Lab based projects

Laboratory based Honours and Masters Projects offered in 2017.

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 Honours/Masters 2017 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. Development of a method for transferring neural precursor cells to the aneural colon for cell therapy for the birth defect Hirschsprung disease.
2. How does ACTN3 influence muscle wasting during active ageing?
3. Adaptive thermogenesis and the evolution of alpha-actinin-3 (R577X)
4. Examining the effect of alpha-actinin-3 deficiency on skeletal muscle injury
5. Epigenetics and other stress-related biomarkers in depression
6. Epigenetics as a mediator of gene: environment interactions underlying early life programming of cardiovascular and metabolic risk.
7. The utility of epigenetic profiling to improve outcome in childhood CNS tumours.
8. Prognostic utility of epigenetic biomarkers in paediatric leukaemias.
9. Detecting and Investigating the molecular biology of novel translocations and mutations in paediatric cancer
10. Understanding the causes of craniofacial birth defects
11. Induction of different cell lineages from PIK3CA mutation-carrying iPSC cells
12. Rapamycin effect on endothelial thrombogenic potential

Clinical Sciences

13. Towards developing an individualised approach to neonatal respiratory support: Assessing the usefulness of biomarkers of lung injury and function

Genetics

14. Solving Rare Diseases via the Australian Genomics Health Alliance
15. Human Stem Cell Models of Mitochondrial Disease
16. Master regulator of chromosome compaction, DNA repair and gene expression, and impact on disease aetiology
17. The role of centromere defects in cancer formation and progression
18. Genome-editing: applications in stem cells and gene therapy
19. Epigenetic modifications of the human beta-globin locus: new therapeutic targets for haemoglobin disorders
20. Does skewed X-linked inactivation predict the severity of Rett Syndrome?
M1. Developing a diagnostic blood test for autism
21. Investigating repeat-associated disease mechanisms in Friedreich ataxia
22. Investigating the factors involved in FXN silencing in Friedreich ataxia
23. Determining the genetic basis of novel neurogenetic disorders
24. Investigating the molecular basis of Parkinson's disease
25. Identifying the genetic causes of brain malformation in children
26. Identifying novel genetic targets that underlie Synucleinopathy and Tauopathy.
27. Characterisation of the parkin protein and how it causes Parkinson's disease
28. A genetic approach to identifying drug targets for prevention of deafness

Infection & Immunity

29. Streptococcus pneumoniae gene expression and pathogenesis
30. Investigating the pneumococcal whole cell vaccine in an infant mouse model of pneumonia
31. Interactions between Streptococcus pneumoniae and respiratory viruses
32. Immunomodulatory effects of Vitamin D on the host response to respiratory infections
33. Exploring a new approach for preventing stomach cancer
34. Animal model with undescended testes may provide the key to understanding cellular interactions necessary for testicular descent
35. Effect of congenital UDT on Gonocyte development
M2. Pneumococcal carriage dynamics in children hospitalised with acute respiratory infection in Fiji
72. Impact of multiple pathogen infection on respiratory syncytial virus evolution

Population Health 

36. Developing novel methods to diagnose and predict the prognosis of food allergy
*New* 73. An epigenetic analysis of twins discordant for epilepsy

 
 

Project Descriptions:

Cell biology

1. Development of a method for transferring neural precursor cells to the aneural colon for cell therapy for the birth defect Hirschsprung disease.

 

Available as Masters Project: Yes

In Hirschsprung disease, the distal-most colon is not colonised by neural precursor cells embryonically and so it fails to develop an intrinsic enteric nervous system (ENS). This means the colon cannot function once the baby is born. The current treatment for this fatal birth defect is, at neonatal stage, to surgically remove the non-functional part of the colon, and join the upstream functional colon to the rectum. This saves the patient's life but loss of distal colon typically 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 partial 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 late embryo avian embryo, and secondly, human and pig colon tissue obtained at surgery. The avian model is chosen because the maturity of the late embryo avian colon resembles that of a human neonate, and because avian ENS precursor cells are readily obtainable, and the pig model closely resembles human tissue in structure and size. We have carried out successful preliminary experiments using this approach on neonatal mouse colon, but this tissue is too immature to be an appropriate model for the human neonatal colon. Labelled ENS precursor cells will be seeded and grown on a polymer membrane which will then be wrapped onto the outer or serosal surface of the colon. The ability of the ENS precursor cells to penetrate (transmigrate across) the serosa will be assayed, and chemical manipulation of the serosa will be attempted to increase cell penetrability.

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2. How does ACTN3 influence muscle wasting during active ageing?

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

Available as Masters Project: Yes

Alpha-Actinin-3 (ACTN3) is a skeletal muscle protein responsible for maintaining the integrity of the contractile apparatus in fast-glycolytic muscle fibres. We have previously identified a common null polymorphism (R577X) in human alpha-actinin-3. Approximately 1 in 5 people worldwide are homozygous for the X-allele, which results in complete absence of alpha-actinin-3 protein. While this deficiency does not cause disease, its absence results in significantly lower muscle mass and strength/power, but provides a benefit for endurance performance in elite athletes and in the general population. We have generated an alpha-actinin-3 knockout mouse model (Actn3 KO) that mimics the human muscle phenotype. Using this model, we have shown that the absence of alpha-actinin-3 in muscle changes muscle metabolism, calcium handling, and increases susceptibility to eccentric contraction induced damage - all of which explains the alterations in muscle performance in mice and humans.
Muscle wasting is the loss of muscle mass and strength, and is caused by ageing, chronic illnesses or prolonged bed rest. It is associated with increased disease morbidity and mortality and reduced quality of life. This project will study how alpha-actinin-3 expression influences muscle wasting during active ageing. Wildtype and Actn3 KO mice (aged 24-27 months) will be placed under voluntary freewheel exercise for one month and compared to age-matched sedentary mice. This project may require some animal handling and will involve laboratory-based techniques such as immunohistochemistry, western blotting, molecular biology and muscle physiology to examine the structural, metabolic and signalling changes in skeletal muscle.


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3. Adaptive thermogenesis and the evolution of alpha-actinin-3 (R577X)

Dr Jane Seto
Neuromuscular Research
Cell Biology
E 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 digital droplet PCR (ddPCR) to further study the role of alpha-actinin-3 in adaptive thermogenesis.


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

Dr Jane Seto
Neuromuscular Research
Cell Biology
E 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 see 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.


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5. Epigenetics and other stress-related biomarkers in depression

 

Available as Masters Project: Yes

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 mental health, in particular depression and anxiety. The underlying biological mechanisms driving these associations are also unclear.
The aim of this project is to identify novel stress-related biomarkers which are associated with the prevalence and incidence of depression. 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 molecular biology and an interest in mental health.


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6. Epigenetics as a mediator 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 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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7. The utility of epigenetic profiling to improve outcome in childhood CNS tumours.

Assoc. Prof. David Ashley
Cancer
Cell Biology
E david.ashley@mcri.edu.au

 
 

Available as Masters Project: Yes

Childhood tumours of the central nervous system are the second most common group of cancers behind leukaemias, yet account for a disproportionate majority of cancer deaths. To date, the primary cause(s) of such tumours, and the molecular mechanisms that lead to poor outcome, remain unclear. The key to addressing these knowledge gaps lies in developing the appropriate tools for risk stratification of disease, increasing our understanding the oncogenic pathways within prognostic subgroups, and developing novel therapies targeting key pathways to facilitate a 'personalized' approach to treatment. We hypothesise that the combined profiling epigenetic disruption (by methylation arrays), copy number variation and mutation status (exome:seq), and gene expression (by RNA:seq) has potential to refine tumour risk stratification, inform treatment responsiveness and improve long term outcome for childhood CNS cancers. This project will utilise (i) archival CNS tumour samples housed in RCH Anatomical Pathology and (ii) fresh:frozen tissue from the Childrens Cancer Centre Tissue bank and (iii) matched clinical data, to identify molecular biomarkers for refining diagnostic and prognostic sub-groups and the identification of potentially reversible epigenetic marks important in tumour aetiology.


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8. Prognostic utility of epigenetic biomarkers in paediatric leukaemias.

Dr Francoise Mechinaud
Cancer
Cell Biology
E francoise.mechinaud@mcri.edu.au

   
 

Available as Masters Project: Yes

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 leukemia pathobiology.


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9. Detecting and Investigating the molecular biology of novel translocations and mutations in paediatric cancer

Dr Seong Khaw
Cancer
Cell Biology
E seong.khaw@mcri.edu.au

 
 

The Children's Cancer Centre Research Laboratory aims to understand the molecular basis of childhood cancer and to use this knowledge to develop better diagnostics and treatments for children with malignant disease. Associate Professor Paul Ekert leads the laboratory. His research has focused on aspects of programmed cell death (or apoptosis), particularly on the intersections between cytokine signaling pathways and cell death pathways. The team also studies acute myeloid leukaemia to examine cytokine signaling in this cancer and how new drugs might target these pathways.

An important project within the laboratory is the study of cancer samples deposited in the Children's Cancer Centre Tissue Bank. We use RNA sequencing to detect novel translocations and mutations that drive childhood cancer. In this project, you will take one of these translocations, and using the tools of molecular and cellular biology, you will clone the fusions gene arising from the translocation and develop new cell line models expressing the fusion to determine how it drives oncogenic transformation and potential therapeutic approaches that may target the fusion. There will also likely be opportunities to learn new skills in the generation and analysis of RNA sequencing data.


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10. Understanding the causes of craniofacial birth defects

 

Available as Masters Project: Yes

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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11. Induction of different cell lineages from PIK3CA mutation-carrying iPSC cells

 

PIK3CA (Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha) mutations are identified in a diverse group of rare disorders called PIK3CA-Related Overgrowth Spectrum (PROS). These conditions are due to somatic activating mutations identified in the phosphatidylinositol-3-kinase/AKT/mTOR pathway. The PROS umbrella covers some vascular malformations, fibroadipose hyperplasia or overgrowth (FAO), hemihyperplasia multiple Lipomatosis, (HHML), Congenital lipomatous overgrowth, epidermal nevi, scoliosis/skeletal and spinal (CLOVES) syndrome, Klippel-Tranaunay syndrome, macrodactyly, fibroadipose infiltrating lipomatosis, and the related megalencephaly syndromes, megalencephaly-capillary malformation (MCAP or M-CM) and dysplastic megalencephaly (DMEG).

To date, we have produced 2 induced-pluripotent stem cell (iPS) cell lines carrying single point PIK3CA mutations from a CLOVES patient and a Klippel-Tranaunay patient, where both syndromes are characterised by tissue overgrowth and include lymphatic malformation as part of their clinical presentation. Tissue, blood and derived cells from these patients were subjected to whole exome sequencing in collaboration to confirm a single base point mutations in PIK3CA gene. The next step in this repertoire is to differentiate the derived iPSCs that carry known PIK3CA mutations into skeletal and fat cells.


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12. Rapamycin effect on endothelial thrombogenic potential

 

Recent reports have indicated that rapamycin (sirolimus), a drug with a long history of use as an immunosuppressant, is effective in the treatment of some types of vascular anomalies, the inborn errors of the vascular and lymphatic systems. Rapamycin acts via Mammalian Target of Rapamycin (mTOR) signalling pathway which is involved in regulation of cell proliferation, survival and metabolism. Rapamycin-mediated inhibition of the mTOR pathway may potentially occur via two mTOR associated complexes: mTOR complex 1 (mTORC-1) or mTOR complex 2 (mTORC-2). As each complex performs different functions in cells, different cellular processes will be affected. Although rapamycin improves symptoms in patients, clinical studies in other conditions have suggested that rapamycin can increase thrombosis and the risk of fatal pulmonary embolism. How this may occur is unknown.

This project proposes to clarify the ability of rapamycin to induce clot formation by examining how rapamycin affects the expression of endothelial cell molecules involved in thrombus formation and thrombolysis. This will be done by assessing the expression of these cellular markers following treatment in vitro with rapamycin both under static and shear stress conditions.


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Clincial Sciences

13. Towards developing an individualised approach to neonatal respiratory support: Assessing the usefulness of biomarkers of lung injury and function

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

Preterm infants often need prolonged respiratory support (mechanical ventilation) to survive, however, ventilation of these immature lungs can lead to the development of ventilation-induced lung injury (VILI), which is associated with prolonged hospital stay and long-term morbidity. Lung injury is a complex interaction between intrinsic biological and developmental factors and the way in which mechanical ventilation is applied. We know that the volume and pressure used to inflate the lung has the potential to be harmful as well as beneficial. Identifying biomarkers that can accurately predict the early development of the many different forms of lung injury will be essential to improving outcomes for preterm infants.

The goal of this project is to perform a controlled validation of both current and recently unveiled indicators of lung injury and function in preterm lambs who have undergone various, clinically relevant ventilation strategies. To do this students will employ a range of techniques including qPCR, histology, immunohistochemistry, image analysis and protein based technologies to study the Neonatal group preterm lamb tissue bank. In addition to aiding the development of essential monitoring tools, this project has the potential to unravel not only how currently monitored markers relate (or actually don't relate) to each other, but also assess the validity of the injury/function parameters across a range of ventilation strategies.


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Genetics

14. Solving Rare Diseases via the Australian Genomics Health Alliance

 

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. The Australian Genomics Health Alliance is a collaboration of over 40 Australian centres seeking to translate new genomic technologies into improved outcomes for rare diseases and cancer. Mitochondrial diseases are one of the first flagship projects of the Alliance. They are the most common group of inherited metabolic disorders and highly complex as they comprise over 200 different genetic disorders with a wide range of clinical phenotypes and types of inheritance. We will perform whole genome or whole exome sequencing on a cohort of 240 patients over a 2-year period starting in the last quarter of 2016.

In previous studies we have used these technologies to achieve diagnostic yields of over 50% in retrospective cohorts, identifying over a dozen novel disease genes. This project will focus on a prospective cohort of paediatric patients with probable mitochondrial disease. Some patients will have sequence variants identified that have been previously shown to cause disease, which are straight forward to classify. Other patients 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.


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15. 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. 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 are known to cause inherited disorders of mitochondrial energy generation.

The overall aims are to:
1) Assemble a representative panel of cellular models of OXPHOS disease in HEK293T cells and human Embryonic Stem Cells (hESCs) 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 hESC, as well as the impact on mitochondrial function and cellular physiology.
3) Define the impact of targeted therapeutic strategies in these cellular models on the cellular proteome and on other markers of cellular homeostasis.

The research project will thus involve generation of hESCs with CRISPR/Cas9 mediated gene disruption, followed by confirmation of the impact on the targeted gene and pathway and assessment of the molecular karyotype and retention of pluripotency. Selected cell lines will then be differentiated to cardiomyocyte and/or neural lineages to enable comparison (with isogenic 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.


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

 

Available as Masters Project: Yes

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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17. The role of centromere defects in cancer formation and progression

 

Available as Masters Project: Yes

The centromere is an essential chromosome structure required for the transmission of replicated DNA to daughter cells during cell division. It has been shown that chromosome instability (CIN) driven via disruption of centromere function, formation of dicentric chromosomes (and its associated amplification of oncogenes via chromosomal Breakage-Fusion-Bridge cycles), and the overexpression of centromeric repeats may be associated with cancer development, but there have been no systematic study of the role of the centromere in different cancer types. We have preliminary data showing that a major driving force in liposarcoma development is through the formation of oncogenic neochromosomes that contain ectopic centromeres or neocentromeres - a phenomenon first described by us. Owing to the typical association of centromeres with highly-repetitive satellite DNA, current efforts including the International Cancer Genome Consortium to conduct large-scale nextgen sequencing of cancers cannot reveal changes to the number, structure or function of the centromere in tumours.

Our hypothesis is that centromere abnormalities are common and a key factor in cancer development, and propose to determine the extent, form and functional significance of centromeric defects within cancer.
Our specific aims are 1) To investigate the frequency and forms of centromere abnormalities in cancer development in a panel of paediatric tumours samples and cell lines from many different cancer types that we have assembled; and 2) To determine the role aberrant expression of centromere transcripts play in cancer development. This will be the first in-depth study of the association of centromere defects with tumorigenesis. The study that will yield valuable insight into the roles centromeres play in the onset and progression of cancer. This knowledge will complement existing large-scale cancer genome sequencing projects and translate into a better understanding of the causes and biomarkers of cancer.


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18. Genome-editing: applications in stem cells and gene therapy

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

 

Available as Masters Project: Yes

The recent development of targetable nucleases has introduced a highly flexible technique for modification of specific genomic sequences. CRISPR-Cas9-generated double stranded breaks (DSB) may be resolved by the host cell through either non-homologous end joining (NHEJ), or homology directed repair (HDR) given the presence of an appropriate DNA template. The latter carries great promise for the field of gene therapy as it can be utilised for the correction of disease-causing mutations. Several groups have demonstrated the potential for site-specific modification of the beta-globin locus by HDR following generation of a targeted DNA break. However, for modification of patient primary HSCs to be clinically useful, the genetic alteration must be made as uniformly as possible throughout the entire cell population.

This project aims to develop strategies for targeted modifications of haematopoietic stem cells using the CRISPR-Cas9 targetable nuclease. Conversion of the fluorescent reporter gene GFP to BFP fluorescence will be used to monitor efficiency of genome editing. Initial studies will be conducted in vitro and will involve culture of both cell lines and primary cells expressing GFP. In vitro differentiation will be used to assess the capacity of modified stem cells to differentiate along multiple lineages. Further studies will also be conducted in vivo using our unique humanised beta-thalassaemia mouse models.


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19. 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

 

Available as Masters Project: Yes

Haemoglobin disorders, such as sickle cell disease and ß-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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20. Does skewed X-linked inactivation predict the severity of Rett Syndrome?

Available as Masters Project: Yes

Rett syndrome (RTT) is a severe neurodevelopmental disorder, where most cases arise from mutations within the MECP2 gene (RettBASE; http://mecp2.chw.edu.au). The great majority of MECP2 gene mutations occur on the paternally inherited X chromosome. Specific mutations can affect clinical severity, but skewing of X-inactivation is proposed to also modulate the phenotype in RTT. X-linked inactivation is a process whereby one copy of the X-chromosome is randomly transcriptionally inactivated.
We hypothesise that the proportion of RTT cells with an MECP2 mutation on the active X chromosome at birth decreases over time because of selection disadvantage. This is reflected by a significant change in X chromosome methylation between birth and later on in the childhood, and its relation with transcription of RTT related genes. The rate of this change may be correlated with the severity of clinical involvement. This project will examine X chromosome methylation using previously developed methods shown to identify skewed X-chromosome inactivation in X-linked disorders, including fragile X syndrome and sex chromosome aneuploidies (Godler et al 2013 HMG; Inaba et al 2013 Med Genet; Godler 2015 Ex Rev Mol Med).
Aim 1: To examine methylation patterns in a cohort of clinically mild and severe RTT patients carrying known MECP2 gene mutations.
Aim 2: To examine methylation in newborn blood spots retrospectively retrieved from 100 RTT patients, and in blood collected at time of recruitment, and compared to control data.
Aim 3: To examine transcription of RTT related genes by absolute RNA qualification using droplet digital PCR.
Outcomes: Relationships between DNA methylation and clinical severity, changes in methylation over time, and RTT specific mRNA levels will be analysed. These findings could lead to development of a novel way to predict increased risk of developing severe RTT phenotype from methylation analysis of newborn blood spots, well before symptoms become apparent.


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M1. Developing a diagnostic blood test for autism

 

Masters Project Only

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 skills in RNA biology, next generation sequencing, and bioinformatics.

 


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21. Investigating repeat-associated disease mechanisms in Friedreich ataxia

Professor Anthony Hannan
Neuroplasticity
Florey Institute of Neuroscience and Mental Health
E anthony.hannan@florey.edu.au

 

The debilitating neurodegenerative disease Friedreich ataxia results from a trinucleotide (GAA) repeat expansion in the FXN gene. FXN encodes frataxin, a mitochondrial protein important in iron homeostasis and iron-sulfur cluster assembly. Low levels of frataxin is considered the main driver of disease.
In the repeat-associated diseases spinocerebellar type 8 and myotonic dystrophy, a unique translational process known as repeat-associated non-ATG (RAN) translation was demonstrated to be pathogenic. RAN translation does not require a start codon and produces homopolypeptides. We hypothesise that the GAA triplet repeat expansion in Friedreich ataxia expresses homopolypeptides via RAN translation in both the sense and anti-sense directions. Our preliminary data indicate increased signal intensity and differential localisation of a specific homopolypeptide in key tissues of pathology in Friedreich ataxia mice compared to wild-type mice.

This project will evaluate the expression of GAA repeat-associated RNAs and homopolypeptides in animal and cellular models of Friedreich ataxia. Endogenous repeat-associated RNAs will be examined in transcriptome analyses of primary cells from individuals with Freidreich ataxia and control subjects. In human cell lines, plasmid-based expression of repeat-associated peptides tagged in multiple open reading frames will be evaluated via western blot. Repeat-associated homopolypeptide expression will also be examined in tissues from Freidreich ataxia mice, as well as sensory neurons in induced pluripotent stem cell-derived neurospheres from individuals with Friedreich ataxia and control subjects. This study will increase our understanding of the molecular mechanisms in Friedreich ataxia.


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22. Investigating the factors involved in FXN silencing in Friedreich ataxia

Dr Charles Galea
Genetic Health Research (BLC)
Genetics
E charles.galea@mcri.edu.au

 

The debilitating neurodegenerative disease Friedreich ataxia results from a trinucleotide (GAA) repeat expansion in the FXN gene. FXN encodes frataxin, a mitochondrial protein important in iron homeostasis and iron-sulfur cluster assembly. Low levels of frataxin is considered the main driver of disease.
Our team has shown a characteristic DNA methylation pattern surrounding the expansion in Friedreich ataxia (FRDA) where methylation is increased upstream of the DNA expansion and decreased downstream. We showed that when methylation increased at a specific dinucleotide (UP-CpG1) near the expansion, FXN expression decreased. We also found that FXN expression inversely correlated with the clinical features of FRDA, including disease severity.

This project will investigate a novel repeat-associated factor and its contribution to FXN silencing. We recently demonstrated a nuclear protein binds at/near UP-CpG1, and that this binding increases when UP-CpG1 is methylated. Using TRANSFAC (Biobase), we found putative binding sites for three known transcription factors in this region. This project will characterise this protein and examine its effect on FXN expression. FXN transcript and frataxin protein will be measured in a series of over-expression and knock-down studies in human cell lines. FXN reporter constructs will also be generated to identify the exact protein binding site. Binding in intact human cells will be characterised using chromatin immuno-precipitation.
This study will increase our understanding of the molecular mechanisms underlying Friedreich ataxia and could identify much-needed therapeutic targets for treatment development.

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23. Determining the genetic basis of novel neurogenetic disorders

Available as Masters Project: Yes

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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24. Investigating the molecular basis of Parkinson's disease

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

 

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 have identified several families who demonstrate clinical features of early-onset parkinsonism and intellectual disability. 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 with the aim of translation into cell and animal models.


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25. Identifying the genetic causes of brain malformation in children

Assoc. Prof. Richard Leventer
Neuroscience Research
Clinical Sciences
E richard.leventer@mcri.edu.au

 

Available as Masters Project: Yes

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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26. Identifying novel genetic targets that underlie Synucleinopathy and Tauopathy.

Dr Sarah Stephenson
Neurogenetic Research (BLC)
Genetics
E sarah.stephenson@mcri.edu.au

A/Professor David Finkelstein
Neurodegeneration
Florey Institute
E d.finkelstein@florey.edu.au
 

Available as Masters Project: Yes

The Parkinsonian disorders (PDs) all present with selective vulnerability of nigrostriatal dopaminergic populations and abnormal aggregates of the proteins alpha synuclein (asyn) and/or microtubule associated protein tau (tau). This has led to the classification of PDs as either synucleinopathies or tauopathies. However, the pathologies are not isolated categories but rather form a continuum and co-occurrence of asyn and tau pathology is common. This observation suggests that PDs represent a spectrum, rather than discrete disorders and the hypothesis that shared underlying pathways are dysregulated.
A fundamental question that needs to be resolved is what factors (genetic and environmental) underlie these related but diverse clinical presentations and individual patient outcomes. Our hypothesis is that the variable clinical presentation and outcomes of individuals with Parkinsonian disorders are mediated by the interaction of many genes. The identification of these genes will allow us to dissect the complex interactions that underlie disease aetiology and identify novel therapeutic targets for effective treatment and/or cure of these disorders.
We have used the MPTP-induced Parkinsonism model in a panel of recombinant inbred mice to identify strains that are susceptible to dopaminergic neurons loss. This project will involve the identification of susceptible and resistant strain using immunohistochemistry and stereology to determine the number of dopaminergic neurons in the substantia nigra remaining after MPTP exposure. Biochemical quantification of steady-state asyn and tau will be performed in parallel to identify the genes underlying variability of these important disease associate proteins.


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27. Characterisation of the parkin protein and how it causes Parkinson's disease

Dr Sarah Stephenson
Neurogenetic Research (BLC)
Genetics
E sarah.stephenson@mcri.edu.au

A/Professor David Finkelstein
Neurodegeneration
Florey Institute
E d.finkelstein@florey.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, and altered parkin function is a risk factor for several different neurodegenerative diseases. We hypothesise that parkin plays a key role in eliminating toxic proteins within the brain. Failure of parkin function results in the accumulation of toxic proteins and results in the development of PD. We have a number of projects in progress or development that investigate the function of parkin and other related proteins. In particular, we are interested in how parkin functions with its co-regulated gene PACRG in protein turnover and neuron function in the brain. Projects that investigate this relationship between parkin and PACRG can be tailored to the interests and strengths of the right candidate(s). For example, investigation of the significance of the birdirectional promoter, e.g., luciferase and qPCR; molecular mechanisms altering protein turnover, e.g., protein-protein interactions modifying key residues. Furthermore, we have recently generated a number of unique mouse models in the laboratory that can be characterised for markers of altered neuropathology, as well as biochemical and behavioural analyses.


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28. A genetic approach to identifying drug targets for prevention of deafness

 

Available as Masters Project: Yes

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. The aims of this project are to identify molecular targets that can be blocked therapeutically to prevent acquired hearing loss.
THE PROJECT:
Our laboratory uses mouse models to study the genetics and molecular basis of progressive forms of hearing loss. We have a collection of mouse strains with chemically-induced genetic mutations that are resistant to progressive deafness. An opportunity exists for an Honours Student to fully characterise one of these models. The aims of this Honours project are to figure out which gene is mutated in the mouse strain, and to work out how disruption of this gene results in resistance to progressive hearing loss. This project will provide valuable information about the molecular pathways that underpin hearing and may help us identify potential drug targets for preventing deafness. In the long-term we hope to use this information to inform development of drugs that can be used to treat and prevent acquired hearing loss.
TECHNIQUES:
The student will use a wide variety of genetic, molecular biology and auditory biology techniques including: linkage mapping, genomic DNA isolation, single nucleotide polymorphism genotyping, massively parallel DNA sequencing, polymerase chain reaction and dideoxy DNA sequencing, auditory brainstem response testing, micro-dissection of the auditory system and histological analysis of cochleae.


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Infection and Immunity

29. Streptococcus pneumoniae gene expression and pathogenesis

 

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 and is considered a precursor to disease.

Our laboratory is interested in investigating pneumococcal pathogenesis and the processes by which this bacterium transitions from the colonising to the infectious state. Using a combination of clinical samples and experimental models, gene expression studies will identify genes of interest. Candidate genes will be examined by mutagenesis and functional assays conducted to investigate their role in pathogenesis.


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30. Investigating the pneumococcal whole cell vaccine in an infant mouse model of pneumonia

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

Pneumonia is the leading killer of children under five years of age worldwide, and Streptococcus pneumoniae (the pneumococcus) is the most common cause. Pneumococci commonly colonise the nasopharynx of healthy individuals, and can disseminate from this site to infect other tissues of the respiratory tract. The pneumococcal whole cell vaccine (WCV) aims to induce immunity against non-capsular antigens and is currently undergoing clinical trials. Previous studies in our laboratory have shown WCV can reduce pneumococcal density in the nasopharynx and ears of infant mice co-infected with pneumococci and influenza A, but its effect on lung disease remains unknown. There is no experimental model which fully recapitulates pneumococcal disease pathogenesis, particularly the transition from colonisation to lung infection, in a paediatric setting.

This project will investigate specific triggers that disrupt pneumococcal biofilms in the nasopharynx and lead to aspiration of the bacterium into the lungs, in order to establish an infant mouse model of pneumococcal pneumonia. Disease pathology and other clinical signs will be assessed, including measuring local and systemic immune responses by flow cytometry, ELISA and gene expression. The model will then be used to assess the impact of WCV on pneumococcal lung disease in the context of pre-existing carriage, important because children in high disease-burden settings commonly carry pneumococci at the time of vaccination.

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31. Interactions between Streptococcus pneumoniae and respiratory viruses

Dr Salvatore Manna
Pneumococcal Research
Infection and Immunity
E sam.manna@mcri.edu.au

 

Co-infections with viral and bacterial pathogens can lead to severe respiratory infections. These interactions have been well-documented between the bacterium Streptococcus pneumoniae (the pneumococcus) and influenza virus. Clinical evidence suggests that a similar synergy exists between pneumococcus and respiratory syncytial virus, a major cause of respiratory infection and hospitalisation of young infants.

Using in vivo models, this project will investigate the interactions between these two pathogens and generate novel data on the impact of viral infection on pneumococcal colonisation, transmission, and pneumonia.


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32. Immunomodulatory effects of Vitamin D on the host response to respiratory infections

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

Mrs Anne Balloch
Pneumococcal Research
Infection and Immunity
E anne.balloch@mcri.edu.au

 

Available as Masters Project: Yes

Respiratory infections such as those by the pneumococcus and RSV are a major cause of morbidity and mortality in children less than 5 years of age. The host response to infection involves activation of both innate and adaptive immunity both in the mucosal tissue as well systemic immune system. These include modulation of cytokine production, T-lymphocyte function and inflammatory responses.
Vitamin D has been shown to have a variety of biological effects including beneficial effects on the immune system that may help resist against respiratory infections.

In this study, we aim to characterise the effects of Vitamin D on human immune cell populations. We will measure cytokine production and immune cell function in peripheral blood mononuclear cells (PBMCs) and isolated subpopulations when stimulated with various pathogen ligands in the presence of Vitamin D. We will also examine the effect of Vitamin D on functional responses such as bacterial killing. This study has important implications for developing preventative and/or therapeutic strategies in individuals at high risk of disease.

33. Exploring a new approach for preventing stomach cancer

Dr Garrett Ng
Mucosal Immunology
Infection and Immunity
E garrett.ng@mcri.edu.au

 

Infection of the stomach with the bacterium Helicobacter pylori typically starts in childhood and lasts for life. This infection causes a chronic inflammation (gastritis) that in some people drives the development of stomach cancer, globally the 3rd leading cause of cancer-related death. Why some people but not others develop disease is complex but includes the effects of important host regulatory factors.
We have identified a new factor, a potassium channel, which plays such a role. Experiments in mice have indicated that this channel plays a role in inhibiting gastritis and therefore protecting against H. pylori-associated disease. Importantly we have also found that people with particular genetic variants in this channel have a greatly increased susceptibility to gastric cancer, showing this is relevant to humans. As drugs are already available that clinically target this channel, this discovery raises the possibility of a new treatment to prevent stomach cancer. However we need first to confirm that this factor does indeed play a key role in human cells.

AIM: This project aims to explore the functional role of this important host factor in the response of human cells to H. pylori infection.
APPROACH: To achieve this, the student will first use molecular techniques to modify the expression of this channel in human cells, then stimulate these cells with H. pylori before measuring cytokine secretion (by ELISA and real time PCR) in order to observe how modifying the potassium channel changes the inflammatory response of human cells to bacterial stimulation. Drugs that modify this potassium channel will also be tested in the same system, to commence exploring potential candidates for therapeutic use.

34. 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

 

Available as Masters Project: Yes

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, PCR and Western blotting.


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35. Effect of congenital UDT on Gonocyte development

Dr Ruili Li
Surgical Research
Infection and Immunity
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, 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 immunohistochemistry, confocal microscopy, PCR

 

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M2. Pneumococcal carriage dynamics in children hospitalised with acute respiratory infection in Fiji

 Masters Project Only

Pneumonia is the commonest infectious disease causing childhood death worldwide. Pneumococci are responsible for about 1/3 of all pneumonia deaths. We have a number of studies in Fiji documenting the impact of pneumococcal vaccine on pneumococcal disease in Fiji. In this study, we will determine how antibiotics effect the dynamics of pneumococcal carriage.


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72. Impact of multiple pathogen infection on respiratory syncytial virus evolution

Dr Lien Anh Ha Do
Pneumococcal Research
Infection and Immunity
E lienanhha.do@mcri.edu.au

 

Available as Masters Project: Yes

Host immune responses have been shown to have an impact on respiratory syncytial virus (RSV) molecular evolution. Multiple viral co-infections are frequent in children and multiple infections can promote competition between the different strains in terms of host receptors to induce different host immune responses compared to single infections. Our hypothesis is that there are different patterns of molecular characteristics of RSV strains between single RSV infections and those from RSV co-infected (or superinfected) with other viruses. We will use in-vitro models and clinical samples from our Mongolia pneumonia project to test this hypothesis. This project will add valuable data for a better understanding of multiple pathogens co-infection/superinfection roles on RSV evolution for future RSV vaccine design.

 


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Population Health

36. Developing novel methods to diagnose and predict the prognosis of food allergy

Dr Thanh Dang
Gastro & Food Allergy
Population Health
E thanh.dang@mcri.edu.au

Dr Melanie Neeland
Gastro & Food Allergy
Population Health
E melanie.neeland@mcri.edu.au

 

Australia has the highest rate of IgE-mediated food allergy in the world, with the prevalence more than doubling over the past decade to 10%. There is a recognised need for further studies into developing new novel diagnostic methods that are readily available for clinicians to accurately predict disease phenotypes and prognostic outcomes without food challenges.
Currently, the only tool available for monitoring the natural history of food allergy is the Skin Prick Test (SPT) response or serum specific IgE (sIgE) level.

Our group was the first to generate SPT and sIgE 95% predictive probability thresholds for predicting peanut and egg allergy resolution using samples from the internationally unique NHMRC-funded HealthNuts study, the world's largest single centre population based, longitudinal study of food allergy. Despite these findings, the sensitivity of the thresholds were low. We recently developed an algorithm which includes the measurement of Ara h 2 sIgE (a single peanut allergen) using component resolved diagnostics (CRD) instead of using whole peanut extracts (not yet validated for clinical use for many foods), which increased the accuracy of peanut allergy diagnosis and reduced the need for oral food challenges by four-fold (4). In a landmark New England Journal of Medicine article, successful resolution of peanut allergy correlated with the increase of serum specific IgG4 (sIgG4) and not IgE. While IgE levels can be indicative of current disease, IgG4 may be important for determining the prognosis of a food allergic patient, however is not yet validated in a large population cohort.

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73. An epigenetic analysis of twins discordant for epilepsy

A/Professor Lata Vadlamudi
Environmental & Genetic Epidemiology Research
Population Health
E l.vadlamudi@uq.edu.au

Dr Jane Loke
Environmental & Genetic Epidemiology Research
Population Health
E jane.loke@mcri.edu.au

 

Epilepsy is the most common serious neurological disorder and affects over 70 million people worldwide. Epilepsy can have debilitating consequences with significant economic, social and quality of life implications. The importance of genetics in the causation of epilepsy has long been recognized and there has been significant progress with the identification of genes for certain monogenic epilepsy syndromes. However, researchers have had limited success to unravel the complex inheritance pattern of epilepsy. In addition, as identical twins can be discordant for epilepsy, this implicates factors beyond the genetic sequence that contribute towards the causation of epilepsy. We are investigating the extent to which epigenetic factors - small molecules that control gene activity and are inherited across cell division - are associated with epilepsy, using a twin model.
We are conducting a genome-wide analysis of DNA methylation in three tissues from identical twin pairs discordant for epilepsy. We are analysing DNA from cheek and blood cells and in a subset of twin pairs we are looking at neonatal dried blood spots. This work will provide clues to the cause and mechanisms of epilepsy; potential predictive biomarkers for future disease, symptom severity or prognosis; and potential for preventative or disease-modifying treatments for epilepsy.
This Honours project will involve "validation" of the top genomic regions whose methylation state is most likely to associate with or predict epilepsy in twins as identified using methylation microarrays. This validation will use the method of Sequenom MassArray EpiTyping, which measures DNA methylation at specific or groups of CpG sites within a region of 200-400 base pairs. This technique involves techniques such as bisulphite conversion, PCR and mass spectrometry and had been used in A/Prof Craig's lab for over ten years. The project will provide a valuable contribution to a future research publication.

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