PhD projects at the Australian School of Advanced Medicine

Join Macquarie’s world-leading researchers and learn from the best. The Australian School of Advanced Medicine (ASAM) is the first medical school in Australia to offer credentialled sub-specialty, post-fellowship training. Its location adjacent to the Macquarie University Hospital, Australia’s only private hospital on a university campus, affords its researchers and teachers a unique level of support.

Macquarie’s medical precinct has attracted a visionary group of researchers, both basic and clinical, who translate their science into the hospital’s clinical setting.

Students with an excellent record of undergraduate achievement are encouraged to apply to undertake a Master of Research or PhD in a number of exciting research fields at ASAM.

Please visit our website medicine.mq.edu.au for further information.

Research Projects at ASAM

Cardiovascular, Cardiothoracic and Biomechanics Molecular Cancer Professor Tristan Yan, Professor Mark Baker, Professor of Proteomics Professor of Cardiovascular and Thoracic Surgery Professor Helen Rizos, Professor, Professor Alberto Avolio, Precision Cancer Therapy Professor of Biomechanical Engineering Professor Richard Kefford, Professor, Cancer Medicine Professor Itsu Sen (Yi Qian), Professor in Biomechanics

A/Prof Richard Appleyard, Head of Surgical Skills Neuroscience Training and Surgical Biomechanics Professor Mark Connor, Professor of Pharmacology

Professor Jacqueline Phillips, Genetics and Infection Professor of Neuroscience Professor Simon Foote, Dean A/Prof Ann K Goodchild, Associate Professor, Systems A/Professor Brendan McMorran, and Signalling Neuroscience Group Associate Professor in Host Response to Malaria Dr Simon McMullan, Senior Lecturer Dr Gaetan Burgio, Senior Research Fellow, Genetics

A/Prof Anand Deva, Associate Professor Cosmetic Neurosurgery and Plastic Surgery Professor Marcus Stoodley, Professor of Neurosurgery A/Prof Karen Vickery, MQVC Innovation Fellow and Scientific Director, Surgical Infection Research Group Ophthalmology and Vision Science Professor Stuart Graham, Professor of Ophthalmology Medical Education and Vision Science Professor Kirsty Forrest, Director of Medical Education

Professor Wendy Rogers, Professor of Clinical Ethics

Professor John Cartmill, Professor of Surgery

Motor Neurone Disease Professor Roger Chung, Professor of Neurobiology and Neurochemistry

Professor Gilles Guillemin, Professor of Neurosciences

A/Prof Julie Atkin, Associate Professor of Neurochemistry and Cell Biology

A/Prof Ian Blair, Associate Professor (CORE) The Australian School of Advanced Medicine 1 Cardiovascular, Cardiothoracic PhD Research Projects and Biomechanics 1. Computer Modelling of Neuromodulation Using computational modelling tools, we study Associate Professor neuromodulation to be able to better understand Richard Appleyard the mechanisms of neural stimulation and how the stimulation is affecting nearby tissue. Understanding Head of Clinical Skills Training and neuromodulation will help reduce chronic pain and Surgical Biomechanics improve quality of life for those affected by it. The Australian School of Advanced Medicine, Macquarie University Finite element modelling is a numerical approach, which can be used to solve bioelectric field problems BE (Hons), PhD (University of Sydney) with complex geometric features and tissue properties. The project uses ABAQUS as the finite element Contact Details package to simulate how electric fields are generated with human tissue in order to better understand the T: +61 (0)2 9812 3535 interaction of electric pulses with biological tissues in E: [email protected] the brain and spine.

Professional Overview 2. Development of a Bone Remodelling Algorithm with Application to Knee Joint Arthroplasty A/Prof Appleyard is a Mechanical Engineer and has specialised in Biomedical Engineering for over 20 years. It is well accepted that bone adapts to mechanical As Director of the Surgical Skills Laboratory, he has stimuli by remodelling and hence redistributing research interests in surgical biomechanics, implant its’ density. Bone density distribution surrounding design and surgical planning. A/Prof Appleyard knee replacements (in both the femur and tibia) is has worked with number of major orthopaedic of interest to clinicians as it is a reliable predictor of companies and prominent surgeons on a wide variety clinical success after joint replacement surgery. Based research projects. This has lead to six patents and on Wolff’s law, the bone adapts to load decreases as 49 journal papers. a result of stress and strain shielding; hence resulting in bone resorption. This can lead to implant loosening and failure of the implant. Using computational Areas of Research Interest modelling to predict the long-term outcome of knee A/Prof Appleyard’s interest is in the biomechanics replacements is of great benefit to clinicians and of orthopaedics, and, more generally, in surgery. implant developers alike. The following are his main research areas: ƒƒ Mechanisms of Neuromodulation in human tissue – This study involves creating a three-dimensional using finite element modelling techniques to better patient-specific knee joint model using imaging data understand the behaviour of electrical stimulation and running finite element (FE) simulations using on human tissue. published load profiles. This allows us to predict the bone remodelling behaviour in the distal femur and ƒƒ Behaviour of bone following prosthesis implantation proximal tibia following a knee replacement. ƒƒ The effect of shoulder prosthesis design on shoulder kinematics- reverse vs anatomical designs The aim of this project is to further develop the existing bone remodelling algorithm such that it ƒƒ Validity of Dual Energy CT in applies to knee joints following arthroplasty (both Orthopaedic Applications uni and primary). The algorithm will be validated Macquarie University has a well equipped using existing clinical DEXA (dual energy xray biomechanics laboratory with an INSTRON biaxial absorptiometry) images and will be used to predict testing machine, 3D motion tracking system, the density distribution in the bone following cameras, transducers and data collection systems. knee arthroplasty. The biomechanics laboratory is one of a few in the world that can use human tissue for basic research. The Further information about the project can be group works closely with the Mechanical Engineering obtained from Dr Danè Turner (daneh.turner@ department on a range of research projects. mq.edu.au) or A/Prof Richard Appleyard ([email protected])

2 The Australian School of Advanced Medicine Publications Cardiovascular and 1. Askari E, Flores P, Dabirrahmani D, Appleyard Thoracic Surgery R. Study of the friction-induced vibration and contact mechanics of artificial hip joint. Tribology International 70, 1-10 (2014) Professor Tristan Yan

2. Askari E, Flores P, Dabirrahmani D, Appleyard R. Professor of Cardiovascular and Thoracic Surgery Nonlinear vibration and dynamics of ceramic on The Australian School of Advanced Medicine, ceramic artificial hip joints: a spatial multibody Macquarie University modelling. Nonlinear Dynamics 1-13 January (2014) BSc, MBBS (University of New South Wales), 3. Dabirrahmani D, Bokor D, Appleyard R. A novel MS (University of Sydney), MD (University of New South in-vitro testing method for reverse shoulder Wales), PhD (University of New South Wales). FRACS implants. Annals of Biomedical Engineering (2013)

4. Dabirrahmani D, Hogg M, Walker P, Biggs D, Gillies Contact Details RM. Isometric Graft Placement of a Synthetic T: +61 (0)2 9850 2779 Ligament. Computers in Biology and Medicine E: [email protected] (2013)

5. Schneider T, Dabirrahmani D, Gillies RM, Appleyard Professional Overview R. Biomechanical characteristics of the first Professor Tristan Yan is a Consultant Cardiothoracic metatarsophalangeal (MTP) joint following total Surgeon, Professor of Cardiovascular and Thoracic joint arthroplasty. Foot and Ankle International. Surgery at the Macquarie University Hospital and March (2013) Associate Clinical Professor at the University of Sydney, Department of Cardiothoracic Surgery, Royal Prince 6. Lustig, SL., Oussedik, S., Tam, S., Dabirrahmani, Alfred Hospital in Sydney, Australia. He was trained at D., Appleyard, R., Parker, DA.A comparison of the Royal Prince Alfred Hospital and St Vincent’s Hospital temperature rise generated in bone by the use of in Sydney and then obtained a Cardiothoracic Surgery standard oscillating saw blade and the “Precision” Fellowship from the Royal Australasian College of saw blade. Journal of Medical Devices (2012) Surgeons. Following advanced specialty fellowships in the United States, England, Scotland and Germany, he is fully trained in major thoracic aortic surgery, minimally invasive cardiac surgery, and minimally invasive thoracic surgery. He has authored or co-authored more than 180 articles and textbook chapters, with an h-index of 32 and approximately 4000 citations. Professor Yan’s research involvement and leadership extends to international projects. He is the Chairman of CORE Group International, and responsible for establishing and organizing the world’s largest multi-institutional Aortic ARCH Registry, consisting of more than 12,000 patients. He is also the founder and the Editor-in-Chief of the Annals of Cardiothoracic Surgery.

Areas of Interest Professor Tristan Yan is dedicated to surgical innovations. He applies the latest pioneering techniques to minimize surgical trauma and access sites and thus achieves a more rapid and comfortable recovery for his patients. Professor Yan has surgical expertise and specialised research interests in minimally invasive cardiac surgery, minimally invasive thoracic surgery and major thoracic aortic surgery. He also has extensive research experience, with authorship or co-authorship of more than 180 articles and textbook chapters. The high-standard and impact of this research is reflected by his h-index of 32, with approximately 4000 citations to date.

The Australian School of Advanced Medicine 3 PhD Research Projects Minimally Invasive Cardiac Surgery

Aortic Arch Surgery Minimally invasive cardiothoracic surgery has increasingly gained acceptance in the surgical realm, with the Aortic arch surgery remains one of the most challenging aim of achieving equivalent or superior outcomes operations conducted by cardiothoracic surgeons. compared to conventional open sternotomy approaches. Evolving surgical techniques within the past decade Minimally invasive heart surgery can be achieved has renewed interest in understanding neuroprotection utilizing videoscopic or robotic assistance to allow better strategies and endovascular devices and placements. visualization and precise tissue handling. Encouraging This project aims to allow the scholar to investigate, institutional reports of surgical efficacy, reduced trauma, both through the literature, international databases, and shorter hospitalization and improved cosmesis have laboratory models, the optimal surgical techniques to increased the use of the minimally invasive approach improve patient outcomes following aortic arch surgery. in recent years. However, the current evidence is limited by small, underpowered studies and the lack of Video Assisted Thoracoscopic Surgery standardized definitions and reporting criteria. There is Lung cancer remains the most common cause of cancer- also a lack of robust clinical data on newer approaches related deaths today. With improved imaging modalities including sutureless implantation technique for aortic and increased screening programs, more patients are valve replacement, and videoscopic surgical ablation for diagnosed with early-stage non-small cell lung cancer atrial fibrillation. This project aims to provide the highest (NSCLC) than ever before. For eligible patients with early- quality evidence available to evaluate minimally invasive stage peripheral lesions, intervention may be performed cardiac surgery techniques and establish standardized through lobectomy or sublobar resection via video- definitions, reporting criteria and clinical consensus. assisted thoracoscopic surgery (VATS).

VATS lobectomy procedures for NSCLC was first described in the early 1990s. With advancements in thoracoscopic instrumentation and technical development, the VATS approach has revolutionized modern thoracic surgical practice and significantly improved patient outcomes. This study aims to further define the role of VATS lobectomy for NSCLC and to identify the optimal surgical treatment strategy for patients with early-stage peripheral NSCLC.

Minimally invasive aortic valve replacement via a ministernotomy approach.

Illustration credit: Beth Croce

Illustration credit: Beth Croce

4 The Australian School of Advanced Medicine Professor Alberto Avolio 2. Characterisation of pressure-dependent indices of arterial stiffness. Because of the structure of the Professor of Biomedical Engineering arterial wall, and the essential non-linear elastic The Australian School of Advanced Medicine, properties, the stiffness of the wall material is a Macquarie University function of the amount of stretch. At low strains, the load is essentially taken up by the elastin fibres, BE (UNSW), PhD (University of New South Wales) while at high strains it is taken up by the stiffer collagen fibres. This causes vascular stiffness, and Contact Details therefore the pulse wave velocity, to be a function T: +61 (0)2 9850 2747 of pressure. This phenomenon is used to obtain E: [email protected] characteristic curves in the rodent aorta. These experiments are used to compare indices of isobaric stiffness indices in rodent models to investigate Professional Overview factors that alter intrinsic vascular stiffness. To date Professor Alberto Avolio has acquired international these include the effects of genetically determined recognition in the field of cardiovascular hypertension, ionizing radiation and inflammation, haemodynamics and also teaches in the fields of induced calcification, effect of early treatment with cardiovascular dynamics, and in engineering in angiotensin converting enzyme inhibition, genetic medicine and biology. Current areas of research strains of polycystic kidney disease, neurogenic interest include pulsatile relationships between modulation and effects of heart rate using blood pressure and flow, characterization of pressure- external pacing. dependent indices of vascular function, cellular 3. Cellular and molecular mechanism of arterial and molecular mechanisms of arterial stiffness, stiffness. Recent advances in molecular biology of pulse wave analysis and non-invasive estimation nitric oxide (NO) are elucidating novel pathways of central aortic pressure, retinal vascular function involving effects of NO in post-translational and non-invasive assessment of cerebral dynamics, modification of proteins. We are investigating how cerebral aneurysms, cardiovascular modelling and changes in the bioavailability of NO in endothelial biological signal processing. He has received over cells causes alterations in molecules that can $7 million in collaborative research grant support affect the integrity of the extracellular matrix, and is on the assessment panel of national and and so modulate vascular stiffness. Investigations international granting bodies. He is on the editorial on the interaction between NO and tissue board of Hypertension, Journal of Hypertension, Artery tranglutaminase (TG2) are the subject of two recent Research, Current Hypertension Reviews, Advanced major collaborative research grants (NIHGrant Biomedical Engineering, and Pulse and is a reviewer for 1R01HL105296-01; ARC- DP110101134, see below). over 40 international scientific journals. He has over Investigations will be conducted in-vivo in rat 180 publications including a book, book chapters and models and in genetically modified mouse models peer reviewed articles. with knock out genes for endothelial nitric oxide synthase (eNOS) and TG2. In-vitro experiments Areas of Research Interest and will be conducted in organ baths using pressure PhD Research Projects and wire myographs. These experiments will be 1. Pulsatile relationships between arterial blood extended to atherosclerosis mouse models to pressure and flow. Ejection of blood from the heart investigate the interaction of atherogenesis and is by necessity pulsatile. This lends itself to the arterial stiffness. Further investigations will include description blood pressure and flow in arteries in effects of cyclic mechanical stretch on function of terms of oscillatory phenomena, including concepts endothelial cells. of wave propagation in uniform and non-uniform 4. Pulse wave analysis and non-invasive estimation transmission lines, and vascular impedance. These of central aortic pressure. Although there are concepts are used in arterial models to simulate recognised limitations to the conventional brachial changes that occur in large arteries due to ageing cuff sphygmomanometer, the basic methodology and other factors affecting mechanical properties has not changed since Riva Rocci (1896) and of the arterial wall. Arterial models have recently Korotkoff (1905) proposed the technique of been extended to predict the response of changes quantifying the blood pressure in arteries, and so in wave propagation characteristics to gravitational cardiovascular risk. However, since the pressure effects due to posture. Models are currently being is measured in the arm, the differences in systolic used to assess the effect of vascular properties on pressure due to wave propagation phenomena optimization of cardiac resynchronisation therapy. can be substantial, and so changes in peripheral pulse pressure are not accurate estimates of pulse pressure changes at the heart. Techniques have been developed that combine the conventional

The Australian School of Advanced Medicine 5 cuff sphygmomanoter with a peripheral pulse Professor Itsu Sen (Yi Qian) waveform to determine the pressure at the aorta non-invasively. This technique is used to compare Professor in Biomechanics changes in peripheral and central pressure with The Australian School of Advanced Medicine, interventions, such as different types of anti- Macquarie University hypertensive agents. Central pressure is also BS, ME, PhD (Tokyo) combined with transcranial Doppler flow measured in cerebral arties to investigate mechanisms of cerebral haemodynamcs. Contact Details

5. Retinal vascular function and non-invasive T: +61 (0)2 9812 3551 assessment of cerebral dynamics. The magnitude E: [email protected] or [email protected] of pulsations of intraocular vessels is determined by the relationship between intraocular pressure and Professional Overview intravascular pressure. The pressure in the larger Prof Sen (Qian) has 30 years continuous experience venous vessels is also related to the pressure of the in computational fluid dynamics (CFD) research fluid in the cerebral cavities. The pulsations of retinal and application in bioengineering. He has worked vessels are detected by a device using laser Doppler in the field of circulatory assistance and was techniques. By altering the magnitude of the instrumental in the development of the artificial pulsations by means of pharmacologically induced heart program (Left Ventricular Assist Device, LVAD), changes in intraocular pressure, statistical models in Japan and Australia. He is primarily responsible can be constructed to estimate the magnitude for the development of the CFD technique, which is of intracranial pressure. These techniques are employed in the design of the blood pump. Prof Sen being combined with MRI scans for quantification used computational haemodynamic techniques to of cerebral fluid flow using phase contrast improve the problems related to haemolysis of the methodology to assess conditions of altered VentrAssit artificial heart, which has been implanted pressure and volume of intracranial fluid. in over 450 patients around world. Prof Sen has also 6. Haemodynamics and cerebrovascular function. In developed novel methodologies based on the CFD collaboration with other researchers, haemodynamc techniques for improvement of the cardiovascular and investigations are applied to vascular malformations cerebrovascular surgical method, and estimation the in the brain (cerebral aneurysms) using risk of cerebral aneurysms. This system has been used computational fluid dynamics and finite element for over 300 patients, and validated by the results from analysis is used to simulate idealized vascular in-vitro and in-vivo testing. He has more than 10 years structures to study the effects of morphology and work experience in global industry and has worked for blood flow on aneurysm formation and rupture. eight universities in three different countries. Student projects are co-supervised with the aim to Prof Sen (Qian) has global collaborative links with improve management and treatment of unruptured biomedical engineers, neurosurgeons, cardiovascular aneurysms when detected during medical imaging surgeons and neuroradiologists in Australia, USA, Japan procedures. Research projects also combine and China. He has published over 50 peer-reviewed haemodynamic and mechanical analysis with articles and is a referee for many international journals molecular biomarkers. including; Stroke, AJNR, ASME, and International Journal 7. Activation of baroreceptors for treatment of resistant of Artificial Organs and other leading journals. Prof Sen hypertension. Treatment of high blood pressure has attracted over $5M in funding. is not always successful using pharmacological agents. Recent studies have shown that what Areas of Research Interest and was once thought to be a short-term controller PhD Research Projects of blood pressure (the baroreceptor system), can 1. Computational Fluid dynamics (CFD). The CFD also be used for long term control. This is done by researches in this group focus on blood flow electrical stimulate of nerves on the carotid artery in simulation. The projects include haemodynamic the neck. Investigations are underway to elucidate flow basic researches and application in vascular mechanisms responsible for the long term control flow simulation; see following issue No. 2 and of blood pressure using this technique and to No.3. In basic research, we are interesting in blood uncover additional cardiovascular benefits beyond flow multi-phase reaction, vascular (solid) and the reduction of blood pressure. This is done in blood (liquid) interface, blood flow thrombus collaboration with the US company that produces formation, non-Newtonian flow, turbulent flow, the stimulation technology (CVRx) as part of an ARC and haemolysis. linkage grant.

6 The Australian School of Advanced Medicine 2. Cerebral vascular haemodynamics research. The Genetics and Infection biomechanical group is soon to have five high performance workstations in order to perform patient-specific cerebrovascular blood simulation. Professor Simon Foote Research projects are to be aimed at assisting Dean of the Australian School of Advanced Medicine vascular surgeons in the management, treatment, Macquarie University and risk estimation of cerebrovascular aneurysms. MBBS, PhD (University of Melbourne), 3. Cardiovascular haemodynamics research: Patient- DSc (University of Tasmania) FFS (RCPA), FTSE specific haemodynamic technologies have also been developed to simulate cardiovascular diseases. The aim is to provide a virtual surgical environment Contact Details for cardiovascular surgeons. The group is also T: +61 (0)2 9812 3517 aiming to develop a ventricular assistance device E: [email protected] or artificial heart, which will be used to partially or completely replace the function of the failing heart. Professional Overview 4. Haemodynamic in-vitro validation tests: Professor Foote received his MBBS and PhD from The research groups’ facilities are equipped with the University of Melbourne and his DSc from the mock circulation systems with cardiovascular University of Tasmania. He did his postdoctoral training modelling technology to perform simulations of at the Whitehead Institute at MIT, Massachusetts and cerebrovascular and cardiovascular circulation. has worked as Division Head at the Walter and Eliza 5. Medical image segmentation: A series of medical Hall Institute, Melbourne and Director at the Menzies image segmentation software technologies has Research Institute Tasmania. been developed and this system will enable the provision of intelligent medical-image Areas of Research Interest segmentations for the vascular system, and Prof Foote is interested in the genetic control of serve as a training tool for both radiologists and susceptibility to disease, with particular focus on surgeons alike. infectious disease. His laboratory has identified loci 6. Neurosurgery and cardiovascular training program: governing the response to leishmaniasis and malaria. The aims of the project are to provide specialised However the major focus of the laboratory is on trying training tools based on advanced robotic to identify new drugs to combat malaria. By using technologies for implementation by cardiovascular the example of natural mutations that affect the red and neurosurgeons. cell and making it difficult for the parasite to grow, his laboratory has found genes, that when mutated, 7. Heart assistant device (artificial heart) and medical prevent growth of malarial parasites. These genetic device R&D: The project aims to introduce changes point the way to the creation of a new computational hemodynamic technology to type of treatment that will be steadfast against the improve the problem in blood pump suspension development of drug resistance. This genetic research technology. The group is also cooperating with is undertaken by identifying candidate target genes multi-international medical device companies using mouse genetics and genomics. Mutant mice on research and development of new medical harbouring ENU-induced mutations are screened for devices, including artificial heart, cardiovascular resistance to malaria. In those mice that are resistant, and cerebrovascular stents, artery graft R&D, and the mutation is identified by exome sequencing and medical image software development. the gene involved is studied to determine its role in 8. Intracranial aneurysm molecular and biomarker: malaria susceptibility. His laboratory is also interested This project is to investigate pathophysiology of in the genetic susceptibility to other diseases of intracranial aneurysms, an abnormal bulging of humans. He is currently working on investigating the cerebral arteries. It aims to specifically investigate reasons that renal disease is so common in Aboriginal various cellular and molecular basis, that make communities and in the genetic changes that underpin cerebral arteries prone to mechanical weakness. the familial nature of some of the common cancers. The weakness leads to initiation and progression of aneurysms and using animal models, the group is PhD Research Projects evaluating the association between cerebrovascular Prof Foote’s research projects are listed with A/Prof remodelling, hemodynamic factors and biomarkers. McMorran and Dr Gaetan Burgio’s projects as they co-supervise PhD students in their research team.

The Australian School of Advanced Medicine 7 Associate Professor PhD Research Projects Brendan McMorran Prof Foote, A/Prof McMorran and Dr Burgio supervise all research projects listed below. Associate Professor in Host Response to Malaria Macquarie University 1. Biological analysis of malaria resistant mice. BSc (Hons), PhD (University of Otago, New Zealand) ENU has been used to induce mutations into the genome of male mice. These mice have been mated Contact Details to normal females of the same strain. This strain is normally susceptible to malaria, i.e. all mice normally T: +61 (0)2 9850 2703 die from the disease. The progeny of the ENU-treated E: [email protected] by wild-type cross (G1 generation) are infected with malaria, or analysed for abnormal red cells. Mice Professional Overview that are either resistant to malaria or have abnormal red cells are again mated to wild-type mice and Areas of Research Interest their progeny challenged or analysed for abnormal red cells. If there is transmission of the trait in this A/Prof McMorran has a general interest in confirmation mating, then the animals are bred, understanding the genetic and molecular mechanisms two separate animals undergo exome sequencing involved in host-pathogen interactions. He has and the contributive mutation identified through previously investigated lung disease and the associated segregation analysis. bacterial infections that occur in the genetic condition, cystic fibrosis. His current focus is on understanding Specific mutants: host mechanisms involved in protection from malaria a) Cytoskeletal mutants: Ankyrin, Spectrins alpha and infection, conducted in collaboration with Professor beta and Proteins 4.1 and 4.2. Simon Foote. Specific projects include understanding b) Various red blood cell enzymes how platelets protect from malaria parasite infections of the blood stream, identifying novel genes involved c) Various red cell ion channels in host protection against infection, and development of novel host-directed therapeutic approaches to treat Analysis of these mutants involves a detailed study malaria infection. All these studies utilise murine and of the abnormal red cell, the kinetics and biology cell culture models, and employ various genetic, cell of infection with murine malarial parasites and, in biology and protein chemistry methods. some cases the use of known inhibitors to prevent the growth of malaria in P. falciparum cultures. A/Prof McMorran also conducts studies investigating Each student will be responsible for studying genetics underlying kidney disease in Tiwi Islanders several related mutants. in collaboration with researchers at the Menzies Research Institute Tasmania, Hobart, and the 2. Biological analysis of the role of Duffy in University of Queensland. malarial resistance. We have identified the platelet as a major element in the host response to malarial infection. The platelet binds to infected red cells, releases platelet factor 4 which binds the Duffy antigen, is internalized and kills the parasite. There are still many questions around the mechanisms involved and the role that the Duffy antigen plays in Africa that a student could join in.

All of these projects involve parasitology and genetics, often using mouse models and cultured P. falciparum.

8 The Australian School of Advanced Medicine Dr Gaetan Burgio Associate Professor Anand Deva Senior Research Fellow (Genetics) Associate Professor Cosmetic and Plastic Surgery The Australian School of Advanced Medicine, The Australian School of Advanced Medicine, Macquarie University Macquarie University

MBBS, MSci, MD (University of Paris), PhD (Pasteur BSc(Med), MBBS(Hons) (University of Sydney), MS, FRACS Institute and National Museum of Natural History, Paris) Contact Details Contact Details T: +61 (0)2 9812 3890 T: +61 (0)2 9850 2701 E: [email protected] E: [email protected] W: mcps.com.au

Professional Overview Professional Overview Dr Burgio’s research focuses on the genetics of host A/Professor Anand Deva is a Plastic & Reconstructive resistance to malaria and the genetic architecture Surgeon and has pursued both clinical and research of quantitative traits. He has previously identified interests. He has numerous academic awards and has genetic loci responsible for the genetic variation been recognised for his research with six research and the evolution of various traits (biochemical, awards. A/ Prof Deva currently serves on the Board of haematological, embryonic lethality or skull traits) to Surgical Research for the Royal Australasian College determine the genetic basis for phenotypic variation. of Surgeons. He has 48 publications and has been His current focus is to identify new genes and novel awarded just under $1.7million in competitive grant biological mechanisms responsible for host resistance funding and industry funding in recognition of his to malaria infection. This is done using a quantitative research expertise. trait loci approach or a large scale N-Ethyl-N- Nitrosourea to explain why some children succumb to a malarial infection whereas other survive in endemic Research Interest areas. The identification of these genes will uncover Associate Professor Deva has made significant novel antimalarial drug targets and novel mechanisms research contributions in the field of implant infection underlying the host response to malaria infection. and wound healing. His work on breast implant safety has led to major improvements in outcomes PhD Research Projects around the world. He is co-director of the Surgical Infection Research Group and is co-supervisor to Dr Burgio’s research projects are listed with Prof Foote full time postgraduate research students. Current and A/Prof McMorran’s projects as they co-supervise laboratory work is centred around the science and the PhD students in their research team. clinical significance of bacterial biofilm infection using both in vitro and in vivo models. The role of bacteria in the pathogenesis of breast implant failure and technologies to prevent bacterial attachment to breast implants and other medical prostheses are being investigated. Clinical research interests include the treatment of craniomaxillofacial trauma, use of fat grafting and evaluation of outcomes in cosmetic surgery.

PhD Research Project A/Prof Deva works closely with A/Prof Vickery and their research projects are described after A/Prof Vickery’s profile.

The Australian School of Advanced Medicine 9 Associate Professor Karen Vickery MQVC Innovation Fellow and Scientific Director, Surgical Infection Research Group The Australian School of Advanced Medicine

BVSc (Hons), MVSc, PhD. (University of Sydney)

Contact Details T: +61 (0)2 9850 2706 E: [email protected]

Professional Overview A/ Prof Vickery has been awarded almost a one million Figure 1: Bacteria biofilm infection around an implanted medical device. dollars in competitive research funding since 2013 for her work on bacterial biofilms. She has published one book and has over 50 publications, the majority related to infection control.

Areas of Research Interest A/Prof Vickery studies laboratory-grown biofilms, in vivo animal models and clinical samples to investigate the effect of biofilm on instrument decontamination, infection control and biofilm in chronic wounds. A biofilm consists of bacteria attached to a surface and to each other surrounded by exopolysaccharide (EPS) that they secreted. The EPS forms up to 50-90% of the biofilm and confers resistance to environmental Figure 2: Lymphocytes attached to implanted medical device. desiccation and standard decontamination and disinfection. Biofilm bacteria can survive up to 1500, Photographer: Dr Anita Jacombs (typically 100-250), times the amount of an antibiotic needed to kill the same bacteria growing in liquid 2. Evaluation of the host immune response to biofilm culture. Bacterial biofilms have been implicated in infection on medical implants (Figure 2) instrument sterilisation failure, medical implant failure The host immune response to biofilm infection on and in chronic wounds. A/Prof Vickery has undertaken medical implants will be assessed in human patients using: a prospective study of augmentation mammaplasty a) advanced Proximity Extension Assay (PEA) to correlated the presence of Staphylococcus epidermidis characterise the inflammatory biomarker response biofilm with contracture and is currently using a to infection. This will aid in early diagnosis of pig model to investigate methods of treatment and implant infection; and prevention of contracture. b) characterisation of the lymphocytic response. PhD Research Projects 3. Preventing biofilm infection of medical implants by 1. Early diagnosis of medical implant infection modification of implant surfaces Biofilm infection of most implants result in chronic The efficacy of Implant surfaces will be modified using low-grade inflammation. Clinically patients therefore a) nanotechnology, b) antibiofilm surface coatings, and present with vague signs such as aseptic loosening c) anti-quorum sensing molecules, to prevent bacterial of orthopaedic implants. Samples sent to pathology adhesion. Testing will in vitro and in vivo. are often culture negative due to the low bacterial metabolic rate in biofilms. Using advanced proteomics 4. Improved killing of biofilm contamination on surfaces we will identify biofilm specific proteins associated We have shown that biofilms on dry hospital with infection in human serum. ELISA assays will then surfaces protect antibiotic resistant organisms and be developed to aid diagnosis. we hypothesise that these biofilms act as a source of infection for patients. We aim to improve biofilm removal and killing by developing new chemistries targeting components of the biofilm structure.

10 The Australian School of Advanced Medicine Medical Education PhD Research Projects 1. Accelerated learning of clinical reasoning and Professor Kirsty Forrest diagnostic skills Director, Medical Education While it has been evidenced that skill acquisition in The Australian School of Advanced Medicine, medicine can be accelerated, there is little research Macquarie University regarding whether clinical reasoning and diagnostic skills can also be accelerated. The aim of this project MBChB, BSc(Hons) (University of Edinburgh), FRCA UK, is to investigate clinical knowledge acquisition and FAcadMEd UK, MMEd UK synthesis and the formulation of differential diagnosis to identify whether clinical reasoning and diagnostic Contact Details skills can be accelerated in the same way in which technical skills are. T: +61 (0)2 9850 3515 E: [email protected] 2. Teaching and feedback in the operating theatre in continuing surgical education Professional Overview The pathway way to proficiency in all skills related Professor Forrest is an anaesthetist by clinical training to a career as a surgeon primarily relies on an and an academic educator. She has been involved apprenticeship model. After a surgeon has completed in educational research for over 10 years and has defined training programs, their continuing surgical an extensive publication list including medical education experience can vary significantly, depending education textbooks. on their mentor(s), their unit, and their specialty. The aim of this project is to investigate the ways in which teaching and feedback are currently managed Areas of Research Interest in continuing surgical education in Australia and to Prof Forrest aims to provide evidence-based identify best practice to improve this aspect of the education, with the backing of an experienced surgical training pathway. and excellent Faculty and using innovative and cutting edge technologies and methodologies. 3. Inter-specialist education Her academic expertise in medical education includes Interdisciplinary clinical education has been gaining leadership, mentoring, supervision, simulation, significant ground internationally over the past few and communication. decades, particularly in undergraduate education. More recently, there has also been interest in pursuing inter-specialist education in medicine for those already working towards a specific specialty or career pathway. The aim of this project is to investigate how inter- specialty training interacts with more siloed medical curricula and to identify improvements in this field of education.

For more information, please contact the Medical Education Office: [email protected]

The Australian School of Advanced Medicine 11 Professor John Cartmill Medical Ethics Professor: Surgery Head of Discipline: Surgery Professor Wendy Rogers The Australian School of Advanced Medicine, Professor of Clinical Ethics Macquarie University The Australian School of Advanced Medicine and MBBS, BSc(Med), MM, FRACS (University of Sydney) Department of Philosophy, Macquarie University BM.BS, BAHons, PhD (Flinders University), DipObst RACOG, Contact Details MRCGP, FRACGP T: +61 (0)2 9850 3880 E: [email protected] Contact Details T: +61 (0)2 9850 8858 Professional Overview E: [email protected] John Cartmill regards surgery as one of the finest of cooperative human achievements. Combining joint Professional Overview action, vision, invention, improvisation and learning in Professor Rogers initially trained as a general practitioner a contained arena of heightened vigilance and care. before undertaking philosophy honours and a PhD in The operating room is the ideal theatre, indeed the medical ethics at Flinders University. She was then awarded ideal laboratory, to study fundamentals of human an NHMRC post-doctoral fellowship at the University of cooperation and meaning making as they are brought Edinburgh. She has spent five years at Flinders University, to bear in a consequential environment that combines served on a number of national committees in her interest modern technology with tradition and evolved area, and is a current member of the Australian Health Ethics systems with engineered systems of organisation. Committee. Prof Rogers has raised over $2 million in peer- Each of Macquarie University Hospitals 16 procedure reviewed funding and has published over 100 articles in rooms (and its’ simulation theatre) is equipped as a peer-reviewed journals and edited collections. human factors laboratory with cameras and sound recording capability. PhD candidates from Psychology, Areas of Research Interest Engineering, Linguistics, Management and others should consider jointly supervised projects at the Professor Rogers’ research spans a number of areas in Australian School of Advanced Medicine. biomedical ethics and uses theoretical and empirical methods. She has a long-standing interest in research ethics including issues such as the generation of evidence and the ethics of evidence-based medicine, research with vulnerable populations, justice in research, and conflicts of interest. She is leading a multi-disciplinary team at Macquarie in the INCISIVE project (INterdisciplinary Collaboration Investigating Surgical Innovation, Values and Ethics), which is investigating ethical and regulatory issues related to surgical innovation. From mid 2014, Prof Rogers will be working on a four-year project on defining disease and addressing the ethical challenge of overdiagnosis.

The Research Project Applications are invited to join Wendy Rogers on her Future Fellowship project, funding which will enable her to study defining disease and preventing overdiagnosis. The broad aim of the project is to develop an account of disease. Answers to this question will help define when a presentation is a disease warranting intervention, and when it is simply a risk factor or mild condition. Using this definition, her team will be able to address some of the problems of overdiagnosis. The successful candidate will develop their own project in a related area. Potential topics include the ethics of disease definition; screening ethics, the distinction between disease and risk factors; specific cases of overdiagnosis; or policy responses to overdiagnosis. Projects may be entirely theoretical or use qualitative methods.

12 The Australian School of Advanced Medicine Neurobiology Professor Roger Chung Professor of Neurobiology & Neurochemistry Macquarie University

BSc (Hons) PhD (University of Tasmania)

Contact Details Credit: Roger Chung T: +61 (0)2 9850 2724 A second interest of this group has been investigating E: [email protected] why particular proteins are prone to abnormal aggregation in neurodegenerative diseases such as Motor Neurone Disease (ie: SOD1 and others), Professional Overview Alzheimer’s disease (beta-amyloid) and Parkinson’s disease (alpha-synuclein). The hypothesis is that the Areas of Research Interest metal-binding property of these proteins plays a critical Prof Chung’s research interests focus upon role in this process, and that this represents a tractable understanding how neuronal and non-neuronal target for therapeutic intervention. Current studies cells (glia) within the brain respond to brain injury or focus upon the aggregation and neurodegenerative neurodegenerative diseases such as Motor Neurone properties of metal-bound SOD1, beta-amyloid and Disease and Alzheimer’s disease. His research has a alpha-synuclein, and developing approaches to either particular focus upon understanding how these cells stop abnormal protein aggregation, or enhance the are able to support or hinder neuronal function in clearance of these toxic proteins from the brain. response to stress. Prof Chungs’ research has a strong focus upon using cellular, molecular and biochemical techniques to develop an understanding of the processes underlying injury or disease to the brain, with the goal of developing novel therapeutic strategies.

Professor Chung has attracted more than $5 million in research funding from the National Health and Medical Research Council and Australian Research Council. He has 45 publications in journals including Journal of

Neuroscience, Journal of Biological Chemistry, Cellular & Credit: Roger Chung Molecular Life Sciences. An ongoing interest of this group is translational research – taking the laboratory understanding of Areas of Research Interest molecular and cellular mechanisms that regulate nerve regeneration and neurodegeneration and using One major interest of this research group over the this as the foundation for understanding how these past 10 years has been investigating the neurotrophic events develop in patients and how this knowledge properties of the metallothionein (MT) family of may inform future therapeutic drug development. proteins. Prof Chung’s research group was the first The groups’ patented research in this area covers to discover that a particular MT isoform is a potent biomarker discovery, and pre-clinical evaluation of promoter of nerve regeneration (Chung et al, J therapeutic compounds for treating neurotrauma and Neurosci 2003). This introduced a paradigm shift in neurodegenerative diseases. the field, because since the groups’ discovery, MTs had been considered as primarily intracellularly PhD Research Projects located and functioning proteins. Since this time, the team has identified some mechanisms that 1) Understanding the molecular signalling that regulates regulate MT secretion by glia, the first neuronal MT axonal growth and regeneration of injured neurons receptor and some of the biochemical mechanisms 2) Revealing the molecular causes of abnormal protein that underlie MT-mediated regeneration of injured aggregation in motor neuron disease and other nerves. Because MT is only produced by glia in the neurodegenerative diseases brain, this research also provides intriguing insights 3) Understanding the interaction between neurons into the roles of neuron-glia interactions in the injured and glia, and how glia can either protect or worsen brain. The research efforts are now focussed upon neurodegeneration translating these discoveries into potential therapeutic applications. Prof Chung’s group has patented MT- Further information about the project can be obtained based synthetic peptides and are currently evaluating from Prof Roger Chung ([email protected]) their ability to promote regeneration of injured nerves. The Australian School of Advanced Medicine 13 Professor Gilles Guillemin Using new laser ablation technology, ICP-MS technology, the student will ‘map’ metals and Professor of Neurosciences metalloenzymes in MND and study the effect of The Australian School of Advanced Medicine, chelation therapy in MND mice. Macquarie University

BSc (Hons), PhD (University of Burgundy, France). Justice of the Peace of NSW

Contact Details T: +61 (0)2 9850 2727 E: [email protected]

Professional Overview Prof Gilles Guillemin has been working in the fields of neuroimmunology and tryptophan metabolism for more than 20 years. He is currently the Co-Director of the MND Research and Neurodegenerative Diseases Centre. In 2012, he was elected as President of both of the International Society for Tryptophan Research (ISTRY) and the Credit: Gilles Guillemin International Neurotoxicity Society (NTS), demonstrating his international standing in both fields of research. Fig 1. A 3D map of Fe concentrations in the mouse brain produced by laser ablation- inductively coupled plasma-mass spectrometry Professor Guillemin has raised over $6M in competitive (LA-ICP-MS) shows the great promise of this technique for modelling grant funding and has 130 publications, 85 in the last distribution of Fe, Cu and Zn in MND. five years, of which are in the top journals including Nature, Journal of Neuroscience, and Cancer Research. 2. KMO inhibition in Neurodegenerative disease Prof Guillemin has successfully converted his research The involvement of kynurenine pathway of tryptophan findings into several treatment and diagnostic metabolism in mediating neuroinflammation is patents. He has recently sold two Patents to private becoming increasingly appreciated. Recently, we international companies. showed that production of the key neurotoxic metabolite quinolinc acid (QUIN) by activity of the Areas of Research Interest enzyme kynureneine-3-monooxygenase (KMO) plays a role in tau phosphorylation and leads to tau-related Professor Guillemin is studying the involvement of cytoskeletal derangement in Alzheimer’s disease tryptophan (an essential amino acid) and its’ derived (AD). The aim of this project is to further explore the molecules (kynurenines) in neurodegenerative and pathophysiological impact of KMO inhibition in animal neuroinflammatory diseases such as amyotrophic lateral models of neurodegenerative disease. The student will sclerosis, multiple sclerosis, Alzheimer’s disease, brain use a variety of molecular biology techniques, including tumours and breast cancer. All these studies utilise a new a PET-based method using F18 ligands to assess broad of methods including primary cultures of human neuroinflammation. The project has the potential to brain cells (unique models), microscopy, molecular consolidate KMO inhibition as a valid therapeutic target biology, protein chemistry, and analytical methods. in AD and other neurodegenerative conditions.

PhD Research Projects

1. Metals in Motor Neuron Disease In recent years a variety of scientific evidence has accumulated suggesting that regulation of iron and other metals may play a role in Motor Neuron Disease (MND; or amyotrophic lateral sclerosis, ALS). Levels of the Fe storage protein ferritin were shown to correlate Credit: Gilles Guillemin to disease progression in MND patients and animal Fig 1. QUIN co-localisation with phosphorylated tau in an AD patient. models of MND show a variety of changes in iron Left panel: Hippocampus from a 73-year old neurologically normal trafficking in the central nervous system and metal- control. Right panel: Hippocampus of a mild AD case (Braak stage IV) binding chelating drugs are capable of extending showing QUIN and AT8+ intraneuronal tangles. From Guillemin et. al., lifespan in MND mice. PLOS One 2009. Scale bar = 50 mM

14 The Australian School of Advanced Medicine 3. Investigating the potential role of BMAA in motor neuron disease The research will focus on elucidating the potential role that BMAA (an amino acid produced by cyanobacteria but not by mammals) plays in neurodegenerative diseases. Indeed, there is mounting evidence that BMAA is associated with motor neuron disease and Credit: Gilles Guillemin other pathologies of the nervous system but our QUIN accumulates in the Substancia Nigra (SN) of MPTP molecular understanding is still lacking. Our group has treated macaques. Using Immunocytochemistry on SN privileged access to primary neuronal cells, including sections from MPTP treated macaques; we found a co- motor neurons. The candidate will thus be in the localisation of activated microglia producing QUIN and unique position to investigate the effects of BMAA tyrosine hydroxylase (TH) neurons directly on such cells. A combination of experimental and computational approaches is suggested. Cells This project will be done in collaboration with Prof will be grown and exposed to BMAA in controlled Maria Trinidad Herrero (University of Murcia, Spain). conditions. Their response will be tested using multiple technologies spanning immunohistochemistry, 5. Quantitative Imaging of neurometallomics in imaging and expression arrays. We are particularly experimental autoimmune encephalomyelitis interested in the effect of BMAA on neurite dynamics (extension/retraction, protein trafficking, and formation (EAE) progression of connections with other neurons). This research This project will employ of state-of-the-art technology will expose the candidate to DNA and RNA biology, laser-ablation inductively coupled advanced microscopy, image analysis, DNA methylation plasma mass spectrometry to generate high definition assays, western blots, HPLC, etc. Applicants should images to visualize and accurately quantify the have some laboratory experience with strong biology biometals present in the brain. Metallomics has knowledge and interest to learn new techniques. progressively gained its importance in various fields There are 2 PhD positions for this project: one in for their roles in pathological events. This study collaboration with Dr. Pascal Vallotton at CSIRO and will determine where and how changes in levels of one with Dr Kenneth Rodgers at the University of biometals, such as copper, zinc, iron, and cobalt, in Technology Sydney (UTS). the central nervous system affect the progression of neurodegeneration during inflammation 4. Involvement of the kynurenine pathway in insult, particularly in experimental autoimmune Parkinson’s disease encephalomyelitis. We aim to demonstrate that tryptophan metabolism within the brain through the kynurenine pathway (KP), which is switched on in neuroinflammation, plays an important role in the pathogenesis of Parkinson’s disease (PD). Several neuroactive metabolites are **Reconstruction of all the slices of mice brain to form a 3D-imaging to produced via the KP and are very likely to be involved in give both qualitative and quantitative imaging data. the neurodegenerative or neuroprotective mechanisms. Credit: Gilles Guillemin This PhD project aims to determine ex vivo presence of KP metabolites in patient samples and its potential This study is undertaken in collaboration with Prof correlation with PD severity: 1) The co-localisation of Philip Doble at the University of Technology Sydney. KP metabolites (excitotoxin quinolinic acid – QUIN) with activated microglia (HLA-DR) will be assessed in autopsy brain sections from PD patients and from PD animal models (mice and macaques) using immunohistochemistry. 2) The various KP metabolites will be quantified in longitundinal samples from PD, patients and animal models. This study might lead to the identification of a new neuropathological mechanism leading to the loss of dopaminergic neurons. This may lead to the development of new biomarkers and a new therapeutic strategy for PD patients.

The Australian School of Advanced Medicine 15 Associate Professor Julie Atkin 2. The role of C9ORF72 in Amyotrophic Lateral Sclerosis (ALS)/Motor Neuron Disease (MND) Associate Professor of Neurochemistry and Cell Biology ALS/MND and frontotemporal dementia (FTD) are The Australian School of Advanced Medicine, neurodegenerative disorders with clinical, genetic, Macquarie University and neuropathological overlap. However the exact BSc (Hons) (Manchester UK), PhD (Sheffield UK). mechanisms that trigger motor neuron degeneration in these disorders remain elusive. Recently, hexanucleotide (GGGGCC) repeat expansions in a Contact Details non-coding region of C9ORF72 were identified to be T: +61 (0)2 9850 2772 the major cause of both familial ALS (~40%) and FTD E: [email protected] (~20%) in Australia and worldwide and they are also present in sporadic ALS. C9ORF72 encodes a protein Professional Overview of previously unknown function, and how mutations in C9ORF72 lead to ALS and FTD also remain unclear. A/Prof Atkin is internationally recognised as a leader Recently our group made an important discovery in the role of cellular stress responses in motor neuron when we was the first to describe the normal cellular disease (MND). Her research has opened up promising function for C9ORF72: regulation of both autophagy novel therapeutic targets, which she is investigating and endosomal transport. This project will further further. A/Prof Atkin has received over $2.3 million in define the normal cellular role of C9ORF72 and how competitive grant funding during the last 10 years this dysfunction in this process leads to ALS. and has over 43 publications. The most relevant to this research project are listed after the project. Most relevant publications to these projects: 1. Sundaramoorthy V, Walker AK, Yerbury J, Soo Areas of Research Interest KY, Farg MA, Hoang V, Zeineddine R, Atkin JD. “Extracellular wildtype and mutant SOD1 induces Molecular and cellular mechanisms leading to ER-Golgi pathology characteristic of amyotrophic neurodegeneration in Amyotrophic Lateral Sclerosis lateral sclerosis in neuronal cells” Cell. Mol. Life Sci: (ALS)/ Motor Neuron Disease (MND) 70 (21):4181-95, 2013

2. Farg MA, Sundaramoorthy V, Sultana JM, Yang PhD Research Projects S, Atkinson RAK, Levina V, Halloran MA, Gleeson 1. The role of intracellular trafficking as a novel P, Blair IP, Soo KY, King AE, Atkin JD. “C9ORF72, pathogenic mechanism in Amyotrophic Lateral implicated in ALS and FTD, regulates endosomal Sclerosis (ALS)/ Motor Neuron Disease (MND) trafficking”. Hum Mol Genet (Epub ahead of print), 2014 ALS/MND leads to the death of motor neurons in the brain, brainstem and spinal cord and it is fatal within 3 to 5 years of symptom onset. The cellular mechanisms leading to disease are poorly understood. However, we have previously identified that disruption of protein trafficking between the ER and Golgi apparatus is a common pathogenic mechanism shared by several different misfolded proteins that cause ALS. ER-Golgi trafficking is a Rab1 dependent process and we have also shown that overexpression of Rab1 can rescue pathology in neuronal cells in culture. It is now vitally important to (i) specifically define the mechanisms by which transport is inhibited by each protein, and (ii) to determine if targeting this mechanism therapeutically is beneficial in animal disease models. This project will examine the molecular mechanisms underlying transport inhibition and whether restoration of transport can prolong lifespan and rescue pathology in both mouse and zebrafish disease models.

16 The Australian School of Advanced Medicine Associate Professor Ian Blair Molecular Cancer Associate Professor (CORE) Macquarie University Professor Mark Baker

BSc (Hons) (Macquarie University), MIP (University of Professor of Proteomics Technology Sydney), PhD (University of Sydney) The Australian School of Advanced Medicine, Macquarie University

Contact Details BSc (Hons1), PhD (Macquarie University) T: +61 (0)2 9850 2725 E: [email protected] Contact Details T: +61 (0)2 9850 8211 Professional Overview E: [email protected] Associate Professor Blair’s research career has focused on determining the molecular and cellular basis of a variety Professional Overview of neurological disorders including motor neuron disease Prof Mark S. Baker completed his PhD at Macquarie (amyotrophic lateral sclerosis, ALS/MND), hereditary University in 1985. His research has focused on the role sensory neuropathy (HSN), Charcot Marie Tooth disorder of proteins in human health and disease pathology (CMT), the spinal cerebellar ataxias (SCA), Joubert (e.g., arthritis, breast, ovarian, prostate and colorectal syndrome, and bipolar disorder. At Macquarie University, cancer) for more than 30 years. He has been actively in Associate Professor Blair conceives, instigates and leads human proteomics since the earliest inception of this studies to unravel the molecular genetic and cellular basis new discipline at Macquarie University. of ALS/MND. In the past 5 years, his group has played a key role in several ALS gene discoveries worldwide. Professor Baker has made These discoveries have opened new chapters in ALS/MND stellar contributions to research and produced publications in high-impact the growth of proteomics journals. His work has also led to the development of societies at the national, effective diagnostic tests for ALS, CMT1A and HSN1. regional and global A/Prof Blair has received numerous awards during his levels, including a successful stint in the US biotech career, he currently has over $1.5million in grant funding industry. In 2004, he co-founded the Australasian and has received over $4.5million during his career. He has Proteomics Society, was a founding AO-HUPO over 50 publications in top-ranked journals. Councilor and foundation member of the Human Proteome Organisation (HUPO). Mark returned from the Areas of Research Interest US to serve as the CEO of the world’s first proteomics facility, the Australian Proteome Analysis Facility ƒƒ Disease gene discovery in familial ALS/MND and (APAF), supporting Australia’s national proteomics related neurodegenerative disease. services effort and subsequently securing significant ƒƒ Unravelling the epigenetic contribution to government support for national infrastructure. Mark neurodegenerative disease. was elected to the HUPO Board in 2005 and has ƒƒ Pathological studies in familial and sporadic ALS/MND. served there since. He was elected HUPO Executive ƒƒ In vitro study of ALS/MND molecules, to member-at-large in 2012 and elected to be the next determine the functional consequences of HUPO President in 2013. Mark co-chaired the 9th HUPO pathogenic mutations. World Congress in Sydney where the Human Proteome Project was launched. He is a chair or member of many ƒƒ Developing animal models of ALS/MND, based HUPO activities/committees, sits on prestigious journals’ upon mutant ALS/MND genes, for study of disease Editorial Boards and industry Advisory Boards. Prof Baker biology and therapeutic discovery. was recognized for his international service as the 2012 HUPO Distinguished Service Awardee demonstrating PhD Research Projects the impact of his research and his international standing An opportunity is available to undertake a PhD in in this emerging field of research. ALS/MND gene discovery using computational and Prof Baker has published >130 peer-reviewed papers, bioinformatic analysis of next-generation sequencing supervised more than 41 Honours/PhD graduates and data. The candidate would use their experience in is the inventor of numerous proteomics technology computational and bioinformatic analysis to examine patents. He remains an advocate for industry:academia exome, genome, transcriptome and epigenome data in collaborations, media engagement and promotion a biological context, to identify and prioritise candidate of career paths for young researchers. He has raised genes for further investigation in disease, as well as in over $50M in competitive grant funding, and sits on vitro assays. The goal is to identify those genes and 3 proteomics journals Editorial boards, including being alleles that cause or modify ALS/MND phenotype, or an Associate Editor of Clinical Proteomics. predispose individuals to ALS/MND. The Australian School of Advanced Medicine 17 Areas of Research Interest acquisition and maintenance of cancer characteristics Professor Baker’s current research interests cover cancer essential to transformation, de-differentiation and proteomics, biomarkers and molecular cell biology, metastasis (spread). These have become promising including: advanced proteomic technologies, cancer therapeutic targets. In this project we are targeting the metastasis and how protease receptors (e.g., uPAR), uPAR•avb6 integrin PPI interfaces that we discovered growth factor receptors (e.g., TFGFbR) and integrins a few years ago and that we now see as a potential (e.g., avb6 integrin) membrane protein networks anti-metastasis cancer strategy. PPI interface modelling, regulate the pathobiology of cancer. These include the characterization, chemical library design and patient- development of novel platforms to determine what proteomic subpopulation-driven clinical studies are and how proteins interact to regulate metastasis and anticipated as part of this project, which aims to early cancer blood protein biomarker discovery. He is accelerate development of the next generation of the currently Chair of the HUPO Plasma Proteome PPI-based agents for personalized precision medicine. Project and is coordinator of a number of Australian/ The project may also expand into other identified NZ efforts in the Chromosomal and Biology/Disease proteins we found to also be involved in PPI we have “pillars” of the global Human Proteome Project (HPP). termed the “metastasome”. He has active collaborations with scientists in Australia, 3. Plasma Protein/Peptide Biomarkers of NZ, USA, Sweden, Spain, Colorectal Cancer Switzerland, China, Germany and Japan. Colorectal cancer (CRC) is the second most common malignancy by incidence and cause of death in the Western world. CRC is the most common registrable PhD Research Projects cancer in Australia with 13,000 new cases resulting 1.Membrane Proteomics (Colorectal and Breast Cancer) in 13.1% ( 12.7%, 13.5% of the total 4,000) of all Australian cancer deaths. Human blood plasma Membrane proteins are of particular interest in cancer continues to be our most available biomarker fluid because of their acknowledged potential therapeutic because it is easily available and it comprehensively utility. Membrane proteins are represented by 30% samples the human condition in all states of health of the genome and constitute approximately 70% and disease. This project elucidates the normal of all human protein based drug targets. Analysis of and diseased human plasma proteome (in great membrane proteins has been notoriously difficult, depth) and peptidome in order to discover novel as seen by their under-representation in 2DE gels, prognostic/diagnostic markers of cancer onset, where proteins have a tendency to be hydrophilic staging and recurrence. Unfortunately, like many with grand average hydrophobicity (GRAVY) scores protein-rich biofluids (e.g., serum, plasma, saliva, of less than 0.3. Recently, these difficulties have been tears and urine) plasma has an extraordinary protein resolved by analysing membrane protein enriched concentration range – some say as high as 13 logs. samples using “shotgun” proteomics. We have Great discovery opportunities exist if one can “drill developed and pioneered many new methods that more deeply”. This project is based upon new patented improve membrane proteome coverage dramatically technologies developed at Macquarie University. (e.g., peptide IPG-IEF). New cell biology approaches (developed collaboratively with industry) have 4. The Human Proteome Project been used on cancer cell lines and verified in major pathology studies to determine changes in the The Human Proteome Project (HPP) will characterise all membrane proteome during colon and breast cancer 20,300 genes of the known genome and will generate invasion metastasis and how these can translate to the map of the protein-based molecular architecture better clinical tools for decision making. Our research of the human body and become a resource to group also uses proteomics to examine specific help elucidate biological and molecular function metastasis-related “interactomes” that determine and advance diagnosis and treatment of diseases. important signaling biology downstream in cancer and Australia’s effort in the HPP is currently divided into the chemical biology combined with structural modelling Chromosomal C-HPP and the Biology/Disease B/D-HPP to develop potential “lead” drug antagonists of approaches, and Prof. Baker’s group has projects in these interactions. both for emerging bioinformaticians (in collaboration with Prof. Ranganathan at Macquarie University), 2. Protein Interactions In Cancer Metastasis immunologists and mass spectrometrists (MRM-based assays against missing and colorectal cancer blood- The emergence/convergence of oncogenomics, based biomarker proteins) currently available. molecularly-targeted therapeutics, and systems biology network analyses have significantly expanded the discovery landscape for protein•protein interactions (PPI) in the biology of human cancer. This has led to the identification of protein interaction hubs (lynchpins) and nodes that appear to be critical for the

18 The Australian School of Advanced Medicine Selected Recent Publications 11. Startsev MA, Inglis DW, Baker MS and Goldys EM. 1. Saldanha RG, Molloy MP, Bdeir K, Cines DB, Song Nanochannel pH Gradient Electrofocusing of Proteins. X, Uitto PM, Weinreb PH, Violette SM, Baker MS. Anal Chem. 2013 Aug 6;85(15):7133-8. doi: 10.1021/ Proteomic Identification of Lynchpin Urokinase ac4014447. Epub 2013 Jul 24. [IF = 5.7] Plasminogen Activator Receptor Protein Interactions 12. Islam M-DT, Mohamedali A, Garg G, Khan JM, Associated with Epithelial Cancer Malignancy. Gorse A-D, Parsons J, Marshall P, Ranganathan S, and J Proteome Res. 2007 6(3): 1016-1028. [IF= 5.113] Baker MS. Unlocking the puzzling biology of the black 2. McKay MJ, Sherman J, Laver MT, Baker MS, Clarke Périgord truffle Tuber melanosporum. J Proteome Res. SJ, Molloy MP, The Development of Multiple Reaction 2013 Nov 6. [Epub ahead of print] PMID: 2414793. [IF Monitoring Assays for Liver Derived Plasma Proteins. = 5.1]. Proteomics (Clin Apps), 1 (12), 1570-1581, 2007 [IF= 6.1]. 13. Islam M, Garg G, Hancock W, Risk B, Baker MS, 3. Lee, A, Kolarich D, Haynes PA, Packer, NH, Baker, MS. Ranganathan S. Protannotator: A semi-automated Liver Membrane Proteome Glycosylation Changes in Mice pipeline for chromosome-wise functional annotation of Bearing an Extrahepatic Tumor. Mol. Cell Proteomics, the “missing” human proteome Manuscript ID: Sep;10(9): M900538MCP200, 2011. [IF = 8.8]. pr-2013-00794x. 2013. in press. J. Proteome Res. [IF = 5.1]. 4. Randall SA, McKay MJ, Baker MS, Molloy MP. Evaluation of blood collection tubes using selected 14. Sethi MK, Thaysen-Andersen M, Smith JT, Baker MS, reaction monitoring MS: implications for proteomic Packer NH, Hancock WS, Fanayan S. Comparative biomarker studies. Proteomics. 2010; 10(10), 2050-6 N-Glycan Profiling of Colorectal Cancer Cell Lines (Erratum issued August 15th, 2011) [IF=4.2]. Reveals Unique Bisecting GlcNAc and α-2,3-Linked Sialic Acid Determinants Are Associated with Membrane 5. Jankova L, Chan C, Fung CL, Song X, Kwun SY, Proteins of the More Metastatic/Aggressive Cell Lines. Cowley M, Kaplan W, Dent OF, Bokey L, Chapuis J Proteome Res. 2013 Dec 2. [Epub ahead of print]. PH, Baker MS, Robertson GR, Clarke SJ, Molloy MP. PMID: 24295106. [IF = 5.1]. Proteomic comparison of colorectal tumours and non-neoplastic mucosa from paired patient samples 15. Gopichandran S, Khan JM, Anand S, Ahn SB, using iTRAQ mass spectrometry, Mol. BioSyst., 2011, 7, Baker MS, Ranganathan S. A site for direct integrin 2997–3005. αvβ6uPAR interaction from structural modelling and docking. J. Structural Biol. J Struct. Biol. 2014 6. Lee LY, Hincapie M, Packer N, Baker MS, Fanayan Jan 11. pii: S1047-8477(14)00002-1. doi: 10.1016/j. S, Hancock WS. Optimization of native multi- jsb.2014.01.001. [Epub ahead of print]. [IF = 3.36] lectin affinity chromatography for enrichment of glycoproteins from MCF 7 total protein lysate, J Sep 16. Fanayan S, Hancock W, Thaysen-Andersen M, Lee L, Sci. 2012 Sep;35(18):2445-52. doi: 10.1002/jssc. Baker MS, Packer N. Comprehensive N-glycome 201200049. [IF=2.6]. profiling of cultured human epithelial breast cells identifies unique secretome N-glycosylation signatures 7. Tan S-H, Kapur A, Abidali M, Baker MS. A Novel enabling tumorigenic subtype classification. J Human Plasma Ultradepletion Strategy. J Proteome Proteome Res. 2014. Manuscript ID: pr-2014-00331m. Res. in press Oct 22nd 2012. Manuscript ID: pr-2012- [IF = 5.1]. 007182.R1. [IF=5.1].

8. Fanayan S, Smith JT, Sethi MK, Cantor D, Goode R, Baker MS, Hancock WS, Nice E. Chromosome 7-centric analysis of proteomics data from a panel of human colon carcinoma cell lines, J Proteome Res., in press, accepted December 10th, 2012. [IF = 5.1].

9. O’Neil SE, Palviainen MJ, ten Have S, Filiou M, Gonzalez A, Hodge K, Surinova S, Penque D, Baker MS. Clinical proteomics stretch goals: EuPA2012 roundtable report. J. Proteomics, accepted April 10th 2013.

10. Cantor D, Slapetova I, Kan A, McQuade LR and Baker MS Overexpression of αvβ6 integrin alters the colorectal cancer cell proteome in favour of elevated proliferation and a switching in cellular adhesion which increases invasion. J Proteome Res. 2013 Jun 7;12(6):2477-90. doi: 10.1021/pr301099f. Epub 2013 May 24. [IF = 5.1].

The Australian School of Advanced Medicine 19 Professor Helen Rizos of patients with BRAF-mutant metastatic melanoma. Despite the dramatic clinical activity of combining Professor, Precision Cancer Therapy BRAF and MEK inhibitors, only 41% of patients on this The Australian School of Advanced Medicine, combination therapy are progression-free at 1 year. Macquarie University We propose to determine new drivers responsible for BSc (Hons), PhD (University of New South Wales) melanoma resistance to combination BRAF and/or MEK inhibition. Most significantly this work will examine Contact Details paired melanoma tumours cells collected prior to (PRE) and following relapse on this MAPK inhibitor treatment T: +61 (0)2 9850 2762 (PROG). This work will integrate proteomic analyses E: [email protected] 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 Professor Richard Kefford identification of new therapeutic targets and the development of rational combination therapies. Professor, Cancer Medicine The Australian School of Advanced Medicine, Project 2: Manipulating oncogenic c-Kit signalling in Macquarie University the treatment of melanoma MBBS (FRACP). PhD (University of Sydney) In this project, our focus is on a subgroup of patients with melanomas arising on sun-protected skin (such as Contact Details palms, soles and nail beds; acral melanomas), mucosal membranes (mucosal melanomas) or on skin showing PA to Prof Kefford: evidence of chronic sun-induced damage. A significant T: +61 (0)2 9850 2766 proportion of these melanomas carry mutations in the E: [email protected] c-Kit receptor tyrosine kinase, and although clinical trials with the c-Kit inhibitor imatinib show responses in Professional Overview 54% of c-Kit-mutant melanoma patients, most patients will progress within 4 months of treatment. Few Prof Helen Rizos has been working in the field of alternative treatments have been tested, but as many melanoma cell biology and oncogenic signalling since new promising therapies enter the clinic, recognition 1995. She is a leader in the functional and genetic of the molecular features driving melanoma survival analyses of melanoma-associated tumour suppressors will provide new treatment options. and oncoproteins. In this project we will explore the molecular Professor Richard Kefford has been investigating the determinants that modulate and predict c-Kit inhibitor molecular genetics of melanoma since 1986. He is a sensitivity and investigate the potential of combination consultant Medical Oncologist, founding member of therapies in the treatment of c-Kit-mutant melanoma the International Melanoma Genetics Consortium and patients. To obtain new insights into how c-Kit plays a major role in the design and conduct of clinical inhibitors may alter signalling in melanoma we will trials in melanoma. conduct whole genome gene expression analyses Profs Rizos and Kefford have received over $10million of sensitive melanoma cell lines treated with c-Kit in NHMRC research funding since 2010 and have co- inhibitors. We will also investigate mechanisms and authored over 40 publications. signalling changes that confer resistance to current treatment strategies, and potential therapies to circumvent resistance. PhD Research Projects

Project 1: Melanoma resistance to BRAF and Project 3: Dissecting the contribution of baseline MEK inhibition oncogenic alterations in melanoma survival and drug resistance Until recently, patients with metastatic melanoma were treated with single agent chemotherapy Targeting the mitogen activated protein kinase (MAPK) drugs, including dacarbazine and temozolamide, pathway with combined BRAF and MEK inhibition that produce response rates of less than 10%, with was recently approved by the USA Food and Drug no improvement in overall survival. New drugs Administration for the treatment of BRAFV600- targeting the mitogen activated protein kinase (MAPK) mutant metastatic melanoma. Despite significant pathway have now shown significant activity. The improvements in clinical outcomes 50% of patients pharmacological inhibition of the mitogen activated treated with combination MAPK inhibitors progress protein kinases BRAF and MEK produces response rates within 10 months. We have recently confirmed that of approximately 76% and prolongs the overall survival re-activation of the MAPK pathway occurs in the

20 The Australian School of Advanced Medicine majority of resistant melanomas, but many of these Publications relevant to the project melanomas responded poorly initially, suggesting that 1. Carlino, M. S., Gowrishankar, K., Saunders, C. A., Pupo, baseline genetic alterations diminished responses to G. M., Snoyman, S., Zhang, X. D., Saw, R., Becker, MAPK inhibition. Many melanomas had established T. M., Kefford, R. F., Long, G. V. & Rizos, H. (2013). oncogenic alterations affecting RAC1, AKT, PTEN, Antiproliferative effects of continued mitogen- p14ARF, p53 and SOS1. To determine the precise role of activated protein kinase pathway inhibition baseline genetic changes on melanoma survival and following acquired resistance to BRAF and/or MEK drug resistance, a series of mutations will be generated inhibition in melanoma. Mol Cancer Ther 12, 1332-42. and introduced into BRAF-mutant, drug-sensitive melanoma cell models. The role of these baseline 2. Carlino, M. S., Todd, J. R., Gowrishankar, K., Mijatov, B., changes on melanoma drug sensitivity, survival Pupo, G. M., Fung, C., Snoyman, S., Hersey, P., Long, and proliferation and the requirement for MAPK G. V., Kefford, R. F. & Rizos, H. (2014). Differential re-activation will be explored. activity of MEK and ERK inhibitors in BRAF inhibitor resistant melanoma. Mol Oncol. (in press) Project 4: Circulating tumour DNA and RNA: biomarkers 3. Gowrishankar, K., Snoyman, S., Pupo, G. M., Becker, of melanoma treatment response T. M., Kefford, R. F. & Rizos, H. (2012). Acquired We propose that circulating tumour DNA and RNA can resistance to BRAF inhibition can confer cross-resistance provide an accurate and complete genetic profile of to combined BRAF/MEK inhibition. J Invest Dermatol a patient’s tumours. These cell-free nucleic acids are 132, 1850-9. released from cancer cells into plasma and represent non-invasive liquid biopsies containing a mix of 4. Long, G. V., Wilmott, J. S., Haydu, L. E., Tembe, multiple metastatic lesions. Recent studies confirm V., Sharma, R., Rizos, H., Thompson, J. F., Howle, that mutant allele analyses (K-RAS, BRAF, NRAS) in J., Scolyer, R. A. & Kefford, R. F. (2013). Effects plasma and tumour tissue are strongly correlated and of BRAF inhibitors on human melanoma tissue that the allele fraction of mutations conferring therapy before treatment, early during treatment, and on resistance increased in plasma in association with progression. Pigment Cell Melanoma Res 26, 499-508. therapy resistance. These data suggest that circulating 5. Rizos, H., Menzies, A. M., Pupo, G. M., Carlino, M. S., DNA may provide a snapshot of all developing Fung, C., Hyman, J., Haydu, L. E., Mijatov, B., Becker, resistance mechanisms in multiple tumour sites T. M., Boyd, S. C., Howle, J., Saw, R., Thompson, J. F., In this project we plan to determine whether Kefford, R. F., Scolyer, R. A. & Long, G. V. (2014). circulating melanoma DNA/RNA can be used as a BRAF Inhibitor Resistance Mechanisms in Metastatic prognostic tool, to assess therapeutic response and Melanoma: Spectrum and Clinical Impact. tumour heterogeneity and whether it allows for the Clin Cancer Res 20, 1965-77. early detection of resistant clones, allowing for timely 6. Todd, J. R., Becker, T. M., Kefford, R. F. & Rizos, H. informed precision therapeutic intervention. (2013). Secondary c-Kit mutations confer acquired Most significantly this work will integrate data resistance to RTK inhibitors in c-Kit mutant generated from melanoma tumours and liquid biopsies melanoma cells. Pigment Cell Melanoma Res 26, collected prior to (PRE) and early during therapy (EDT) 518-26. with BRAF and/or MEK inhibitors and following relapse 7. Todd, J. R., Scurr, L. L., Becker, T. M., Kefford, R. F. & on this treatment (PROG). Rizos, H. (2014). The MAPK pathway functions as a Mutant alleles detected in pre-treatment tumour redundant survival signal that reinforces the PI3K biopsies will be utilized specific quantitative droplet cascade in c-Kit mutant melanoma. Oncogene 33, PCR assays to track patients on immune check-point 236-45. inhibitor treatment (ipilimumab, pambrolizumab) 8. Wilmott, J. S., Tembe, V., Howle, J. R., Sharma, R., to assess the possible potential of his technology Thompson, J. F., Rizos, H., Lo, R. S., Kefford, R. F., to be used as a biomarker of tumour response Scolyer, R. A. & Long, G. V. (2012). Intratumoral and progression. molecular heterogeneity in a BRAF-mutant, BRAF inhibitor-resistant melanoma: a case illustrating the challenges for personalized medicine. Mol Cancer Ther 11, 2704-8.

The Australian School of Advanced Medicine 21 Neuroscience

Research Projects in this area could incorporate: Professor Mark Connor ƒƒ Identifying ligand biased signaling at human opioid Professor of Pharmacology and cannabinoid receptors; The Australian School of Advanced Medicine, ƒƒ Understanding the mechanism of action of Macquarie University allosteric modulalors of human µ-opioid and cannabinoid receptors; BSc (Hons) (University of Sydney), PhD (University of Washington) ƒƒ Defining the effects of single nucleotide polymorphisms on human µ-opioid and cannabinoid receptor function; Contact Details ƒƒ Understanding the pharmacology of synthetic T: +61 (0)2 9850 2719 cannabinoid drugs of abuse; and F: +61 (0)2 9850 2701 ƒƒ Defining the effects of endocannabinoids and E: [email protected] related molecules on pain-related GPCR and ion channels Professional Overview Recent Key Publications Areas of Research Interest Knapman AJ, Santiago M, Connor M (2014). Professor Connor’s work focuses on the receptors Buprenorphine signaling is compromised at the N40D and ion channels that affect neurons involved in polymorphism of the human µ-opioid receptor in vitro. the detection and processing of pain, with a view British Journal of Pharmacology, In Press to understanding how drugs and endogenous neurotransmitters affect these processes. A particular Redmond WJ, Gu L, Camo M, McIntyre P, Connor M area of interest is how G protein coupled receptor (e.g. (2014). Ligand determinants of fatty acid activation of opioid and cannabinoid) signalling differs between the pronociceptive ion channel TRPA1. PeerJ, e248. closely related drugs, and how it changes following Cawston EE, Redmond WJ, Breen C, Grimsey N, prolonged exposure to drugs. The research team is also Connor M, Glass M (2013). Real-time characterisation interested in identifying novel actions of currently used of Cannabinoid Receptor 1 (CB1) allosteric modulators drugs, or new compounds that act at important drug reveals novel mechanism of action. British Journal of targets. Professor Connor’s laboratory primarily uses Pharmacology, 170, 893-907. high throughput fluorescence and electrophysiological techniques to study native and recombinant channels Gilmore AJ, Heblinski M, Reynolds A, Kassiou M, and receptors, as well as contemporary biochemical Connor M (2012). Inhibition of recombinant human assays to study second messenger pathways. T-type calcium channels by N-arachidonoyl serotonin. British Journal of Pharmacology, 167, 1076–1088. Professor Connor has received over $3.5million in competitive research funding and has contributed to more than 70 papers in leading pharmacology and neuroscience journals.

PhD Research Projects

1. Poppies, Pot and Peppers The treatment of chronic pain and drug abuse remain two significant challenges in Pharmacology. Opioid agonists are the mainstays of pain therapeutics, yet for many people they provide suboptimal relief with unwanted effects that can make their use intolerable. Our group studies the signaling and regulation of human opioid and cannabinoid receptors, with the aim of developing better strategies to target these receptors, particularly in light of the significant genetic heterogeneity of opioid- and cannabinoid-related signaling proteins. Our primary aim is to contribute to developing better therapeutic strategies for treating pain, drug abuse and other conditions by identifying better ways to use exiting drugs, and identifying novel drugs or combinations of drugs.

22 The Australian School of Advanced Medicine Professor Jacqueline Phillips The function of the NEK8 kinase in cilia is unclear and this project aims to identify differences in its activity Professor of Neuroscience in mutant animals. A quantitative proteomics study is The Australian School of Advanced Medicine, proposed, examining the global impact of impaired Macquarie University NEK8 activity in kidney epithelial cells, aiming to reveal novel proteins regulated by this pathway. The first PhD ANU, BVSc (Hons) (University of Sydney) phase of the project will develop a cultured renal epithelial cell line transfected with wild type and Contact Details mutant protein, with rat, mouse and human variants, to T: +61 (0)2 9850 2753 provide a stable cell model system. E: [email protected] The second phase of the project will examine the hypothesis that mutations in the RCC1 domain of Professional Overview the Nek8 protein and resulting change in functional activity of the kinase will significantly alter the kidney Professor Phillips has attracted over $4million epithelial cell proteome, the study of which will reveal in funding in the past 10 years. She has over 55 novel and key protein network interactions. Triplicate publications; most of her publications are published in analysis of whole cell lysates incorporating membrane the best-ranked journals in her research area. protein extraction, 1D SDS-PAGE, trypsin digest and alkylation will be undertaken at the Australian Area of Research Interest Proteomic Facility. Data will be analysed with Ingenuity High blood pressure (hypertension) causes heart attack analysis. Western blot and immunohistochemical & stroke, which are primary causes of death in people analysis of cell lines will be undertaken for validation of with kidney disease. We believe the autonomic nervous major proteomic changes. system, which is responsible for controlling involuntary A final goal will be to assess the expression of key actions like heart rate and breathing, is key in linking identified proteins in human renal tissue samples, hypertension, the heart and the kidney. Research within both normal and where possible from patients with my team aims to understand how the sympathetic polycystic kidney disease. and parasympathetic arms of the autonomic nervous system control the heart and blood pressure in the Publications relevant to this project are: diseased state. Much of our work uses a model of renal 1. Phillips, JK, et al., Temporal relationship between failure – the Lewis polycystic kidney disease rat (LPK), renal cyst development, hypertension and cardiac to understand this relationship. A key aspect of our hypertrophy in a new rat model of autosomal recessive studies is fully characterising this model from a genetic polycystic kidney disease. Kidney and Blood Pressure and phenotypic perspective. Our research uses multiple Research, 2007. 30(3): p. 129-44. approaches including molecular techniques assessing gene expression, immunohistochemistry and electron 2. McCooke, J.K., et al., A novel mutation causing microscopy, to assess structure relative to function, nephronophthisis in the Lewis polycystic kidney rat protein levels and distribution patterns. We use animal localises to a conserved RCC1 domain in Nek8. BMC models to measure physiological parameters such as Genomics, 2012. 13(393): p. 1471-2164. nerve activity, blood pressure and heart rate.

The PhD Research Project

1. NEK8: A new player in the gene-network linking cilia function to cell cycle regulation Supervised by Professor Jacqueline Phillips and co- supervised by Professor Mark Baker.

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 Australian School of Advanced Medicine 23 Associate Professor Ann K Goodchild in catecholaminergic brain regions: a marker of activation following acute hypotension and Associate Professor, Systems and Signalling glucoprivation. PLoS ONE accepted 26th October Neuroscience Group The Australian School of Advanced Medicine, 2. Pardey, M, Kumar NN, Goodchild AK, Cornish JL Macquarie University (2012) Catecholamine receptors differentially mediate impulsive choice in the medial BSc(Hons), PhD (University of Sydney) prefrontal and orbitofrontal cortex Journal of Psychopharmacology (in press)

Contact Details 3. Pardey, M, Kumar NN, Goodchild AK, Clemens K, T: +61 (0)2 9850 2711 Homewood J, Cornish JL (2012) Long-term effects of F: +61 (0)2 9850 2701 chronic oral Ritalin administration on cognitive and E: [email protected] neural development in non-ADHD adolescent rats Brain Science (in press)

Professional Overview 4. Bowman BR, Kumar NN, Hassan SF, McMullan S, Goodchild AK (2012) Brain sources of inhibitory Areas of Research Interest and PhD Projects input to the rat rostral ventrolateral medulla. Journal of Comparative Neurology in press The goal of the Systems and Signalling Neuroscience Group is to understand how neurons and neuronal 5. Sreenivasan VK, Kim EJ, Goodchild AK, Connor networks operate normally during the healthy state M, Zvyagin AV (2012) Targeting somatostatin and what changes underpin their dysfunction evident receptors using in situ-bioconjugated fluorescent in disease. The neural systems of interest are those nanoparticles Nanomedicine 7(10) 1551–1560 controlling cardiovascular, metabolic and respiratory function. A/Prof Goodchild collaborates with numerous 6. Parker LP, Tallapragada VJ, Kumar NN and Goodchild national and international groups, and has received AK (2012) Distribution and localisation of Gα proteins over $3.5million in grants and publishes extensively in in the rostral ventrolateral medulla of normotensive top ranked journals in her field. and hypertensive rats: focus on catecholaminergic neurons Neuroscience 218:20–34. The specific objectives of our group are: to identify neurons in the central nervous system that regulate or 7. Sreenivasan VK, Stremovskiy OA, Kelf TA, Heblinski modify these functions; to understand the circuitry by M, Goodchild AK, Connor M, Deyev SM, Zvyagin which they influence the key brain sites that control the AV. (2011) Pharmacological characterization of a functions of interest; to determine the neurochemistry of recombinant,fluorescent somatostatin receptor the neurons and receptors and downstream intracellular agonist. Bioconjug Chem. 22(9):1768–75. signalling mechanisms that influence their activity; and to 8. Burke PG, Neale J, Korim WS, McMullan S, Goodchild determine neuronal recruitment/adaptation and protein AK (2011) Patterning of somatosympathetic reflexes changes/ modifications that occur within these neural reveals nonuniform organization of presympathetic systems in response to acute or chronic challenges. drive from C1 and non-C1 RVLM neurons. Am J Acute challenges include altering blood sugar levels, Physiol Regul Integr Comp Physiol. 301(4):R1112–22. blood pressure or drugs of addiction. Chronic challenges include hypertension, diabetes, and mental health 9. Hildreth CM, Goodchild AK. (2010) Role of ionotropic disorders including depression, schizophrenia and GABA, glutamate and glycine receptors in the tonic methamphetamine addiction. These challenges alter the and reflex control of cardiac vagal outflow in the rat. function of neurons and we are examining the cellular BMC Neurosci. 11:128. and molecular mechanisms responsible. 10. Bobrovskaya L, Damanhuri HA, Ong LK, Schneider JJ, Techniques used include in vivo and in vitro Dickson PW, Dunkley PR, Goodchild AK. (2010) Signal electrophysiological techniques in conjuction with transduction pathways and tyrosine hydroxylase pharmacology, functional neuroanatomy using regulation in the adrenal medulla following multilabelling approaches in addition to ‘shot gun’ glucoprivation: an in vivo analysis. Neurochem Int. label and label free proteomic techniques. We 57(2):162–7. IF=2.9 welcome enquiries for study at the Masters or PhD 11. Burke PG, Abbott SB, McMullan S, Goodchild AK, level. Please feel free to discuss your options by email Pilowsky PM. (2010) Somatostatin selectively ablates or phone at any time. post-inspiratory activity after injection into the Bötzinger complex. Neuroscience;167(2):528-39. Recent Publications related to PhD projects 12.Allen K, Parker L, Damanhuri H, Goodchild AK. (2010) 1. Damanhuri HA, Burke PGR, Ong LK, Bobrovskaya Neuropeptide coding of sympathetic preganglionic L,Dickson P Dunkley PR and Goodchild AK neurons; focus on adrenally projecting populations. (2013) Tyrosine hydroxylase phosphorylation Neuroscience 170:789–799.

24 The Australian School of Advanced Medicine Dr Simon McMullan Senior Lecturer The Australian School of Advanced Medicine, Macquarie University

PhD (University of Bristol), UK, BSc PhD (Hons) Figure 1 Spinally projecting neurons in the RVLM have enhanced (University of Manchester), UK responsiveness to acute hypoxia (NaCN) in vitro compared to neighbouring neurons that do not project to the spinal cord. Histology shows examples of two spinally projecting neurons labelled during Contact Details recording in a different experiment. Recorded neurons are labelled T: +61 (0)2 9850 2710 green (biotin); spinally projecting neurons are labelled magenta (CTB). E: [email protected] Credit: Lama Bou Farah

Professional Overview 2. Neurochemical coding of respiratory neurons Dr McMullen undertook his postdoctoral Fellowship at Since the advent of histological techniques that the University of Bristol (2002-4) and at the University allow neuroscientists to identify the distribution of Sydney (2005-2007). In 2007 he was recruited to the of proteins in individual neurons, researchers have Australian School of Advanced Medicine at Macquarie attempted to divine the relationship between University and is currently a Senior Researcher with neurochemical (i.e. what proteins the cells synthesise) responsibilities in research and teaching. Dr McMullan and functional (i.e. the behavioural profile of the cell) is the departmental co-ordinator of the Master of phenotypes. Establishing discrete expression of a Research (MRes) degree program at ASAM. given neurochemical within a functionally distinct subpopulation of neurons not only provides clues to Dr McMullan has been part of a group that has the biochemistry and pharmacology involved in a attracted over $1.5 million for his research, and neural pathway, but may also provide researchers with published in high ranked journals. anatomical markers of function that can be combined with anatomical, transgenic, or viral gene manipulation PhD Research Projects strategies. Identification of discrete functional markers is therefore an important objective, but difficult and 1. Sensitivity of brainstem sympathetic premotor time-consuming to perform. neurons to metabolic stimuli The expression of neurochemical such as somatostatin, Neurons within a small heterogeneous region of the neurokinin-1, galanin and somatostatin receptor 2a brainstem, the rostral ventrolateral medulla (RVLM), seems to correspond closely with distinct respiratory are critically important for maintaining blood pressure phenotypes in neurons in the ventrolateral medulla, and sympathetic nerve activity, and are a major site of and several of these neurochemicals have been convergence for many cardiovascular reflex pathways. proposed as putative markers of neuronal function. They also play an important role in driving adaptive Although in some cases (e.g. galanin) the evidence responses to metabolic stimuli, such as brain oxygen, for a relationship between neuronal chemistry and glucose, and carbon dioxide concentrations, but there function is robust, in some cases (e.g. somatostatin is some uncertainty as to whether these neurons are 2a receptor) the expression pattern is suggestive of intrinsically sensitive to these stimuli, or just respond to a role in respiratory rhythm generation, but lacking afferent input from other neurons that are. definitive evidence.

My team is currently investigating the mechanisms To determine whether somatostatin 2a receptor is that underlie the enhanced responsiveness of RVLM expressed in respiratory neurons we are conducting sympathetic premotor neurons to hypoxia (oxygen in vivo electrophysiology experiments in which starvation: Figur 1) and glucoprivation (glucose neurons are first functionally identified by correlating starvation) in vitro, and, working with colleagues at the neuronal discharge with diaphragmatic activity, University of Melbourne, have recently shown that the and then dye-labelled with a modified form of the activation of spinally projecting RVLM neurons that juxtacellular labelling technique. The recovered occurs following glucoprivation is not a result of any neurons are then examined for expression of direct sensitivity of these neurons to the stimulus, but somatostatin 2a receptor (see Figure 2). rather is dependent on drive from orexinergic neurons in the hypothalamus (Korim et al., 2014).

The Australian School of Advanced Medicine 25 Neurosurgery Professor Marcus Andrew Stoodley Professor: Neurosurgery The Australian School of Advanced Medicine, Macquarie University

BMedSc (University of Queensland), MB.BS(Hons), PhD (University of Adelaide), FRACS Credit: Sheng Le

3. Mapping the structure of neural networks that Contact Details control breathing and blood pressure Neurosurgery Unit, Suite 201, Level 2 One of our long-term goals is to understand the The Australian School of Advanced Medicine detailed structure of the neural networks that 2 Technology Place, Macquarie University NSW 2109 control blood pressure and breathing. To do this Australia we are working with collaborators at the University T: +61 (0)2 9812 3800 of Melbourne and Macquarie University to develop E: [email protected] viral tracers that can be used to trans-synaptically label single neurons, targeted in electrophysiology experiments similar those described above, or Professional Overview populations of neurons selected according to the behavioural properties or neurochemical content. Areas of Clinical Interest These experiments use a combination of Prof Stoodley’s two major interest areas are (a) adeno-associated, lentiviral (LV) and G-deleted rabies Cerebrovascular neurosurgery for cerebral aneurysms to chart the sources of synaptic drive received by and stroke (including bypass surgery and carotid these populations. endarterectomy), and (b) management of moyamoya disease. In addition, he has a keen research interest in management of Chiari malformation, syringomyelia, and spinal cord tumours. Professor Stoodley has over 100 publications in leading journals, and has attracted over $3 million in research funding. Prof Stoodley also maintains an active clinical workload, and is a leading surgical expert in his areas of research interest.

Research Interest and PhD Projects

Current Research Projects ƒƒ Pathophysiology of syringomyelia: Following on from work demonstrating that cerebrospinal fluid (CSF) flows from the spinal subarachnoid space into syringes via perivascular spaces, current research is examining fluid origins and flow in models of syringomyelia. ƒƒ Developing new treatments for brain arteriovenous malformations: This project involves an analysis of endothelial molecular changes in arteriovenous malformations in an animal model and in humans. The aim is to augment the efficacy of radiation in the treatment of these lesions, by using vascular targeting.

26 The Australian School of Advanced Medicine Opthalmology & Animal models – with Dr Yuyi You (Research Fellow) ƒƒ Development of a rat model of optic neuritis with Vision science optic nerve micro-injection ƒƒ Development of a rat model of glaucoma with Professor Stuart L Graham microbead injection Professor: Ophthalmology and Vision Science ƒƒ BDNF+/- mice (with Uni Melbourne) The Australian School of Advanced Medicine, ƒƒ Akita mice (diabetes – with Uni WA) Macquarie University ƒƒ Implantable electrode recording for VEPs MBBS, MS, PhD (University of Sydney), FRANZCO Electrophysiology and psychophysics ƒƒ The Multifocal VEP/ERG in glaucoma, optic neuritis Contact Details and retinal disease T: +61 (0)2 9812 3933 or 9812 3542 ƒƒ Novel electrophysiological techniques including E: [email protected] binocular simultaneous recording, high resolution stimuli and selective pathway mfVEPs. Professional Overview ƒƒ The mfVEP tracking recovery and predicting Professor Graham is a practicing Ophthalmologist, progression of optic neuritis in multiple sclerosis specialising in Glaucoma and Clinical Electrophysiology. ƒƒ Wireless technology for electrophysiology He has raised over $3million in research and industry ƒƒ Structure /function relationship in glaucoma funding, and been awarded numerous Fellowships ƒƒ Early detection of glaucoma – comparison of and peer-reviewed awards. Prof Graham has over one new technologies hundred publications in the past 13 years, and 123 in total. His area of clinical interest is in developing and Imaging reviewing techniques for early diagnosis of glaucoma ƒƒ High resolution OCT in glaucoma and using new technologies including high-resolution retinal disease. retinal imaging, electrophysiology and psychophysical ƒƒ High resolution MRI imaging (incl DTI tractography) testing. He has extensive experience with lasers in optic neuritis - relationship to axonal loss in glaucoma treatment, including Selective Laser Trabeculoplasty (SLT). ƒƒ Development of a high speed high resolution imaging system for assessing the retinal circulation

Area of Research Interests ƒƒ Functional MRI in glaucoma (with A/Prof Williams – Macquarie University) Prof Graham works with his team on several project areas, all of which are able to support PhD students. Vascular – with Dr Mojtaba Golzan (Research Fellow) Please contact Prof Graham if you are interested in ƒƒ Characteristics of arterial pulse waves, arterial joining his team as a PhD student. stiffness, blood pressure and their relationship to ocular disease Molecular Biology – with Dr Vivek Gupta ƒƒ Measurement of dynamic retinal vascular changes in (Research Fellow) vivo – autoregulation in the retina ƒƒ Neurotrophin signalling in the retina with emphasis ƒƒ Retinal changes in congenital heart disease (with on TrkB receptor signalling axis Prof Celemejer – RPAH) ƒƒ Use of rat models and mice genetic manipulations ƒƒ Measurement of spontaneous venous pulsation at to study signalling proteins affecting retinal cell the optic disc – (with Prof Morgan, Perth) survival in pathological conditions ƒƒ Non-invasive estimation of CSF pressure using ƒƒ Investigating the molecular effects of increased retinal venous pulsation intra-ocular pressure on the retina, in rodents ƒƒ Studying the membrane protein biology with Corneal emphasis on post-translational modifications of the ƒƒ Corneal biomechanics in keratoconus, cross-linking caveolar proteins in glaucoma ƒƒ Changes in corneal thickness and hysteresis ƒƒ Cell biology and molecular biology to study in glaucoma potential neuroprotective molecules

Email: [email protected], [email protected], [email protected], or [email protected] for further information about the following research projects.

The Australian School of Advanced Medicine 27 Contact us T: +61 (0) 2 9812 3547 F: +61 (0)2 9812 3600

E: [email protected]

medicine.mq.edu.au

28 The Australian School of Advanced Medicine The Australian School of Advanced Medicine 29