Honours Projects in The School of Medical Sciences

Title: Mechanisms and interventions for mucosal barrier injury: Investigating the Rho pathway

Project 1: Dextran sulfate sodium (DSS)-induced mucosal barrier injury.
DSS is used as an inducing agent in models of ulcerative colitis, a type of inflammatory bowel disease characterised by severe mucosal barrier injury.  This project will investigate expression of Rho signalling proteins as well as tight junctions and their scaffolding proteins in rat colitis tissue.  This project will be supervised by Dr Joanne Bowen and Professor Gordon Howarth. The key methodologies include electron microscopy, immunohistochemistry, Western blot and real time PCR.

Project 2: Irinotecan-induced mucosal barrier injury.
Irinotecan is a chemotherapy agent used in a variety of cancer treatment regimens.  It's use is commonly associated with severe mucosal injury, leading to dose-limiting toxicity.  This project will build on previous research that has found activation of gene transcription in Rho pathway induced by irinotecan.  The current project will investigate pathway markers at the protein level over a timecourse of injury in a rat model.  The supervisors will be Dr Joanne Bowen and Dr Rachel Gibson.  The key methodologies include laser capture microdissection, Western blot and immunohistochemistry.

Title: Genetic influences on human brain plasticity and motor function

Supervisor: Dr John Semmler

Rationale: Up to 50% of healthy people have a polymorphism involving the brain-derived neurotrophic factor (BDNF) gene, which influences motor system plasticity and plays a vital role in motor learning and recovery from brain injury. The goal of this study is to examine the functional implications of the BDNF polymorphism on motor system plasticity and motor performance.

Approach: Students will use transcranial magnetic stimulation (TMS) to assess motor system excitatory and inhibitory mechanisms when performing novel motor tasks in healthy young participants possesing different BDNF genotypes.
Significance: Results from this study may suggest that common alterations in the BDNF gene could be used to guide therapy choice to induce optimal corticomotor function and improve recovery in neurological patients.

Title: Brain plasticity after short-term immobilisation in humans

Supervisor: Dr John Semmler

Rationale: Limb immobilisation is a model of disuse associated with injury, and is known to cause rapid cortical reorganisation and impaired motor performance. The aim of this study is to examine the effect of short-term immobilisation of the thumb on cortical plasticity for control of the immobilised and contralateral (non-immobilised) hand.

Approach: Students will use transcranial magnetic stimulation (TMS) to measure changes in cortical excitability after immobilisation of the non-dominant thumb in a splint for up to 3 days.  Cortical plasticity will be assessed before and after immobilisation of the immobilised and non-immobilised hemisphere with repetitive TMS (rTMS).

Significance: These studies may help refine therapeutic interventions that target optimal cortical plasticity (e.g. sensory retraining in dystonia, constraint induced movement therapy in stroke) and improve the functional outcome after reduced muscle use following brain injury or limb fractures.

Assoc Prof Peter Catcheside
peter.catcheside@health.sa.gov.au
8275 1309

Prof Doug McEvoy
doug.mcevoy@health.sa.gov.au
8275 1187

Assoc Prof Nick Antic
nick.antic@health.sa.gov.au
8275 1187

The Adelaide Institute for Sleep Health provides a clinical service for patients with sleep related problems, such as obstructive sleep apnoea (repeated obstructive breathing events in sleep in otherwise healthy people), insomnia and sleep hypoventilation in patients with known respiratory muscle weakness or lung disease. Breathing disturbance and sleep fragmentation have important daytime consequences including pathological daytime sleepiness, neurocognitive impairments and a substantially increased risk of traffic and other accidents. Sleep apnoea is also associated with cardiovascular disease (eg hypertension and heart disease).

Our group is one of the leading clinical research laboratories in Australia. AISH has a strong cardiorespiratory sleep physiology research stream, with a particular focus on mechanisms and consequences of sleep breathing disorders. In 2012 there are opportunities for up to 2 Honours projects in the research areas listed below in this area.

AISH leads the Sleep Apnea cardio Vascular Endpoints (SAVE) study www.savetrial.org , an international academic multi-centre randomised controlled trial of continuous positive airway pressure (CPAP) therapy in high cardiovascular risk patients with obstructive sleep apnea (OSA). The objective of SAVE is to determine whether the incidence of cardiovascular events such as strokes and heart attacks can be reduced by OSA treatment. There is an opportunity for a PhD student to work with the SAVE trial team to investigate various strategies to maintain and enhance CPAP treatment adherence.

Location of lab: Repatriation General Hospital

Title: The SAVE trial: CPAP treatment optimisation strategies  
Project type: PhD
Supervisors: Prof Doug McEvoy, Assoc Prof Nick Antic
Location: Adelaide Institute for Sleep Health
 
CPAP was shown 3 decades ago to be a highly effective way of treating OSA. However, a relatively high proportion of patients (up to 40-50%) are not accepting of the treatment or use it only intermittently over the long-term.  One of the major challenges facing the sleep apnea field therefore is how to improve long term adherence to nightly CPAP mask therapy.  The SAVE trial, which now extends to 7 countries in 4 continents is in the patient recruitment phase with 1400 of an expected final target of approximately 5000 patients thus far enrolled.  SAVE is thus is an ideal opportunity to better understand the various personal, ethnic, cultural and physical barriers to CPAP therapy and to investigate various interventions within the trial to enhance therapy. A PhD student working on this project would have the opportunity to work both with leading sleep clinician scientists at AISH and our clinical trials partners in SAVE at the George Institute for Global Health (University of Sydney). 

Relevant Publications
1. McEvoy RD, Anderson CS, Antic NA, Chen BY, He QY, Heeley E, Huang SG, Huang Y,  Wang JG, Zhong NS The Sleep Apnea cardiovascular Endpoints (SAVE) trial: rationale and start-up phase J Thoracic Dis 2010; 2: 138-143.
2. Gantner D, Ge JY, Li LH, Antic N, Windler S,  Wong K, Heeley E, Huang SG,  Cui P, Anderson C, Wang JG, McEvoy RD. Diagnostic accuracy of a questionnaire and simple home monitoring device in detecting obstructive sleep apnea in a high cardiovascular risk Chinese population. Respirology 2010; 15:952-60

Title: Treatment effectiveness and compliance with a new supine-avoidance therapy for posture dependent obstructive sleep apnoea and snoring
Project type: Hons or PhD (scope for both)
Supervisors: Peter Catcheside, Doug McEvoy
Location: Adelaide Institute for Sleep Health

Around one third of OSA patients and many heavy snorers could be effectively treated by simply avoiding sleeping on their back. Classic supine-discomfort based treatments are remarkably effective, but most patients cease treatment within a few months due to the inherent discomfort of this approach. Our group has developed and tested a simple vibration alarm device to monitor and record sleep posture and discourage supine sleep, without discomfort and with minimal sleep disturbance to the bed partner. We have already shown the device accurately and reliably records body position, almost completely abolishes supine sleep and appears to be highly effective in treating supine OSA. However, long-term acceptance and use of this therapy and the effectiveness in snorers remains to be established. This project will investigate the effectiveness and longer-term patient usage of the supine-avoidance device for treating OSA and/or snoring, and investigate overnight changes in breathing disturbances and snoring with this supine avoidance treatment.

Relevant Publications
1. Bignold JJ, Deans-Costi G, Goldsworthy MR, Robertson CA, McEvoy RD, Catcheside PG, Mercer JD. Poor long-term patient compliance with the tennis ball technique for treating positional obstructive sleep apnea. J Clin Sleep Med 5(5):428-30, 2009.
2. Bignold JJ, Mercer JD, Antic NA, McEvoy RD, Catcheside PG. Accurate position monitoring and improved supine-dependent obstructive sleep apnea with a new position recording and supine avoidance device. J Clin Sleep Med 7(4):376-383), 2011.

Type of project: Honours project, PhD project
Scholarship available: yes
Expected honours intake:  2

The molecular Oncology group is focused on the identification and validation of biomarkers for 1) the prediction of response to targeted therapies for metastatic colorectal cancer (CRC), 2) the detection of circulating tumour stem cells as a prognostic indicator of impending relapse in CRC, and 3) further understanding of the pathways involved in CRC and determination of a potential diagnostic/prognostic biomarker panel in plasma samples.

Location of lab: Basil Hetzel Institute, The Queen Elizabeth Hospital

Project 1:
Title: Determination of predictive biomarkers of resistance/sensitivity to targeted antibody therapies in colorectal cancer.

Mutations in KRAS or BRAF have been found to be useful markers of resistance to anti-EGFR antibody therapy, yet a proportion of patients wild-type at these loci still develop resistance. Thus there is a need to investigate further biomarkers to predict response to this and other targeted therapies. We have identified a number of genes differentially over-expressed between cell lines resistant or sensitive to anti-EGFR treatment. The hypothesis is that knocking down expression of these genes will result in reversal of the resistant phenotype.

Specific aims:

0. To validate differential expression of genes from expression-profiling arrays using RT-PCR.
0. To knockdown gene expression using RNA interference technology.
0. To isolate RNA and protein and perform comparative expression analyses using RT-PCR and Western blotting respectively.
0. To test reversal of phenotype (resistant to sensitive) using cell proliferation assays.

Project 2:
Title: Identification of specific tumour cell surface biomarkers for tumour cell capture or targeting using mass spectrometry techniques

Currently, magnetic bead capture of tumour cells relies on the epithelial-specific antibody EpCAM, an antibody specific to epithelial-derived tumour cells as well as normal epithelial cells. Although EpCAM is the antibody used in recently developed commercial kits for detection of CTCs in blood (CellSearch™, Veridex, NJ, USA), it has been reported that EpCAM expression was some 10-fold lower on circulating tumour cells compared to primary and metastatic tissues, suggesting that EpCAM expression is dependent on the local microenvironment and is down-regulated in disseminated cells. Thus there is an explicit need for a more effective surface membrane antibody panel to increase the specificity of immunobead capture of tumour cells. Further, surface membrane colon tumour biomarkers are needed for specific targeting of tumour cells by novel therapeutics such as antibody-coated nanoparticles encapsulating RNA interference (RNAi) molecules or small molecule inhibitors. We have a large frozen tissue bank of colon tumours and matched normal mucosa for this work.

Specific aims:

0. To isolate surface membrane protein
0. To use a new mass spectrometry technique (SIEVE) to determine differential expression of proteins
0. To validate findings using flow cytometry and RT-PCR.

Techniques include proteomics, quantitative mass spectrometry, cell culture, flow cytometry, RT-PCR. Mass spectrometry will be done in collaboration with Flinders Proteomics Facility.

Project 3:
Title: Investigation of stem cell markers for the identification of circulating colon cancer stem cells

In colorectal cancer (CRC), a proportion of patients with early stage (TNM stage I or II) disease still die of recurrent or metastatic disease within 5 years of diagnosis despite undergoing "curative" resection. The implication is that tumour cells with metastatic potential had already escaped from the primary tumour, before or at the time of surgery, into the bloodstream or the peritoneal cavity. We have developed a test using magnetic antibody-labelled beads to capture circulating tumour cells (CTC) followed by qRT-PCR of tumour markers as an early predictive test for metastatic disease. However, while the test showed 80% specificity there was still a significant number of patients who were positive for CTC but did not relapse. We hypothesise that it is the stem cells within the circulating epithelial tumour cell pool that are responsible for subsequent relapse.

Specific aims:

0. To improve the magnetic capture step by using ficol gradient separation followed by MACS magnetic bead capture of EpCAM positive cells, with CD45 MACS depletion of leucocytes.
0. Establish the sensitivity of detection of cancer stem cells in a 7.5 mL blood sample using the capture system in aim 1 and qRT-PCR of stem cell markers.

Project 4:
Title: Determination of protein biomarkers in plasma in colorectal cancer.

Plasma is a convenient sample to use for diagnostic, prognostic or predictive tests, however as yet there are no suitable plasma markers for clinical use. We have frozen plasma samples from patients with colorectal cancer diagnosed at TQEH over the last 5 years.

Specific aims:

0. To measure cancer related biomarkers in plasma using the Bioplex platform.
0. To correlate biomarker expression with progression-free and overall survival in these patients to obtain a profile of markers for poor versus better prognosis. (Honours project)

Projects are adaptable to Honours, Masters, or PhD. Supervisory panel: J Hardingham, Tim Price, K Grover

Key references:
[1]    Grover PK, Hardingham JE, Cummins AG. Stem cell marker olfactomedin 4: critical appraisal of its characteristics and role in tumorigenesis. Cancer Metast Rev. 2010; 29:761-75.
[2]    Price TJ, Hardingham JE, Lee CK, et al. Impact of KRAS and BRAF Gene Mutation Status on Outcomes From the Phase III AGITG MAX Trial of Capecitabine Alone or in Combination With Bevacizumab and Mitomycin in Advanced Colorectal Cancer. J Clin Oncol. 2011; 29:2675-82.

[3]    Abdollahi A, Folkman J. Evading tumor evasion: Current concepts and perspectives of anti-angiogenic cancer therapy. Drug Resist Updat. 2010; 13: 16-28.
[4]    Todaro M, Francipane MG, Medema JP, Stassi G. Colon Cancer stem cells: Promise of Targeted Therapy. Gastroenterology 2010; 138: 2151-62.
[5]     SIEVE Software for Differential Expression-Thermo Scientific
SIEVE Software for automated, label-free semi-quantitative differential expression analysis of proteins, peptides, and metabolites. http://www.thermoscientific.com/ecomm/servlet/productsdetail?productId=11962143&groupType=PRODUCT&searchType=0&storeId=11152

The Visual Physiology Laboratory investigates how brains make sense of the world viewed by the eye. We study neural pathways used to analyse visual motion in both humans and insects. While similar mechanisms operate in both groups, insects are an ideal model system for tackling key questions at theoretical, physiological and behavioural levels. With a visual system that accounts for as much as 30% of the lifted mass, some flying insects invest more in vision than any other animal. What happens to the abundance of information collected by such large eyes? How has the brain evolved to optimally extract the features from scenes that are most relevant to the behaviour adopted? We address these questions using electrophysiological recordings from neurons in the brain of large insects such as dragonflies and hoverflies, in combination with computational modelling and neuroanatomical techniques. We focus on two visual pathways with different roles in motion analysis. The first is sensitive to ‘optical flow’ – the apparent motion of the world as we move through it. Analysing optical flow helps animals understand their own motion relative to the surrounding world. The second pathway analyses the motion of small objects that move against complex backgrounds and is used in pursuit of other insects – either potential mates or prey.

For more information see:

http://health.adelaide.edu.au/school_medsci/research/physiology/visual/

Location of lab: North Terrace (Medical School South)

Projects:

(1) Comparative analysis of photoreceptor specialization in the acute zones and bright zones of flies

Supervisors: A/Prof David O’Carroll (Physiology) & Dr Steve Wiederman (Physiology)

Background: Many animals have regional specializations of the retina. In humans, for example, the central retina or fovea, provides a zone of high visual acuity which we use for discriminating fine detail and colour, surrounded by peripheral vision that is more sensitive to motion. Many insects also have high acuity eye regions (‘acute zones’). In male flies, frontal directed acute zones are used to help guide territorial pursuit of other flies – either rival males or potential mates – a visually challenging task that requires tracking a small object as it moves across a complex background. In some other species, the same eye region seems to be used for a similar purpose, but is optically different, with larger facet lenses and lower acuity. This provides a much brighter image and has thus been called a ‘bright zone’. Why some eyes have bright zones, and others acute zones, for apparently similar tasks remains a mystery.

Aims: This project will involve recording intracellular physiological responses from photoreceptors within the bright zones and acute zones of closely related fly species, whilst stimulating them with targets moving across the visual field of the neuron against different background patterns. The aim is to establish whether the acute zone or bright zone type eye has advantages or disadvantages for target tracking against complex textures (e.g. foliage), versus plain backgrounds such as the sky.

Project level(s) offered: This project is available as a 3rd year group or honours project. In addition to learning intracellular electrophysiology techniques, motivated students will have an opportunity to learn computer graphics techniques and data analysis using Matlab. Prospective PhD projects are also available on this topic, with suitable expansion of project aims and additional techniques (e.g. computational modelling of optical sampling by the eye).

(2) Analysis of micro-eye movements and their influence on image formation

Supervisors: A/Prof David O’Carroll (Physiology) & Dr Steve Wiederman (Physiology)

Background: Many animals use well-studied and large-scale eye movements for a variety of object tracking tasks. Less well studied however, are a number of very small tremor and microsaccade eye movements, which humans are barely aware of during normal vision. The precise function of these movements is a hotly debated subject, but without them, stationary objects would effectively disappear when we look at them because of rapid adaptation in our early visual pathways. In insects, similar early visual processing is well studied and should cause the same problem. Tantalizing preliminary evidence from flies suggests that they may use small tremor movements (around 6-10 per second) to keep the visual image ‘refreshed’ and visible under some conditions. This has been barely studied however.

Aims: This project will involve recording intracellular physiological responses from photoreceptors and development of new techniques for tracking the movement of the visual image on the retina at high speed by mapping the receptive field of a single neuron many times each second (up to 30). This will allow quantification of the influence of retinal movements on the scene projected onto the retina under different conditions. The aim is to establish when movements occur and what sort of visual stimuli elicit them. For example, are movements associated with novel stimuli, or do they occur spontaneously?

Project level(s) offered: This project is available as a 3rd year group or honours project. In addition to learning intracellular electrophysiology techniques, motivated students will have an opportunity to learn computer graphics techniques and data analysis using Matlab. Prospective PhD projects are also available on this topic, with suitable expansion of project aims and additional techniques (e.g. computational modelling of optical sampling by the eye).

(3) Physiological responses of neurons involved in target tracking

Supervisors: A/Prof David O’Carroll (Physiology)& Dr Steve Wiederman (Physiology)

Background: Visual target detection against a cluttered, moving background is a challenging problem for any visual system, natural or artificial. Our lab has pioneered study of a set of neurons from the brain of insects, which achieve this in spectacular fashion.

Aims: This project aims to explore fundamental physiological
mechanisms for target selectivity and robust responses against complex visual clutter and to apply this knowledge to development of an efficient computational model for target detection. In addition to providing insight as to how complex tasks are solved by biological brains using a tractable model system, the bio-inspired models have potential applications in a number of different areas including defence, surveillance, robotic and artificial vision.

Project level(s) offered: This project is available as a PhD or postdoc project. Depending on the background and prior training of the participants, it will involve a combination of techniques - intracellular electrophysiology, stimulus control and computer graphics techniques, data analysis using Matlab and neuronatomical analysis using fluorescent intracellular markers. Students with a computational or engineering background may also be interested to expand project aims to development of computational models for target analysis.

(4) Human responses to motion in natural scenes

Supervisors: A/Prof David O’Carroll (Physiology), Dr Steve Wiederman (Physiology) & Dr Anna Ma-Wyatt (Psychology)

Background: Many years of studying the visual system with simple stimuli such as striped grating patterns has allowed understanding of the neural mechanisms by which motion is extracted and analysed. An interesting problem that has emerged from this research is that this mechanism is predicted to be very poor at analysing the speed at which a visual scene moves, yet humans are excellent at judging the speed of patterns. Recent work from our lab on insect motion processing suggests that they use an additional component of motion processing – dynamic adaptation to pattern motion – to hugely improve speed estimates when viewing complex natural scenes. Very little work to date however has been done on human subjects in response to such scenes to see if similar mechanisms exist.

Aims: This project aims to use visual psychophysics techniques to study human perception of pattern speed before and after adaptation to moving natural scenes. We hypothesize that with no prior exposure to a scene, the fundamental problems of the underlying motion detector mechanism will produce large variations in speed perception for different scenes, but that prior exposure to motion will improve the robustness of speed estimates as in insects

Project level(s) offered: This project is available as a 3rd year, Honours, or PhD project. The main techiques involved will be based on well-trusted visual psychophysics methods, such as 2-alternative forced choice, in order to match the speed of different patterns presented to subjects in computer animations of natural scene motion. Depending on the level of the student, there will also be opportunities to learn stimulus control and computer graphics techniques, and data analysis using Matlab.

Current research of this group is defining the basic molecular mechanisms that control the activation and regulation of store-operated Ca2+ channels and transient receptor potential (TRP) channels in non-excitable cells in general and in hepatocytes in particular, establishing the role of these channels in generating responses in primary hepatocytes to hormones that regulate metabolism and transport of bile salts, and the role of these channels in liver pathology. The technique that best allows identification of ion channels and the investigation of their properties is patch clamping. We combine patch clamping of primary cells with fluorescence imaging and molecular biology, which puts our work at a forefront of international research in Ca2+ signalling.

Group members: A/Prof Grigori Rychkov (Head); Dr Linlin Ma (postdoctoral fellow); Mr Nathan Scrimgeour (PhD student); Mr Ehsan Kheradpezhouh (PhD student); Mr Dan Gavrilouk (Honours student).

Funding sources: NHMRC, ARC, Diabetes Australia

Recent publications:   http://www.ncbi.nlm.nih.gov/pubmed?term=Rychkov%20G

Location of lab: North Tce

1.    Molecular mechanisms of store-operated Ca2+ entry
Store-operated calcium channels play a central role in the functions of all animal cells. They participate in generating the cellular responses to hormones, antigens, growth factors and other physiological stimuli. The aims of this project are to elucidate cellular mechanisms that regulate interaction between the molecular components of store-operated calcium channel, Orai1 and STIM1. Using techniques of electrophysiology and molecular biology we expect to answer a fundamental question how STIM1 and Orai1 proteins interact to form functional store-operated calcium channels, and how the expression of STIM1 and Orai1 is regulated.

2.    Role of TRPM2 channels in oxidative damage and drug toxicity in liver
Oxidative damage and enhanced hepatocellular death are the hallmarks of many liver disorders, including liver damage by paracetamol overdose and ischemia-reperfusion injury. Often in these conditions hepatocellular death is preceded by a sustained increase in intracellular Ca2+ concentration. In this project will investigate the role of a particular type of Ca2+ channels on the surface of hepatocytes in mediating Ca2+ influx and liver damage produced by paracetamol and ischemia-reperfusion.

Project 1 Title: Characterising the neuroprotective effects of novel bioactive molecules: new drug treatments for Alzheimer’s Disease.

The aims of this project are to further characterize the mechanisms of neuronal protection afforded by bioactive compounds against beta-amyloid toxicity, via enchancing cellular protection and/or a direct anti-amyloid fibril action. Such new treatments that prevent amyloid formation may offer new treatments for Alzheimer's disease.

Methodologies; neuronal and glial cell culture, various biochemical assays, transmission electron microscopy, immunohistochemistry.

Supervisors: Scott Smid, Ian Musgrave

Project 2 Title: Cannabinoid drug discovery as new treatments for human gastrointestinal colitis.

Cannabinoid molecules have been shown to suppress the inflammatory response in the gut, and as such may be useful new drug treatments for colitis. This project will explore the pathways through which cannabinoids and other novel ligands work to strengthen epithelial structure and function under pro-inflammatory conditions and modulate innate immune barrier function.

Methodologies: students will be liaising with medical staff, collecting biopsies and performing tissue and cell culture experiments, utilising histological and biochemical analyses, organ bath experimentation and other techniques such as immunohistochemistry and Western blotting.

Supervisor: Scott Smid

Project Title 3: Assessment of effects of cannabidiol in cannabis withdrawal

Cannabis is one of the most frequently used illicit substances and users exhibit variable dependence. Recent evidence suggests that some non-psychoactive cannabinoids found in cannabis may offset adverse symptoms or dependence potential. This project will be undertaken in collaboration with clinical staff at Drug and Alcohol Services SA. It will involve collecting data on withdrawal symptoms in clients undergoing inpatient cannabis withdrawal, documenting the medication received during withdrawal, duration of the episode and withdrawal status on discharge. Withdrawal severity will be related to recent history of cannabis use. Some analyses of cannabis samples may be undertaken to determine cannabidiol content of cannabis typically used by people who are cannabis dependent.

Supervisors: Scott Smid, Linda Gowing

The focus of the project can for example be:

a. Identification of genes related to cognitive function and emotion processing in depression
b. Investigating the neurobiology whereby early life events increase likelihood of addiction and mental health problems later in life.
c. Investigating pharmacological substrates relevant to cognition, emotion processing and addiction behaviour
d. Identify Immune markers of Cognitive Function and Mood
e. Study Immune-modulating interventions with effects on Neuropsychiatric Disorders
f. Study neuroprotective factors

You will use some of the following approaches (depending on project):

Supervision:
Depending on the project the student will have a primary supervisor in  Pharmacology or Psychiatry. You will be part of the dynamic research group and have have both Prof. Bernhard Baune and an primary honours supervisor. You will take part in the lab meetings, journal club and go to the bi-weekly presentations.

If you are interested in doing an honours project with us, please contact prof. Bernhard Baune (bernhard.baune@adelaide.edu.au) or Femke Buisman-Pijlman (pharmacology: femke.buisman-pijlman@adelaide.edu.au).

more info can be found on http://health.adelaide.edu.au/psychiatry/research/

COLLABORATIVE PHARMACOGENOMIC STUDIES
Dr Janet Coller, Dr Daniel Barratt, Assoc Prof Betty Sallustio & Prof Andrew Somogyi

Several pharmacogenomic studies are likely to be offered for 2012 in collaboration with clinicians in the hospitals investigating the role of polymorphisms in several CYP enzyme, transporter and drug target genes in the response, both efficacy and toxicity to drugs used in cancer treatment (especially breast cancers and leukaemia), organ transplantation, cardiovascular disease and pain. Please contact Prof Somogyi, Assoc Prof Sallustio, Dr Daniel Barratt or Dr Janet Coller for more details.

PHARMACOGENOMICS OF ADDICTION
Dr Janet Coller, Dr Mark Hutchinson & Prof Andrew Somogyi

Addiction or dependence is a major national and international problem costing hundreds of millions of dollars in Australia alone. Many factors, both environmental and genetic, have been associated with the development of dependence and impact on the successful treatment with traditional pharmacotherapies. In particular the immune cells of the brain (glia) may play a role as they are activated to release pro-inflammatory cytokines when drugs are present. We have recently shown that genetic variability in a gene encoding for a pro-inflammatory cytokine is associated with the risk of developing dependence, most probably as a result of altered response of glia to drugs. Consequently, differences in the genetic variability of the complex network of genes involved in the regulation of pro-inflammatory cytokines and immune signalling pathways in general may also be associated with the development of dependence. These projects will encompass specialized bioinformatics techniques to investigate particular pathways involved in classical and immune modulation of alcohol and opioid addiction.

PROJECTS FOR 2012

Evolution of Mammalian Gametes, Gonads, and External Genitalia

Sexual selection and evolution of the genital system in mammals especially rodents
Bill Breed | Chris Leigh | Eleanor Peirce
In our studies some years ago we found that huge differences had evolved in absolute and relative testis mass and numbers of stored sperm in the Australian native rodents with the species with the smallest testes, Notomys alexis, and fewest sperm having, in addition, very large spines on its external genitalia, the glans penis. Coevolving with the latter there is, in the female of this species, a vagina with a narrow lumen that is surrounded by a highly muscular wall and, related to these anatomical features, a very unusual form of copulatory behavior occurs that involves a physical tie, or lock, between the pair for up to 10 minutes. Since, females of this species are considerably larger, and far more aggressive, than males, it may be that the female, rather than the male, determines the length of time the pair are locked together at mating and hence whether insemination by the male does, or does not, result. We suggest that this species exhibits a form of cryptic female choice as part of its mating strategy and that the female can consequently determine the paternity of her offspring; a hypothesis that will be tested in this investigation.

Co-evolution of molecules involved in sperm – egg interaction and binding at time of fertilisation in mammals
Bill Breed l Chris Leigh l Steve Cooper
At the present time we are investigating the possibility that the molecules involved in sperm – egg interaction at the time of fertilization in marsupials and similar to those in eutherian (=placental) albeit that these two groups of mammals diverged from their most recent common ancestor well over 100 million years ago.  We have shown, in collaboration with an American group, that one of the key proteins on the eutherian sperm surface that is probably involved in binding to the extracellular coat that surrounds the egg, galactosyltransferase, is also present in marsupials (Braundmeier, Breed & Miller,2008, Reprod.Fert.Dev.20:402-407) and, in collaboration with Prof. Richard Oko from Queen’s University at Kingston, Ontario in Canada, we have recently initiated a study as to whether several of the other eutherian sperm molecules, known to be involved in activating the egg at fertilization, are also present in marsupials. We now intend to extend this work and, as a working hypothesis, we predict that the molecular interactions at the time of fertilisation in marsupials are similar to those of eutherian species. If found to be the case, it will demonstrate the very ancient origin of the key molecules involved in fertilization in higher vertebrates and that these processes of molecular interaction evolved in a common ancestor 100s of millions of years ago and that the processes have remained more or less unchanged ever since.

Evolution of sperm form in Australian mammals 
Bill Breed | Chris Leigh | Mario Ricci | Jeremy Austin
The form of the male gamete, or spermatozoon, is markedly different in mammals from that of other vertebrate groups with species of rodents in particular showing a remarkable diversity of sperm form across the various species. We are currently carrying out an investigation to determine the reasons as to why this is the case. Our work has shown that, in a few species, highly polymorphic spermatozoa are produced, even by fully sexually mature males, whereas in other species this is not the case and in these latter animals a far more morphologically complex spermatozoon has evolved. We have good reason to believe that these differences in the morphology relate, at least in part, to the differences in the breeding system of the species concerned and it is this hypothesis that will be tested in the present study.

Environmental control of reproduction in rodents
Bill Breed | Brian Setchell l David Taggart l Chris Leigh l Eleanor Peirce
Our long term field studies on the arid zone old endemic rodent, The Spinifex Hopping Mouse, Notomys alexis, in the Northern Territory have shown suppression of female reproductive activity at high population density although males continue to produce sperm at these times. Related studies carried out on the environmental control of reproduction in the laboratory include an investigation into the effects of heating on sperm quality by PhD student, Harsha Wechalekar, who has shown that the male germ cells of these animals are highly susceptible to heat stress in spite of the animals being adapted for life in the arid zone. The current study will extent these observations and, as a working hypothesis, we predict that the life style of these animals prevents them from being exposed to high environmental temperatures and thus minimizes the exposure to heat stress in spite of their natural range being throughout much of the arid region of central and western Australia.

Application of reproductive technology to conservation of Australian mammals
Bill Breed | David Taggart | Hassan Bakos | Michelle Lane | Nicole Palmer
Over the last few years cryopreservation of spermatozoa has been successfully developed in laboratories overseas for several mammalian species. Using the Australian old endemic native rodents, and in particular Pseudomys australis and Notomys alexis, we have managed to develop a superovulation regime for these species and, in collaboration with researchers at ReproMed, we are now planning to develop the optimal conditions for the cryopreservation of the spermatozoa of these animals. As there are several closely related Australian rodents that are currently listed as threatened, the successful development of these techniques could be extended to cryopreservation of the sperm from these threatened species with the consequence that this study could assist in conservation programs rare and threatened species of Australian mammals.

Honours /PhD project title -  Investigating the role of the amyloid precursor protein as a neuroprotectant in traumatic brain injury.

Traumatic brain injury (TBI) causes more deaths in Australians under 45 years of age than any other cause, with survivors often left with significant neurologic deficits.  The amyloid precursor protein (APP) has recently emerged as having a direct protective role following TBI. Our recent in vivo published data has convincingly demonstrated that APP has a protective role following TBI and that an acute increase in APP is actually part of a reparative / neuroprotective response. Importantly, we have also shown that mice lacking APP are more vulnerable to TBI and have more severe neurological deficits following TBI. Aim - to define the active site of APP that is able to reduce neuronal injury markers and improve both cognitive and motor outcome in mice and rats following TBI.

Key methodologies - RT-PCR and Western Blot analysis of frozen mice and rat brain tissue to investigate neuroinflammatory markers.  Immunocytochemistry for analysis of markers for synaptogenesis, neuronal growth, apoptosis and neuronal and axonal injury.  PhD project will involve extensive animal studies using the well-characterized head injury model, this involves motor and cognitive outcome assessment.

Honours Supervisors - Dr Corinna Van Den Heuvel, Professor Robert Vink
PhD Supervisors  - Dr Corinna Van Den Heuvel, Professor Robert Vink and Dr Emma Thornton

Please Note: Summer Research Projects within Neurological Diseases will not be offered this year.

The Bone and Joint Research Laboratory (SA Pathology, Adelaide)

Mission Statement
To carry out internationally competitive research that leads to a better understanding of bone and joint structure and function as well as practical outcomes for treatment of musculoskeletal disease.

Research Overview
The core focus of the Bone and Joint Research Laboratory is to understand the effects of musculoskeletal disease, injury, ageing, and repair on joint and tissue function. The Laboratory is internationally recognised for human tissue-level analyses, utilising a well-estalished human musculoskeletal tissue bank, unique to Australia. The Laboratory works closely with surgeons, clinicians and pathologists to analyse bone and joint tissue samples. Hypotheses testing in animal models complement the human tissue-level analyses.

Biomaterials and tissue engineering are studied in the context of musculoskeletal disease, such as osteoporosis and osteoarthritis. Applying complementary techniques (microarrays, histology and micro-computed tomography) to analyse human bone tissue samples from patients with osteoporosis and osteoarthritis the Laboratory has been the first to map how changes in the expression of genes that control bone cell activity leads to changes in the bone tissue structure. These advances are making a significant contribution towards the development of therapies that will slow the progression of these prevalent musculoskeletal diseases and delay if not obviate the need for expensive surgery associated with joint replacement.

The Laboratory is located in SA Pathology and is closely affiliated with other institutions including the Hanson Institute, Royal Adelaide Hospital, The University of Adelaide (School of Medical Sciences), and has strong collaborative research programs with Flinders University, as well as national and international research linkages.

SCIENTIFIC MEMBERS

Dr Julia KULIWABA
Dr Ian PARKINSON
Dr Julia HUMPHRIES
Dr John CODRINGTON
Prof Nick FAZZALARI

Location of lab: SA Pathology (IMVS) Frome Road

The Role of Subchondral Bone in the Pathogenesis of Osteoarthritis

Supervisors: Dr Julia Kuliwaba, Dr Ian Parkinson
Although the initiating event of Osteoarthritis (OA) has yet to be identified, the notion that early OA is characterised only by the degeneration of the articular cartilage has recently been reconsidered, as subchondral bone (SCB) alterations were also found to be involved in the early phase of the disease process. Further, clinical and experimental studies suggest that changes in SCB are a driving force behind the cartilage degradation observed in OA. Our Laboratory’s recent research utilising a non-trauma rat model of OA has revealed elevated SCB remodelling at an early stage of the OA disease process that progresses to SCB sclerosis at a later disease stage. SCB changes have been associated with local osteoblast metabolism involving abnormal activation of biochemical pathways. Further, there is in vitro evidence that SCB osteoblasts are capable of influencing chondrocyte metabolism more directly, leading to abnormal remodelling of OA cartilage. Interestingly, many of the candidate susceptibility genes for OA, identified by genetic screening approaches, have bone-related functions, which further suggests the involvement of bone in OA. Research projects are available that aim to characterise the molecular mechanisms of altered SCB remodelling in our non-trauma rat model of OA and in tissue samples from patients with OA. Projects will involve handling rodent/human tissue samples, micro-CT imaging, Fourier Transform Infra Red (FTIR) microspectroscopy, bone and cartilage histology, quantitative morphometry, immunohistochemistry, and quantitative real time RT-PCR.

Molecular Mechanisms of Microdamage-stimulated Bone Remodelling

Supervisor: Dr Julia Kuliwaba
Bone remodelling is achieved by the initial activity of osteoclasts to resorb bone followed by the formation of new bone by osteoblasts. Bone resorption is stimulated in two general ways. First, bone is resorbed in response to a systemic requirement for calcium. Second, and less well understood, is the process whereby osteoclasts are stimulated to remove bone that has sustained microdamage (microscopic cracks in the bone matrix). This project seeks to identify, in human bone samples, the molecules that may link microdamage to the initiation of bone resorption. The project will involve analysis of normal and pathological (Osteoporotic and Osteoarthritic) human bone samples. The identification of regulatory mechanisms that control bone remodelling is essential to design better treatments for musculoskeletal diseases that are characterised by impaired bone quality and/or structure. The project will involve handling human bone tissue samples, fluorochrome labelling of microdamage, bone histology, quantitative bone histomorphometry, immunohistochemistry, and quantitative real time RT-PCR.

The Role of the Osteocyte Cell Network in Human Bone Remodelling

Supervisor: Dr Julia Kuliwaba
Tissue level studies of human bone have not been fully exploited to elucidate the physiology of bone remodelling. In particular, the functional role of the osteocyte cell network in human bone is poorly understood and there is increasing evidence that osteocytes play a significant role in directing bone remodelling to a specific location in the bone mineral. The osteocytes may detect bone strain magnitudes to effect bone remodelling. Also, secretion of soluble factors from damaged osteocytes (induced by microcracks) may locally activate the initial osteoclastic resorptive phase of targeted bone remodelling. This study will explore the direct relationship between osteocyte cell number and distribution with bone remodelling in human bone tissue. In addition, osteocyte cell expression of proteins postulated to be involved in signalling for osteoclastic bone resorption will be investigated. The project will involve analysis of normal and pathological (Osteoporotic and Osteoarthritic) human bone samples. Specifically, the project will involve handling human bone tissue samples, bone histology, quantitative bone histomorphometry, immunohistochemistry, and confocal microscopy.

3D Imaging of Microcrack Propagation in Human Cortical Bone

Supervisor: Dr Julia Kuliwaba
If the skeleton does not adequately repair bone microcracks, they accumulate, resulting in decreased bone strength, which may lead to an increased risk of fracture (presented clinically as stress fractures and Osteoporotic fragility fractures). The process by which microcracks in bone initiate, propagate and ultimately coalesce leading to failure remains poorly understood. This project will investigate the microscopic tissue changes associated with microcracks during crack propagation in human cortical bone and the influence of bone microstructure (such as the vasculature and osteocyte cell network) on this process. The project will involve handling human bone tissue samples, fluorochrome labelling of microcracks, confocal microscopy, micro-CT imaging, and 3D data computer analyses.

Predicting Bone Strength – Contribution of Bone Architecture

Supervisors: Dr Ian Parkinson, Dr Julia Kuliwaba
The mass-based paradigm for bone strength does not adequately enable the identification of individuals at risk of bone fracture. Other factors must influence the quality of bone. Bone architecture is one such factor, not assessable using current clinical tools. Micro-CT imaging allows assessment of bone architecture ex vivo and with further technological advances similar assessment will be possible in vivo, in the near future. Understanding the correlation between bone strength and bone architecture will be essential to the clinical application of this architectural information. This project seeks to investigate bone architecture and bone strength. The strength of whole vertebral bodies will be assessed using a mechanical testing device and this will be correlated with data acquired by micro-CT imaging, before and after testing. The project will involve handling human tissue samples, operation of micro-CT imaging and mechanical testing equipment and histological tissue preparations for analysis.

Bone Architecture – Correlation between Mineralisation and Strength

Supervisors: Dr Ian Parkinson, Dr Julia Kuliwaba
The mass-based paradigm for bone strength does not adequately enable the identification of individuals at risk of bone fracture. Other factors such as bone mineralisation must influence the quality of bone. We use a back-scattered electron imaging (BEI) technique to quantify the degree of mineralisation in ex vivo bone samples. Extending this technique to micro-CT imaging may allow similar analysis to be carried out in vivo in the near future. Understanding the correlation between bone strength and bone mineralisation will be essential to the clinical application of fracture risk. This project seeks to investigate bone mineralisation and bone strength by mechanically testing bone samples and correlating BEI and micro-CT data. The project will involve handling human tissue samples, operation of scanning EM, micro-CT imaging and mechanical testing equipment.

There are a number of research projects on offer focussing on acute brain injury (trauma and stroke) and the identification of the various secondary injury factors associted with injury development and their treatment. Within this theme, projects are usually tailored to suit a student's interest and historically have focussed on such things as oedema, aquaporins, ICP, substance P, neurogenesis, inflammation, modelling, or specific treatments. Techniques employed include surgery, neurological assessment, pharmacological treatments, histology, immunohistochemistry, PCR and electron microscopy. We currently have a particular interest in exploring post-traumatic outcome in genetic knockout animals and in interference RNA technology as a treatment intervention, although projects will not be limited to these themes. All students will have a minimum of two supervisors, with at least one being either Dr Van Den Heuvel or Professor Vink. Other co-supervisors have included Prof. Yool, Prof. Byard, Prof. Blumbergs, Assoc. Prof. Ghabriel, Dr Turner, Dr Helps, and Dr Thornton, although any active research academic who adds to the strength of the supervisory panel can potentially be included. With a number of postdoctoral fellows and current PhD students in the laboratory, there is abundant peer support for any interested students.

Honours topic 1: The role of aquaporins in experimental vasogenic oedema - Supervisors Professor Robert Vink and Dr Stephen Helps

Honours topic 2: Interference RNA as a novel approach to treatment following traumatic brain injury: Supervisors Professor Robert Vink and Dr Renee Turner

Honours topic 3: Histological characterization of brain tissue following stress: Supervisors Professor Robert Vink and Dr Corinna Van Den Heuvel

Please Note: Summer Research Projects within Neurological Diseases will not be offered this year.

OSTEOCYTES AND CANALICULAR DENSITY IN VERTEBRAL TRABECULAR BONE OF OSTEOPOROTIC SUBJECTS

BACKGROUND
Osteocytes are actively involved in the turnover of bone matrix through various mechanosensory mechanisms.  Given the considerable evidence supporting osteocytes as local initiators of bone remodeling, we believe that lacunar and canalicular density may be altered in osteoporotic subjects.

METHODS
A minimum of 10 fresh cortico-cancellous bone samples from the base of the lumbar spinous processes will be collected from osteopenic female patients (matched as close as possible for age) undergoing decompressive laminectomy surgery for spinal stenosis.  As controls, similar bone samples will be collected from female cadavers that do not have osteoporosis.  Bone biopsies will be screened for Bone Mineral Content and Bone Mineral Density by Dual Energy X-ray Absorptiometry.  All bone samples will be processed to yield 3D bone histomorphometry data from Micro-CT images.  The samples will then be decalcified and embedded in paraffin from which 4m sections will be stained to demonstrate osteocytes and the associated canalicular network.  The areal density of osteocytes and canaliculi per unit area of bone will be measured using light microscopy and the Quantimet 500 Image Analyser and correlated with previously acquired histomorphometric data.

POTENTIAL OUTCOME
Osteoporosis is the most common musculoskeletal disorder, characterized by low bone mineral density and structural deterioration of bone, leading to fractures.  Excessive bone resorption (due to increased osteoclast activity) relative to bone formation is the principal cause of bone loss in postmenopausal osteoporosis but recent studies suggest that inappropriate apoptosis of osteoblasts and osteocytes account, at least in part, for the imbalance in bone remodeling.  This study will assist in further characterisation of osteocyte function and the role of these cells in bone turnover in osteoporosis.

COMPARISON INVESTIGATION OF EXPRESSION OF DICKKOPF (DKK-1) BY OSTEOBLASTS LIKE CELLS FROM NORMAL AND OSTEOPOROTIC SHEEP USING A HUMAN DKK-1 ANTIBODY (IN VITRO STUDY).

BACKGROUND
The Wnt signalling pathway plays a major role in promoting and regulating osteoblastogensis. It is well documented that activation of this pathway increases bone formation in numerous species including humans. Wnt signalling is negatively modulated by numerous inhibitors such as Dkk-1 which plays a major role in inhibiting this pathway. Blockage of Dkk1 activity has been proposed as a potential treatment for osteoporosis.
Our group has developed an osteoporotic sheep model for characterising the skeletal pathology and assessing various treatment modalities for this disorder. We propose to investigate the present of Dkk1 on ovine bone under in vitro conditions.

METHODS
Osteobalst like cells from osteoporotic and control sheep will be cultured to have adequate number of cells for conducting this experiments using an established method [1].  Primary human MSCs which have been transduced to overexpress Dkk-1 will be used as positive controls.  1-2 x 10^5 cells per each animal will be fixed in 1% paraformaldehyde for 20 minutes at room temperature. Then the cells (from both sheep and human) will be incubated with an appropriately diluted primary antibody or isotype-matched control (diluted in blocking buffer- as negative control) on ice for 1 hour. Then all cells will be washed twice in ice-cold intracellular wash buffer, to remove unbound antibody, and will be resuspended in 50ul of appropriately diluted secondary antibody (diluted in blocking buffer).  Following incubation with secondary antibody, cells will be washed twice in ice-cold intracellular buffer and be resuspended in FACS Fix to be analysed by flow cytometry, and the data stored as list mode data for further analysis.

POTENTIAL OUTCOME
This study will also demonstrate if the Dkk-1 in sheep has strong homology with Dkk-1 in human.  It will also provide valuable information in regards to role of Wnt pathway in sheep and it will assist our understanding of the mechanisms of bone loss in the current animal model.  Such information can be utilised for pre-clinical validation of anti-Dkk1 antibody as a potential treatment for osteoporosis.

The Dame Roma Mitchell Cancer Research Laboratories in the School of Medicine at the University of Adelaide investigates molecular mechanisms of cancer and the role of key hormone signaling pathways in carcinogenesis. The focus of this group involves research into the initiation, progression, treatment and prevention of prostate and breast cancer.

Our research is a fusion of cancer biology and endocrinology, focusing on hormone signalling in prostate, breast and ovarian cancer. We use a broad range of molecular and cellular techniques that include the latest technologies to investigate how genes, proteins and epigenetic modifications of DNA influence cellular function. These techniques include quantitative real-time PCR, western blotting, chromatin immunoprecipitation, whole genome expression analyses, low density microarray analyses, immunohistochemistry, confocal microscopy, cloning, promoter analyses via transactivation assays, siRNA gene knockdown, and expression vector knock-in. At the cellular level we investigate how hormones and potential new therapeutics influence cancer cell growth and apoptosis. We have unique models of cancer, including cancer tissue from patients that is cultured ex vivo, to further investigate hormone signalling, molecular mechanisms and potential new treatments in cancer. We also have the capability to produce tissue microarrays which allow simultaneous analysis of hundreds of tissues.

Location of lab: Hanson Institute Bldg, behind Medical School, Frome Rd

Androgen receptor signalling in development and progression of prostate cancer
Androgen signalling, mediated by the androgen receptor (AR), is a major determinant of prostate tumorigenesis. We have identified a unique gene signature using a unique mouse model of spontaneous prostate cancer (AR-E231G) that predicts disease progression. The aim of this project is to determine whether expression of key genes identified in the AR-E231G mice are expressed in core biopsy specimens of human prostate and can predict clinically important tumors.  This project will involve gene expression analysis of tissue microarrays and will be supervised by Dr Lisa Butler and Dr Tanya Day.

Androgen hormone action in female tissues: does it protect against development of hormone-sensitive cancers in women?
Androgen and estrogen hormones are physiological antagonists in male and female tissues, but the molecular basis for this interaction and its clinical consequences are not fully understood. Our laboratory has found that the androgen receptor can block signalling of the estrogen receptor in a breast cancer cell line by binding to specific estrogen response elements (ERE) in a subset of estrogen receptor target genes. This study aims are to further investigate the cellular and molecular mechanisms by which androgen receptor signalling regulates normal breast tissues and how this is perturbed in cancerous tissues. Contemporary molecular techniques will be used. This project will be supervised by Dr Theresa Hickey and Dr Nicole Moore.

Developing New Therapeutic Approaches for Prostate Cancer:
Androgen hormon signalling, via the androgen receptor, is essential for the development and maintenance of the prostate gland, and has been linked to all stages of prostate cancer. and therefore the androgen receptor is a viable therapeutic target. In this project, the anti-tumour activity and toxicity of novel androgen receptor-targeted agents alone or in combination with current prostate cancer agent will be compared to current agents alone. The studies will involve the assessment of prostate cancer cell growth and proliferation in culture, and by using cell-death and cell cycle studies, and Affymetrix microarray to identify genes that are modulated by the treatment. These studies will provide proof of concept for future clinical trials of androgen-receptor targeted therapies in prostate cancer.  The supervisors for this project are Dr Lisa Butler and Dr Margaret Centenera.

Investigating miR-375 as a circulating marker and regulator of metastatic prostate cancer
New tools that can accurately identify life-threatening prostate cancers are urgently required. Circulating microRNAs (miRNAs) are emerging as useful non-invasive markers of disease. We and others have recently shown that miR-375 is a sensitive marker of metastatic prostate cancer in the blood. The first aim of this Honours project is to assess whether miR-375 can predict lethal prostate cancer at the time of diagnosis, using serum samples from the Australian Prostate Cancer BioResource. The second aim is to investigate whether miR-375 contributes to disease development and/or progression. Techniques that will be employed to achieve these aims include qRT-PCR, RNA-seq expression profiling  and cell-based assays to assess miRNA function. This project will not only assess the clinical potential of a new biomarker of prostate cancer but will also increase our understanding of how deregulated expression of miRNAs contributes to disease.

The supervisor for this project will be Dr Luke Selth.

Androgen receptor splice variants: novel drivers of metastatic prostate cancer
Recent evidence suggests that aggressive forms of prostate cancer are associated with splice variants of the androgen receptor (AR). However, the molecular mechanisms underlying AR splice variant (ARV) action and the extent of ARV expression in clinical disease are currently unknown. In collaboration with Prof Steven Plymate of the University of Washington, our laboratory has recently initiated a line of research aimed at characterising ARVs in prostate cancer. At least two projects are available. One will involve functional analysis of ARVs using cutting-edge molecular techniques, including ChIP-seq, RNA-seq and biochemistry/mass-spectrometry. The second is a clinical research project aimed at characterising ARV expression at the protein and RNA level in patient samples. These projects are likely to increase our understanding of aberrant androgen signalling in metastatic prostate cancer and may lead to therapeutic strategies to target ARVs.  The supervisor for these projects is Dr Luke Selth.

Inflammatory cytokine profiles of community-dwelling individuals with chronic spinal cord injury: Relationships to physical characteristics and functional decline

Localised or systemic inflammatory responses are a consistently observed manifestation in a variety of pathological states. In spinal cord trauma, the acute inflammatory response occurring in the damaged spinal cord is a significant correlate of neurological outcome, with a variety of chemokine and cytokine biomarkers related to the pathophysiology of the condition and in turn to injury severity and functional outcome. The over-expression of inflammatory biomarkers in tissue and their release to the blood is also known to be implicated in susceptibility for a range of chronic metabolic conditions to which adipose (fat) tissue deposition importantly contributes, such as obesity, atherosclerosis and Type 2 diabetes.

The purpose of this investigation will be to examine the levels of chemokine/cytokine markers in blood (using ELISA and multiplex array systems) obtained from a cohort of community-dwelling individuals with chronic SCI and establish the relationship between these biomarkers and physical characteristics (using standard anthropometrical techniques), as well as the longer-term progression of the associated metabolic syndrome and its functional consequences.

Preliminary data will be used to establish the relationship between the systemic inflammatory status of community-dwelling individuals with chronic spinal cord injury and susceptibility for metabolic syndrome, as well as providing better tools for evaluating the spectrum of metabolic risk in this disorder. Suggested abstract attached on a quick turnaround. The acute group is difficult to recruit (competing studies) and the sources of these molecules will differ acutely and in the chronic situation.  I suggest a cross-sectional design involving the chronic group, which essentially is a descriptive study, but I am leaning towards comparisons with healthy, age and gender-matched controls to add extra rigor. The a priori hypothesis would be that we will identify a unique proinflammatory cytokine profile in CSCI, which will correlate with susceptibility for metabolic syndrome, possibly independently of the usual culprits. A secondary aim, if a comparison with healthy controls, will be to provide better outcome measures for assessing the spectrum of risk for metabolic syndrome, or associated functional decline, in CSCI cohorts.

The Biological Anthropology and Comparative Anatomy Research Unit (BACARU) runs research on human variation and human evolution as well as comparative anatomy studies of marsupials and primates that help to understand general phenomena in evolution of humans. We also use knowledge of human biological variation in practical applications to forensic cases (about 25 cases done per year for Police, Prosecution and Defence) and to public health - child growth, obesity and anatomical variations. We have special interest in brain evolution. The group started working with the appointment of Maciej Henneberg to the Wood Jones Chair of Anthropological and Comparative Anatomy in 1996. Since then our work was funded by large ARC grants and currently we use funding from the Institute of Evolutionary Medicine at the University of Zürich. Evolutionary Medicine is a new discipline and we will run in 2012 the first in Australia course of Evolutionary Medicine at the Level III next year. A number of honours and postgraduate research projects will be related to this emerging strength. Postgraduate students doing these projects will have an opportunity to travel overseas for their research. BACARU Leader is also an International Fellow of the Unit for Biocultural Variation in Obesity at the University of Oxford with a possibility of joint projects. Dr Jaliya Kumaratilake, a Senior Lecturer in anatomy and two Visiting fellows: Dr Renata J Henneberg, a dental anthropologist and Dr Arthur Saniotis, an anthropologist, are co-supervising research projects. BACARU has also strong links with archaeology and a number of research projects are done in collaboration with South Australian Museum and Flinders University.

Location of lab: Medical School

All project topics are worked out jointly by BACARU members and interested students at all levels. Hence no specific titles and descriptions of all possible projects are given below. Just examples are given and then a list of possible topics. These can be modified following discussions between students and prospective supervisors.

A. Physical growth and development of disadvantaged children.
This project entails the use of anthropometric techniques and simple motor performance tests to assess growth of children in a disadvantaged community such as an African nation or an Aboriginal settlement. A student will have to do fieldwork in a community measuring several hundred children and then analyse results statistically. We have extensive collection of comparative data from Africa and Aboriginal settlements in South and Central Australia.

B. Eye shapes in young Australians, a forensic database.
This project will produce a database of variation in eye slit shape, size and anatomical variation of lids, lashes and brows to be used in forensic identification cases. The work will entail collection of standardised photographs of the eye region of a few hundred young Australians and then categorical classification of eye features. The theoretical basis for the distribution of variation frequencies, using concepts of heritability and econsensitivity will need to be presented to provide indications for possible future changes in frequencies.

C. Pongid characteristics in hominin skulls
Early hominins are supposed to be closer to a common ancestor of apes and humans than later forms and hence are more likely to share characteristics with apes. The project, using 3dimensional morphometric and descriptive techniques, will test this assumption and indicate which of the postulated early hominin ancestors could be also ancestors of apes. Actual skulls of modern apes and research quality casts of skulls of hominin ancestors will be used.

List of possible other topics:

1. Do familiar faces appear more lifelike than unfamiliar ones
2. Does eye colour change people’s perception about hominins
3. Facial expressions vs neutral faces in facial reconstructions
4. Differences between various reconstructions of australopithecines
5. Do hairstyles change our perceptions
6. Accuracy of current methods (of ageing, sexing etc) on a series of skulls and comparing information to actual individuals information
7. Placing individual hominin finds into a timeframe of human evolution
8. Generational differences in families – body size and head size
9. Handedness among young Australians – an assessment using Edinburgh Questionnaire
10. Heritability of external ear characteristics
11. Obesity and physical performance – grip strength and time of neuromuscular reaction
12. Frequency of somatotypes among young Australian males
13. Age changes in the human face
14. Types of flexion creases on dorsal surfaces of human fingers
15. Variation of human lip-prints
16. Intergenerational differences in head size and body height