Research training pathway
The Faculty of Medicine and Health Sciences allows opportunities for students to pursue a customised research pathway, as an end in itself if some research experience will be beneficial for future professional work. Alternatively, this pathway can lead to PhD study through programs that provide an optimal research training framework in preparation for doctoral research.
Master of Research (MRes)
The Master of Research (MRes) is a two year, full-time program with a unique combination of advanced coursework and research training that replaces most honours as the main pathway to a Doctor of Philosophy (PhD) and Master of Philosophy (MPhil).
The following are examples of the types of projects that will be offered to second-year MRes students in 2016. These are illustrative; students should contact potential supervisors directly to discuss the availability of positions in their laboratories and to develop a detailed research plan for 2016.
A 1–2 page research application form should be prepared in collaboration with the prospective supervisor and submitted for consideration by the FMHS MRes Committee. Applications should be submitted before:
Domestic (admission and scholarship): 31 October (every year)
International (scholarship): 31 July (every year)
International (admission only): 31 August (every year)
Research projects
Doctor of Physiotherapy
The Doctor of Physiotherapy is the only three-year master’s level professional-entry physiotherapy degree in New South Wales that allows you to learn more advanced skills in physiotherapy as well as business management, leadership and advocacy.
Bachelor of Philosophy/Master of Research (Medicine and Health Sciences)
The Bachelor of Philosophy/Master of Research (BPhil/MRes) is a unique combination of advanced two-year coursework and research training consisting of an advanced undergraduate study program exploration of research frontiers in your discipline and a master’s level postgraduate research training program. You'll specialise in research preparation and focus on a specific research topic at the sub-discipline level.
Understanding opioid and cannabinoid drug action
Prof Mark Connor
Contact: mark.connor@mq.edu.au
Our work is focussed on understanding how analgesic drugs work at a cellular level with the view to identifying new targets for drug action in pain and other major areas where ion channel or GPCR modulation may be therapeutic (i.e. cancer). Our major goal is to understand how different opioid and cannabinoid ligands interact with their receptors and downstream signalling pathways. We have particular interests in ligand biased signalling, allosteric modulation of receptor signalling and signalling at polymorphic variants of human opioid and cannabinoid receptors. MRes projects might include investigation of novel allosteric modulators of µ-opioid receptors, investigation of how the non-psychoactive constituents of cannabis affect cannabinoid receptor signalling as well as how endogenous cannabinoid-like molecules modulate calcium and TRP channel signalling. Our work is done using high throughput live cell assays of receptor activation and contemporary biochemical techniques.
Cardiovascular Systems & Signalling
Assoc Prof Ann Goodchild
Contact: ann.goodchild@mq.edu.au
The goal of the Systems and Signalling Neuroscience Group is to understand how neurons and neuronal networks operate normally, such as in health, and what changes underpin their dysfunction evident in disease. The neural systems of interest are those which control cardiovascular, metabolic and respiratory function.
The specific objectives of our group are: to identify neurons in the central nervous system that regulate or modify these functions; to understand the circuitry by which they influence the key brain sites that control the functions of interest, to determine the neurochemistry of the neurons and receptor and downstream intracellular signalling mechanisms that influence their activity; to determine neuronal recruitment/adaptation and protein changes/modifications that occur within these neural systems in response to acute (e.g. lowering blood sugar levels or administration of drugs of addiction) or chronic challenges (e.g. hypertension or methamphetamine addiction). Techniques used include in vivo and in vitro electrophysiological techniques in conjunction with pharmacology, functional neuroanatomy using multi-labelling approaches as well as 'shot gun' label and label free proteomic techniques. MRes projects could include determining the cellular characteristics of neurons that control cardiovascular, respiratory and metabolic function that mediate the response to an acute challenge.
Neurosurgery Research: Syringomyelia, CSF physiology and Brain Arteriovenous Malformations
Prof Marcus Stoodley, Dr Thomas Woodcock, Dr Zhenjun Zhao and Dr Lucinda McRobb Contact: marcus.stoodley@mq.edu.au | thomas.woodcock@mq.edu.au | zhenjun.zhao@mq.edu.au | lucinda.mcrobb@mq.edu.au
Syringomyelia & CSF Physiology
Syringomyelia is a condition characterised by the formation of fluid-filled cysts within the spinal cord that can cause pain and paralysis. Syringomyelia occurs in patients with spinal cord injury, tumours and congenital abnormalities. The research team consists of two-post docs, and PhD candidates working to understand this condition with the aim of developing better treatments in the future. The lab uses animal models of syringomyelia and techniques such as microsurgery, CSF tracers, immunofluorescence, in-vivo imaging and western blotting. We collaborate with engineers and medical imaging specialists to study the condition in humans and to create computational models.
Developing a novel treatment for brain Arteriovenous Malformations (AVMs)
AVMs of the brain are devastating congenital lesions that are the most common cause of haemorrhagic stroke in children and young adults. Although most small AVMs are curable, over 90% of large lesions are untreatable and/or have high associated risk of haemorrhage.
The overall goal of the AVM neurosurgery group is to develop a new treatment for brain AVMs, which is safer and more effective than the current method of surgery and radiosurgery, using biological methods to promote intravascular thrombosis after radiosurgery ('Vascular Targeting').
Our group has shown that stereotactic radiosurgery can be used to alter AVM endothelium cell surface characteristics. Our work looks at identifying for potential molecules which are induced specifically to the AVM vessels sufficiently different from that of normal endothelial cells to allow selective targeting, by undertaking a comprehensive analysis of endothelial molecular changes after radiation, utilising a number of techniques ranging from cell biology, molecular biology, proteomics, microsurgery, immunohistochemistry, microscopy, in vivo imaging, angiography, flow cytometry in in vitro and in vivo studies. The radiation-induced molecular changes on AVM endothelial surface are under investigation to be used in targeted delivering thrombotic agents to AVM vessels resulting in thrombus formation selectively in these vessels, a method to block AVM vessels without surgery.
Prevention and Treatment of Surgical Infection
Assoc Prof Karen Vickery
Contact: karen.vickery@mq.edu.au
10% of patients develop a hospital acquired infection (HAI) and 80% of these are caused by bacterial biofilms. Our aim is to reduce HAI rates by improved detection and removal of biofilms from environmental surfaces and surgical instruments, as well as preventing biofilm infection of medical implants, such as hip joints and breast implants. We test punitive biofilm removal and prevention methods using in vitro and in vivo models. Bacteria will be quantified and identified using standard microbiological (counts, differential and selective culture), molecular (qPCR, 16S RNA sequencing, terminal fragment length polymormism [TRFLP] and fluorescent in situ hybridisation [FISH]) and visual (Scanning electron and Confocal microscopy) techniques.
Functional connectivity of brainstem cardiorespiratory networks
Dr Simon McMullan
Contact: simon.mcmullan@mq.edu.au
Groups of neurons within the brainstem are responsible for the control of breathing and blood pressure. These cardiovascular and respiratory neural networks are strongly influenced by sensory pathways that convey information describing the internal (e.g. pH) and external (e.g. temperature) environments, but the neural mechanisms responsible for baseline activity and second-to-second adjustment of these crucial systems are poorly described. Our research objective is to identify neurons that provide synaptic input to cardiovascular and respiratory networks and, ultimately, to determine which inputs most strongly influence the behaviour of these neurons. We use a combination of electrophysiological techniques to study neuronal activity in live animals and in slices of live brain, and molecular and genetic approaches to identify neurons that compose these networks. The group currently contains two PhD students and one post-doctoral researcher.
Understanding the causes of Motor Neurone Diseases
Prof Roger Chung, Prof Gilles Guillemin, A/Prof Julie Atkin
Contact: roger.chung@mq.edu.au | gilles.guillemin@mq.edu.au | julie.atkin@mq.edu.au
We have recently established a new research group studying Motor Neurone Diseases (MND), a group of devastating neurodegenerative diseases that cause limb paralysis and ultimately death. We consist of five teams with a broad range of expertise in human genetics, molecular and cell biology, biochemistry and zebrafish biology, which collectively establish a comprehensive and systematic laboratory-based research program that will lead directly to translational studies in partnership with the existing strength in clinical MND research at Macquarie University Hospital led by Professor Dominic Rowe. MRes projects are available to investigate the genetics, biochemistry and cell biology that causes degeneration of motor neurons, using a range of molecular biology, protein neurochemistry, and microscopy techniques in cultured motor neurons and transgenic zebrafish and mouse models of MND. The new MND research group has a vibrant team of 20 postdoctoral fellows, research assistants and PhD students.
Projects that are available for 2nd year MRes projects
What is the role of abnormal and inappropriate aggregation of specific proteins in the development of MND?
A common hallmark of MND is the abnormal formation of accumulations of specific proteins within motor neurons and non-neuronal cells. We don't fully understand why these normal proteins become abnormally "sticky" and aggregate together. However, we think that this process is directly involved in degeneration of motor neurons. We want to understand why this occurs, and develop ways to stop this from happening.
Why does degeneration of motor neurons spread from one region to cover the entire spinal cord, and can this be stopped?
The first clinical symptoms of MND are caused by degeneration in a small region of the spinal cord or brain. However, as the disease worsens the area of degeneration becomes significantly larger. We believe that the non-neuronal cells are involved in this spread of degeneration, and our research aims to understand and ultimately stop this from occurring.
Can muscle or the neuromuscular nervous system be a therapeutic target in MND?
While MND results in the degeneration of motor neurons in the brain and/or spinal cord, the disease also causes the gradual degeneration of muscle. This is because the motor neurons that connect to the muscle and control their function start to lose their connections. Ultimately this leads to the shrinkage of muscle, to the point where it cannot support movement. We believe that if we can understand how the motor neurons and muscle become disconnected that this process will be a viable and important target for therapeutic intervention.
Genetic basis of amyotrophic lateral sclerosis
Dr Nicholas Cole
Contact: nicholas.cole@mq.edu.au
The motor neuron disease amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder that leads to the loss of motor neurons and death within 3 to 5 years of first symptoms. There is no cure or effective treatment. There is a desperate need to develop more effective diagnostic tools and treatments for ALS.
A long-term aim of our research is to understand ALS disease mechanisms and to identify new therapies using animal models of ALS and other motor neuron diseases. We wish to establish a paradigm for high-throughput drug screening. From our preliminary studies, we hypothesise that zebrafish models of motor neuron disease with mutations in TDP-43, FUS and other known motor neuropathy genes will provide crucial insights into disease biology and will allow development of drug screening models to identify compounds with therapeutic potential.
The aims of this proposal are to:
- Establish transgenic zebrafish lines carrying the wild-type and mutant human motor neuron disease genes that allow rapid evaluation of the role of their products in ALS.
- Identify behavioural, morphological, and pathological phenotypes in the transgenic zebra fish at larval and adult stages.
- Development of drug screening models to identify compounds with therapeutic potential.
Novel therapeutic strategies in motor neuron disease (MND)/amyotrophic lateral sclerosis
Supervisor: A/Prof Julie Atkin
Contact: julie.atkin@mq.edu.au
Motor neuron disease (MND) is fatal, rapidly progressive neurodegenerative disease that results from the loss of motor neurons in the brain, brainstem and spinal cord. Death usually results within 3 to 5 years of first symptoms and there is currently no effective treatment. Here is a desperate need to develop more effective therapeutic strategies for MND. Recently we found that a chaperone induced during ER stress, protein disulphide isomerise (PDI), protects against protein misfolding and toxicity induced in MND. Furthermore, a small molecule mimic of PDI is protective against motor neuron loss in mouse models of disease, suggesting that PDI has potential as a novel therapeutic agent. PDI has both chaperone and disulphide interchange activity, but it is unknown which function is protective in MND. This project will examine features of PDI that are responsible for its protective activity, with the aim of designing novel therapeutic agents in the future.
Genetic, bioinformatic and cell biology studies of motor neuron disease (MND)
Prof Ian Blair & Dr Kelly Williams
Contact: ian.blair@mq.edu.au | kelly.williams@mq.edu.au
Motor neurons are nerves that extend from the brain to the spinal cord and muscles and provide the stimulus through which we move, breathe, eat and drink. Unlike other cells of the body, motor neurons are not replaced when they die. Motor neuron disease (MND, also known as amyotrophic lateral sclerosis, ALS) is a rapidly progressive disease that causes the death of motor neurons leading to paralysis and death. MND is a devastating illness with appalling prognosis. Median survival is around two years. There is a pressing need to develop more effective diagnostic tools and treatments for MND. The only proven causes of MND are gene mutations. Identification of the genes that cause or predispose to MND will lead to the unravelling of the underlying molecular mechanisms as a prerequisite to effective disease diagnosis, treatment and prevention. Known MND genes only account for less than 10% of cases. Our research aims to identify gene mutations that cause MND and investigate the effects of those mutations using cell biology techniques. Our laboratory has played an instrumental role in the identification of mutations in several new disease genes among MND patients (published in Science and Nature Neuroscience). Work is now underway to determine how these mutations lead to motor neuron death. Significant variation is seen in disease onset and duration among MND cases, suggesting epigenetic changes may be playing a role in disease development and/or progression.
The aims of this project are to use molecular biology, cell biology and bioinformatic techniques to identify and investigate gene mutations that cause MND, and to investigate epigenetic changes in MND.
Role of the kidney in the development of hypertension
Prof Jacqueline Phillips
Contact: jacqueline.phillips@mq.edu.au
High blood pressure (hypertension) causes heart attack & stroke, which are primary causes of death in people with kidney disease. We believe the autonomic nervous system, which is responsible for controlling involuntary actions like heart rate and breathing, is key in linking hypertension, the heart and the kidney. Research within my team aims to understand how the sympathetic and parasympathetic arms of the autonomic nervous system control of the heart and blood pressure in the diseased state. Much of our work uses a model of renal failure - the Lewis polycystic kidney disease rat (LPK) to understand this relationship. A key aspect of our studies is fully characterisign this model from a genetic and phenotypic perspective. Our research uses multiple approaches including molecular techniques assessing gene expression, immunohistochemistry and electron microscopy to assess structure relative to function, protein levels and distribution patterns, and studies using animal models to measure physiological parameters such as nerve activity, blood pressure and heart rate.
Project 1 (Co-supervised by Dr Mark Molloy):
Quantitative phosphoproteomics of NEK8 signalling in polycystic kidney disease
Polycystic kidney disease is one of the most common monogenetic disorders affecting approximately 1 in 400 people. Nephronophthisis (NPHP) is a recessive form of polycystic kidney disease that ultimately progresses to kidney failure. NPHP is characterised by diffuse interstitial fibrosis, cortimedullary cysts, and altered tubular basement membrane. Our laboratory has recently identified a single nucleotide polymorphism in NEK8 as the causative mutation responsible for a rodent model of NPHP, the Lewis polycystic kidney disease (LPK) rat (1). NPHP proteins are expressed in the base of the primary cilium and are critical for cell division and ciliary function.
The function of the NEK8 kinase in cilia is unclear and this project aims to identify differences in its activity in mutant animals. A quantitative phosphoproteomics study is proposed, examining the global impact of impaired NEK8 activity on the kidney phosphoproteome, aiming to reveal novel proteins regulated by this pathway. A chromatography-based phosphopeptide enrichment method will be coupled with a mass spectrometry (MS) approach (2). The first phase of the project will compare renal tissue from wildtype and mutant animals, and then aim to develop a cultured renal epithelial cell line from the two strains for further analysis.
McCooke, J., Appels, R., Barrero, R., Ding, A., Ozimek-Kulik, J., Bellgard, M., Morahan, G., and Phillips, J. (2012) A novel mutation causing nephronophthisis in the Lewis polycystic kidney rat localises to a conserved RCC1 domain in Nek8. BMC Genomics 13, 1-17
Ali, N. A., and Molloy, M. P. (2011) Quantitative phosphoproteomics of transforming growth factor-beta signalling in colon cancer cells. Proteomics 11, 3390-3401
Project 2 (Co-supervised by Dr Cara Hildreth)
Role of unmyelinated aortic depressor nerve fibres in the development of impaired afferent baroreceptor function in chronic kidney disease
The baroreceptor reflex is a reflex circuit that acts to buffer acute changes in blood pressure by changing heart rate and total peripheral resistance. There are three components to the baroreceptor reflex: 1. Afferent nerves that detect changes in blood pressure and send signals to the brain; 2. a group of neurons within the medulla that become either activated or inhibited; and 3. parasympathetic and sympathetic nerves that alter heart rate and/or total peripheral resistance. In people with chronic kidney disease the baroreceptor reflex does not function effectively. Our research aims to identify why this occurs using a rat model that inherits chronic kidney disease, the Lewis Polycystic Kidney (LPK) rat.
Previously we have identified that in male LPK rats, the afferent nerves cannot sense changes in blood pressure effectively; whereas, in female LPK rats they can. We hypothesise that a difference in the morphological composition of these afferent nerves underlies this. To address this hypothesis we will:
Aim 1: identify if differences in the number of myelinated and unmyelinated nerve fibres in the aortic depressor nerve differs between male and female LPK, and Lewis controls
Aim 2: identify if changes in the ratio of myelinated to unmyelinated nerve fibres correlates with a change in the sensitivity of the aortic depressor nerve to a change in blood pressure
Aim 3: identify if a difference in the ratio of myelinated to unmyelinated nerve fibres translates into a difference in the ability of the baroreceptor reflex to produce changes in heart rate and nerve activity.
Short term and long term regulation of artery stiffness and the impact on end organs
Prof Alberto Avolio and Dr Mark Butlin
Contact: alberto.avolio@mq.edu.au | mark.butlin@mq.edu.au
Arterial stiffness is one of few biological parameters that doubles with age. This stiffening is detrimental both in loading the heart with a higher blood pressure, and in transmitting a pulsatile flow to end organs instead of dampening the pulsatile energy as arteries do in young, healthy individuals. The stiffness of the large arteries is highly predictive of cardiovascular death, and has been associated with end organ damage, such as brain degenerative diseases. However, the mechanisms behind the stiffening of the large arteries and the haemodynamics associated with increased transmission of the pulse to small arteries are not well understood. MRes projects would engage with some of the techniques used in the laboratory in answering the questions raised in the field. These techniques include: non-invasive aortic blood pressure and stiffness measurement in humans; characterisation of changes in arterial stiffness in disease and study of cellular mechanisms of stiffening through use of rodent models; computational fluid dynamics and modelling studies.
Vision Sciences
Prof Stuart Graham
Contact: stuart.graham@mq.edu.au
In Visual Sciences we conduct research projects investigating neurodegeneration in the retina and optic nerve associated with diseases such as glaucoma and optic neuritis, and the relationship of eye diseases to CSF pressure and vascular disorders. Areas of research include animal models including transgenic mice, molecular and biochemical pathways under normal and disease conditions, cellular signalling pathways, electrophysiology (both clinical and experimental), imaging of the eye and vascular research. Current projects involve investigating the role of neurotrophic factors in the retina, neuroprotective molecules for therapeutic application, demyelination and remyelination of the optic nerve, and investigating secondary degeneration in the higher brain centres. Electrophysiology projects involve the Multifocal VEP/ERG in glaucoma and optic neuritis, involving novel techniques (binocular recording and selective pathway mfVEPs). We have developed a rat model for studying eye diseases and VEP/ERG recording. In the imaging field we use high resolution OCT in glaucoma and retinal diseases, and high-resolution functional MRI imaging. Other projects investigate vascular autoregulation in the retinal circulation, and its relationship to glaucoma and disorders in the eye. We have a high-speed retinal camera to study arterial and venous pulsation and regulation. We also study corneal biomechanics and it relationship to eye disease.
Medical Metrology
Dr Martin Turner
Contact: martin.turner@mq.edu.au
Metrology is the science of measurement. Metrologists work to understand the physics and physiology of measurements and also take care of the world-wide measurement system that ensures that measurements are comparable, within well-defined limits in every country. Preliminary studies indicate that many Australians are incorrectly diagnosed due to systematic measurement errors, but these clinical errors are seldom detected and corrected. This research aims to improve understanding and quality control of physiological measurements, and estimate the effects of systematic measurement errors on disease diagnosis and management. Projects available for 2013 include:
Simulation study of the effects of non-linearities in the respiratory system on multifrequency respiratory impedance measurements.
The forced oscillation technique (FOT) is used to measure the complex impedance (resistance and reactance) of the respiratory system at frequencies between approximately 5 and 20 Hz. Small (approximately 2 cm h3O) pressure oscillations are applied to the mouth during normal breathing, and the resulting flow oscillations measured. Seehttp://www.ncbi.nlm.nih.gov/pubmed/14680096. The measurement assumes that the respiratory system is linear. If multiple excitation frequencies are used simultaneously, small non-linearities cause intermodulation distortion. Sum and differences of excitation frequencies are generated and interfere with measurements. In this project we propose to simulate FOT measurements in a respiratory system with small but realistic non-linearities to investigate and quantify this effect.
Non-invasive measurement of pulse wave velocity by electrical impedance measurements.
Arteries tend to stiffen with age, and increasing stiffness is associated with increased risk of cardiovascular disease. Stiffness of arteries is assessed by measuring the speed at which pressure pulses generated by the heart are transmitted. The conventional method for measuring pulse wave velocity involves simultaneous detection of pressure pulses at two points where arteries are close to the body surface, e.g. the carotid artery in the neck and the femoral artery in the groin. This project proposes the design and construction of an electronic device to monitor changes in electrical impedance at two sites on a limb caused by pulse wave propagation. This method may allow pulse wave velocity to be measured over short distances. See http://www.ncbi.nlm.nih.gov/pubmed/22255813.
Biomechanical Group Facilities
Prof Itsu Sen
Contact: itsu.sen@mq.edu.au
The group research is focusing on the haemodynamic studies in cerebrovascular and cardiovascular. Currently, this group contains three post-doctor research fellows, two clinical fellows, and two PhD students. Our projects include in following areas:
- Computational Fluid Dynamics (CFD). The group research interest is in developing image-based patient-specific CFD models development, and application of these models to study human haemodynamics, particularly blood flow to cerebral aneurysms and other cerebrovascular diseases.
- Cerebral vascular haemodynamics research. The biomechanical group is to be equipped by five high performance workstations, in order to perform patient-specific cerebrovascular blood simulation. Research projects are to be aimed at assisting vascular surgeons in the management and treatment of cerebrovascular aneurysms.
- Cardiovascular haemodynamics research. Patient-specific haemodynamic technologies have also been developed to simulate cardiovascular diseases. This aims to provide a virtual surgical environment for cardiovascular surgeons. Moreover, the group is aiming to develop a ventricular assistance device or artificial heart, used to partially or completely replace the function of the failing heart.
- Haemodynamic in-vitro validation tests. Facilities are equipped with mock circulation systems with cardiovascular modelling technology to perform simulations of cerebrovascular and cardiovascular circulation.
- Medical Image segmentation. A series of medical image segmentation software technologies have been developed. This system will enable the provision of intelligent medical-image segmentations for the vascular system, and serve as a training tool for both radiologists and surgeons alike.
- Neurosurgery and cardiovascular training program. The aims of the project are to provide specialised training tools based on advanced robotic technologies for implementation by cardiovascular and neurosurgeons.
Musculoskeletal Biomechanics Research
A/Prof Richard Appleyard, Dr Danè Turner, Dr Janos Tomka, Ms Marian Casey
Contact: richard.appleyard@mq.edu.au | daneh.turner@mq.edu.au | janos.tomka@mq.edu.au | marian.casey@mq.edu.au
Our research goal is to better understand and further the knowledge of biomechanics in surgery, in particular in the field of orthopaedics and trauma. Our team of four highly qualified engineers and surgeons have specialised skills in the areas of mechanical engineering, biomedical engineering, general and orthopaedic surgery, imaging and anatomy. By using experimental and analytical techniques such as mechanical testing, computer modelling (such as finite element modelling), kinematic testing, pressure testing, image analysis, implant analysis and clinical trials we are better able to understand human anatomy and the corresponding surgical implants in terms of implant design and surgical technique. Our laboratory also has the unique advantage of having access to human cadaveric tissue for experimental purposes.
Precision Cancer Therapy Research Group
Professor Helen Rizos, Professor Richard Kefford
Contact: helen.rizos@mq.edu.au | richard.kefford@mq.edu.au
Until recently, patients with metastatic melanoma were treated with single agent chemotherapy drugs, including dacarbazine and temozolamide, that produce response rates of less than 10%, with no improvement in overall survival. New drugs targeting the mitogen activated protein kinase (MAPK) pathway have now shown significant activity. The pharmacological inhibition of the mitogen activated protein kinases BRAF and MEK produces response rates of approximately 76% and prolongs the overall survival of patients with BRAF-mutant metastatic melanoma. Despite the dramatic clinical activity of combining BRAF and MEK inhibitors, only 41% of patients on this combination therapy are progression-free at 1 year.
Project 1: Modulators of melanoma cell sensitivity to targeted therapies
Supervisors: Professor Helen Rizos and Richard Kefford
Genetic alterations identified in pre-therapy BRAFV600 mutant tumours can modulate initial responses to BRAF inhibitors. In this project, we will explore the potential role of recurrent pre-existing gene mutations in predicting clinical responses. A series of gene variants will be introduced into melanoma cell lines, and the effect of these genes on the proliferation, migration, signalling and survival of cells exposed to selective BRAF inhibitors will be explored.
Project 2: Regulation of melanoma antigen expression by targeted therapies
Supervisors: Professor Helen Rizos and Richard Kefford
One potential approach to improve the duration of response involves combining BRAF inhibitors with immunotherapies. This strategy is supported by recent evidence that treatment of melanoma cells with BRAF targeted therapies can increase the expression of melanoma antigens and immune recognition of tumour cells. The level of antigen induction by BRAF inhibitors is highly variable, however, and the mechanism of antigen induction is not understood.
In this study, the expression profile of melanoma differentiation antigens in response to BRAF inhibition will be analysed in a panel of melanoma tumour cells. These melanoma cells have been derived from patients prior to BRAF inhibitor treatment and on progression. The role of the microphtalmia-associated transcription factor in regulating antigen expression will also be investigated. Understanding the effects of BRAF on antigen expression can help identify patients who are most likely to benefit from combination BRAF- and immuno-targeted therapies.
Project 3: Melanoma resistance to BRAF and MEK inhibition
Supervisors: Professor Helen Rizos and Dr Mark Molloy
In this project we will explore new drivers responsible for melanoma resistance to combination BRAF and/or MEK inhibition. Most significantly this work will examine paired melanoma tumour cells collected prior to (PRE) and following relapse on this MAPK inhibitor treatment (PROG). This work will integrate proteomic analyses with the detailed examination of cellular responses and signalling pathway activity in order to develop a detailed view of the changes that occur in melanoma on progression. This information will accelerate the identification of new therapeutic targets and the development of rational combination therapies.
Content owner: Faculty of Medicine, Health and Human Sciences Last updated: 12 Mar 2024 10:57am