesis. 


Back to Project List
 

36. The application of a novel dried blood spot collection device for future diagnostic applications 

Dr Andrew Gooley
Trajan Scientific and Medical
T (0) 3 9837 4200
E agooley@trajanscimed.com

 

Available as Masters Project: No

The dried blood spot technique, in which heel prick (babies) or finger-tip blood (children and adults) blood is dried onto filter paper is the leading method in screening for inherited metabolic diseases. A growing field of research is addressing the use of this technique in other clinical applications including genetic testing for a wide variety of conditions, metabolomics, lipidomics and proteomics. There are, however, some limitations to the filter paper approach.

We are working with a novel, easy-to-use pen-like device, HemaPEN, which will be used as an alternative to venous blood and dried blood spot collection. We are currently testing the precision, integrity and ease of use of this device and optimising protocols for DNA extraction and storage. This project will involve a parallel analysis of other applications such as metabolites and/or proteins. It will build on the experience of A/Prof's Craig's group who have pioneered the use of dried blood spots for genetic and epigenetic analysis and the group's collaboration with Trajan Scientific and Medical.

This lab-based project is ideal for a student with an interest in biological sampling, biochemistry and/or diagnostic and predictive testing.