Centenary Institute Honours, Masters & PhD Student Projects 2020
Cover This booklet contains the list of projects that will be supervised at Centenary Institute in 2020.
If you have any questions of a general nature, please contact Sonya, our Student Recruitment Officer. Email: [email protected] Phone: 02 9565 6141
Using this booklet Projects listed are run through either of the following Discipline at University of Sydney:
●●Project that is run through the Discipline of Infectious Disease and Immunology, University of Sydney ●●Project that is run through the Discipline of Pathology, University of Sydney ●●Project that is run through the School of Life Sciences, UTS Contents
Introduction Masters
About Centenary 4 Gene & Stem Cell Therapy – Dr Bijay Dhungel 25
Facilities and Equipment 6 Gene & Stem Cell Therapy – Dr Dannel Yeo 25
Meet our researchers – Program Heads 7 Centre for Inflammation – Dr Jaesung Peter Choi 26
Meet our researchers – Laboratory Heads 11 Molecular Cardiology – A/Prof Jodie Ingles 26
ACRF Translational Cancer Research – Dr Joyce Chiu 26
Honours Liver Enzymes in Metabolism & Inflammation – Prof Mark 27 Gorrell with Dr Emma Zhang Gene & Stem Cell Therapy – Dr Bijay Dhungel 15 Mycobacterial – Dr Stefan Oehlers 28 Gene & Stem Cell Therapy – Dr Chuck Bailey 15 Gene & Stem Cell Therapy – Dr Ulf Schmitz 29 Gene & Stem Cell Therapy – Dr Dannel Yeo 16 Tuberculosis Research – Prof Warwick Britton, Dr Mainthain 30 Centre for Inflammation – Dr Jaesung Peter Choi 17 Palendira and Dr Diana Quan
Vascular Biology – Prof Jenny Gamble 17
Molecular Cardiology – A/Prof Jodie Ingles 17 PhD
ACRF Translational Cancer Research – Dr Joyce Chiu 17 Gene & Stem Cell Therapy – Dr Dannel Yeo 33
Liver Enzymes in Metabolism & Inflammation – Prof Mark 18 Centre for Inflammation – Dr Jaesung Peter Choi 33 Gorrell with Dr Emma Zhang Vascular Biology – Prof Jenny Gamble 33 Liver Immunology – A/Prof Patrick Bertolino 19 Molecular Cardiology – A/Prof Jodie Ingles 34 Molecular Cardiology – Dr Richard Bagnall 19 ACRF Translational Cancer Research – Dr Joyce Chiu 35 Centre for Inflammation – Dr Sj Sijie Shen 20 Liver Enzymes in Metabolism & Inflammation – Prof Mark 35 Mycobacterial – Dr Stefan Oehlers 20 Gorrell with Dr Emma Zhang
Gene & Stem Cell Therapy – Dr Ulf Schmitz 21 Centre for Inflammation – Prof Phil Hansbro 36
Tuberculosis Research – Prof Warwick Britton, Dr Mainthain 23 Centre for Inflammation – Dr Sj Sijie Shen 37 Palendira and Dr Diana Quan Mycobacterial – Dr Stefan Oehlers 37
Gene & Stem Cell Therapy – Dr Ulf Schmitz 38
Student Research Projects for 2020
3 ABOUT CENTENARY
At the Centenary Institute, researchers for those who wish to further develop their research are bringing renewed health and hope to skills. Australians and people around the world. Location There are other benefits to joining Centenary and the We are home to world-leading researchers in cancer first is location. Our building is in the very heart of the and heart disease. And we are at the forefront of what Camperdown-Ultimo health and education precinct - this is arguably the most exciting emerging area of medical consisting of an active and geographically condensed research today: inflammation and the host of chronic hub of research, teaching, training and industry diseases that it drives. organisations specialising in medicine and healthcare. Campus life is also close at hand with Centenary located Our mission is to increasingly gain a fundamental on the very border of the University of Sydney and right understanding of these diseases — the causes and next door to the newly established ‘Charles Perkins effects, the intricacies and complexities, the threats Centre’, a multidisciplinary research centre committed and predictors. We then look to develop innovative to improving global health outcomes. This means that treatments and cures with the goal of improving health at Centenary you will be at the very center of the latest outcomes and saving lives. and most up to date medical research taking place in Australia, our geography facilitating potential linkages As an independent and internationally recognised and collaboration opportunities - plus you’ll be close to all Medical Research Institute the Centenary Institute of the advantages that University life has to offer. has state-of-the-art facilities and researchers at the top of their field, Centenary offers a perfect balance of challenge and support that will enable you to expand Affliation your skills and knowledge as you consider your future in Critically, the Centenary Institute is also closely affiliated science. with both the Royal Prince Alfred Hospital and the University of Sydney. Many of our senior researchers Notably the Centenary Institute has a long history of are specialist clinicians at the hospital and lecturers at helping students graduate with 1st Class Honours, an the University. This provides Centenary students and extensive PhD program and Post-doctorate opportunities post-doctorates with a ready-made network consisting of
Student Research Projects for 2020
4 some of the brightest minds in basic, applied and clinical Symposiums. The committee, in addition, assists the medical research. At Centenary we know that connection Student Committee with any educational initiatives and and collaboration is key - both to success in the mentoring initiatives that would further enhance student present and to a successful future too. Benefit from the life at Centenary. knowledge, the contacts and the professional expertise that our leading researchers can provide. Inclusion and Gender Equity Program Our Inclusion and Gender Equity Program provides a Life at Centenary forum for staff to raise and discuss issues relating to We have a collegiate approach to student engagement inclusion and gender equity and champions initiatives and offer a number of initiatives to improve, encourage that will help support and progress equity at the and support the education of our students. Centenary Institute.
Social Committee Student Committee The Social Committee organises events to encourage The Student Committee advises on student related intra-institutional relationships within the Centenary issues, coordinates events and engages with supervisors Institute. Annual events include a Welcome Reception and potential students to promote student opportunities for new staff, Harmony Day Potluck Lunch, Winterfest, and recruitment at Centenary. Trivia Night, Christmas Party and Christmas BBQ. Centenary Postgraduate Network Education Committee The Centenary Postgraduate Network (CPN) is a group The Education Committee’s general purpose is to built by, and for, Centenary Institute PhD students that provide advice on the education strategy for the Institute. aims to identify issues and activities of importance It also plans, coordinates and implements activities that to postgraduate students, and to find and generate assist in the continuing education and development of resources. Meeting once a month to share information, Centenary researchers and support staff. discuss technical, organisational, and other issues, and to offer support to members. Masters and Honours The Education Committee coordinates the regular students pursuing PhD studies are invited to participate. seminar series within the Institute, develops and delivers public lectures and also helps organise Colloquia and
Student Research Projects for 2020
5 ABOUT CENTENARY
Facilities systems are equipped with high precision stages, high At the Centenary Institute you will be able to access quality objectives, and some are equipped with cameras. state-of-the-art research equipment, some of which are the only ones available in the southern hemisphere. Intravital Microscopy Hands-on as well as theory training is provided to all Our most advanced microscopes available are the three Honours, Masers and PhD students by experienced LaVision Biotech multi-photon imaging stations that can facility staff. be used for deep tissue image in vitro or in vivo. These systems are the only ones in Australia that can utilise up Flow Cytometry to three different femto-second laser sources. Our many BD Analysers allow you to take quantitative measurements of thousands of individual cells or Software particles. The 10-Laser LSR you can even differentiate For the analysis of flow cytometry data, we provide up to 20 different parameters within a single cell, which is access to the FlowJo Single Cell Analysis Software. something only very few labs in the world are able to do. Images are used to analyse and observations quantified We also have the CyTOF is a mass cytometer, which is in order to generate meaningful outcomes. We provide the first instrument of its kind in Australia. access to a wide range of Image Analysis softwares.
Imaging Cytometry Animal House The advantage of using the Imaging Cytometry is to The Animal Facility is responsible for providing quality analyse a large amount of cells (high throughout) in a animals for research. Comprised of the Animal Facility consistent and unbiased manner. The newly installed Manager, the Animal Facility Officer, Animal Technicians AMNIS ImageStream X Mk2 allowing many hundreds of and Animal Attendants, the staff perform routine cell images can be captured per second. husbandry and welfare checks, as well as procedures training and researcher service requests. Microscopy Our imaging systems include the Leica SP5 Confocal, Zebrafish Facility the LAS Matrix Screener software and a water immersion Our 100 tank zebrafish facility is stocked with a range pump allow for high content screening even when of transgenic and mutant zebrafish concentrated on the performing long-term live cell imaging. The other imaging investigation of inflammation and vascular biology.
Student Research Projects for 2020
6 MEET OUR RESEARCHERS
Program Heads His work has made internationally important contributions and led to the identification of novel avenues for therapy that are under further study. This is being achieved Professor Philip Hogg through the development of novel mouse models that recapitulate the hallmark features of human disease, Head of ACRF Centenary including infections, asthma and COPD and now Cancer Research Centre lung cancer. He employs these models in integrated approaches, with particular expertise in lung function Additional roles: analysis, to understand human diseases, and to develop Sydney Catalyst Chair in Translational Cancer Research new treatment strategies. Research outcomes have Philip Hogg has received many accolades in his a translational goal and his studies are conducted in distinguished research career – including the 2009 parallel with collaborative human studies with clinical Premier’s Award for Outstanding Cancer Researcher. researchers.
In partnership with the Australian Cancer Research Foundation and Sydney Catalyst, the ACRF-Centenary Cancer Research Centre expands the capabilities Dr Justin Wong of Centenary’s cancer research stream. Its goal is to Head of Epigenetics and RNA understand the link between diet, metabolism and Biology Program tumour initiation and development at a molecular level, and to design new therapies using this knowledge. It has Justin Wong currently holds a fellowship awarded by the four core strategic aims: i) making key discoveries about Cancer Institute of NSW. He completed his PhD in the disease mechanisms; ii) their effective translation into the area of cancer epigenetics in the laboratory of Professor clinic; iii) catalyzing medical research by collaborations Robyn Ward at the UNSW Sydney. He is an active and iv) local and international recognition. member of the Australasian Genomics Technologies Association (AMATA) and the RNA Society. Prof Philip Hogg graduated with a PhD in biochemistry from the University of Queensland in 1987. Following His program focuses on deciphering novel gene post-doctoral training in the USA and Sweden he returned regulation mechanisms in normal biology and cancer. He to UNSW as a NHMRC RD Wright Fellow. He is now a is passionate about determining the control of processes NHMRC Senior Principle Research Fellow and was the such as alternative splicing and RNA modification in inaugural director of the Lowy Cancer Research Centre cells. His vision is to acquire knowledge concerning at UNSW. He has won several national and international epigenetic changes, alternative splicing and RNA awards for his research, which focuses on a fundamental modification, which may be useful for the development of chemical modification of proteins he has discovered. This novel therapies for human diseases, especially cancers. research has led to a potential new cancer diagnostic and a therapeutic that are currently in clinical testing. Professor John Rasko AO Head of Gene and Stem Cell Professor Philip Hansbro Therapy Program Director of Centenary UTS Centre for Inflammation John Rasko AO is a clinical hematologist, pathologist and scientist with a productive track record in gene Philip Hansbro is an internationally recognised research and stem cell therapy, experimental haematology and leader in the study of respiratory diseases, such as molecular biology. asthma, chronic obstructive pulmonary disease (COPD, aka emphysema) and infections and is developing In over 150 publications he has contributed to the interests in lung cancer. His work is substantially understanding of stem cells and haemopoiesis, contributing to understanding the pathogenesis and the gene transfer technologies, oncogenesis, human development of new therapies for these diseases. aminoacidurias and non-coding RNAs.
Student Research Projects for 2020
7 MEET OUR RESEARCHERS
His program is focused on better understanding his research as is investigating how we can manipulate regenerative medicines to develop effective treatments the immune system for more infective strategies against for cancer, heart disease and genetic diseases. melanoma and common skin infections, for example Regenerative medicine is the process of replacing or caused by “golden staph”. regenerating human cells, tissues or organs to restore or establish normal function. Professor Mark Gorrell In the laboratory, he is identifying the triggers that Head of Liver Enzymes in switch genes on and off in cancer cells with the long- Metabolism and Inflammation term goal of developing new cancer therapies. By Program integrating Centenary’s bioinformatics expertise into targeted research areas, he has significantly increased Mark Gorrell trained in cell biology, virology, immunology the outcomes of his research in the laboratory. His and protein biochemistry at ANU, the University of research has discovered new ways to target blood Melbourne and Johns Hopkins University. cancer. It has also identified key nutrient pumps, which are vital to the growth of prostrate cancer cells. Using His research is focussed upon liver scarring and these discoveries and the knowledge of how cancer cancer prevention and treatment, chronic liver cells work, he is striving towards better therapeutics for disease pathogenesis, diabetes, protein and enzyme the treatment of cancer. biochemistry and cell biology related to the proteases DPP4, DPP9 and fibroblast activation protein (FAP).
His research experience also includes small RNA Professor Wolfgang Weninger viruses, transcriptomics, proteomics and cell biology. His Head of Immune Imaging research was important in the development of DPP4- Program targetted therapies for type 2 diabetes, which are now used to treat millions of patients. Inside the Centenary Additional roles: Institute, he chairs the postgraduate research and Honorary Professor of Dermatology, Dermatology, Central Clinical equipment grants committees, is Academic Advisor School, University of Sydney for postgraduate research and is a Commercialisation Chair of Dermatology at MedUni Vienna Committee member. Outside the Centenary Institute, Wolfgang Weninger is a preeminent clinician scientist in he is active in the International Proteolysis Society, the fields of dermatology and immunology. the Gastroenterological Society of Australia, NHMRC grant reviews, and editorial boards of Journals including He is a pioneer in the uncovering of immune cell Scientific Reports. behaviour during anti-pathogen and anti-tumour immune responses in the skin using intravital imaging technology. He is recognised for discovering several unique immune Associate Professor Patrick cell subsets and determining their function in the context Bertolino of immune-mediated pathology. Joint Head of Liver Immunology Program His ongoing work is aimed at understanding the mechanisms underlying skin allergies, and the pathways Patrick Bertolino is considered one of the leading experts resulting in successful immunity against skin infections in Liver Immunology internationally, and is acknowledged as well as melanoma. He is also using high end imaging as the leader in this field in Australia. technologies, like multi-photon microscopy, to dissect in real-time the working of the immune system in the skin. He has worked in the same field for the last 20 years The Centenary Institute houses one of Australia’s leading in internationally recognised research institutes, and imaging facilities to enable this research. has been trained by first class immunologists. During this time, he has developed unique transgenic mouse The pathogenesis of several inflammatory skin diseases models and has acquired a leading reputation in liver such as psoriasis and atopic dermatitis is also a target of immunology. This reputation derives from original
Student Research Projects for 2020
8 landmark papers that have transformed the field, and are Upon completion of his postdoctoral training at the now part of current paradigms. These include the first University of Oxford in 1986 as a CJ Martin Fellow, demonstration of naïve CD8 T cell activation in the liver, he returned to Sydney where he developed the basic the first evidence of direct interaction between circulating research program for the AW Morrow Gastroenterology T cells and hepatocytes, the role of intrahepatic T and Liver Centre at the Royal Prince Alfred Hospital of cell activation in tolerance, and the discovery that which he is now the Director. liver-activated T cells are deleted in the lysosomes of hepatocytes. His current research interests include the immunopathogenesis of human chronic liver disease, liver autoimmunity, liver transplant tolerance and Dr David Bowen molecular analysis of hepatitis C virus. His clinical research interests include treatment of hepatitis B and Joint Head of Liver C, management of hepatocellular cancer and long term Immunology Program outcomes of liver transplantation. Addtional roles: His overaching goal is to understand the pathways at the Associate Professor Medicine, Central Clinical School, University cellular and molecular levels that drive liver injury and of Sydney cancer. David Bowen is a Gastroenterologist and Associate Professor of Medicine, Central Clinical School at the University of Sydney. Professor Peter Hersey His research program is helping to improve our Head of Melanoma Oncology understanding of the liver and its impact on immune and Immunology responses, both wanted and unwanted. Although the liver’s tolerance effect leads to better outcomes in Peter Hersey has extensive experience in both clinical transplantation, it can be detrimental during infections and laboratory based research on melanoma. He has such as hepatitis B, hepatitis C and malaria. These held positions as a staff specialist and as Research diseases can use the liver as a means of persisting, Director at the Newcastle Melanoma Unit and Conjoint which can often lead to chronic infection. Professor of Oncology in the University of Newcastle and the Inaugural Chair of Melanoma Biology at the Dr Bowen is also providing some important clues to University of Sydney from 2011. improve the success of human gene therapy. Having already shown that the liver, like the lymph nodes, can His translational research activities have involved activate T cells, a key cell of the immune system, he is phase I-III trials of immunotherapy in melanoma, with now investigating how the liver induces immune tolerance modified peptide antigens and dendritic cell vaccines. and how immunity can be enhanced in this organ. He has taken a leading role in studies on properties of melanoma cells that make them resistant to treatment and devised new treatment approaches to overcome Professor Geoff McCaughan these properties. Head of Liver Injury and He is generally recognized as a pioneer of Cancer Program immunotherapy for melanoma in Australia and in focusing on properties of melanoma cells that make Additional roles: them resistant to apoptosis. He has participated in most A W Morrow Professor in Medicine of the key clinical trials on immunotherapy with immune Medicine, Central Clinical School checkpoint inhibitors. He is a member of the Melanoma Geoff McCaughan leads the Liver Injury & Cancer Research Institute of Australia and has received Program at the Centenary Institute, which covers continuous funding from the NHMRC for his research. Molecular Hepatology, Liver Cell Biology and Alcoholic Current interest centers on the role of epigenetic Liver Disease. regulators in progression and treatment of melanoma.
Student Research Projects for 2020
9 MEET OUR RESEARCHERS
His Program is interested in obtaining a detailed 3D Professor Chris Semsarian AM structural and functional understanding of the proteins involved in human iron distribution. By determining the Head of Molecular Cardiology structures of proteins involved in these processes, he Program aims to be able to provide a scaffold for the development of drugs that can effectively ‘tune’ their function and thus Additional roles: provide new treatments for patients. In particular he is Professor of Medicine, University of Sydney interested in new therapeutics for patients with Anemia of Cardiologist, Royal Prince Alfred Hospital (RPAH), Sydney Chronic Disease. NHMRC Practitioner Fellow Chris Semsarian leads the Molecular Cardiology In humans the acquisition and distribution of iron is Program and is a cardiologist with a specific research required for a range of vital cellular processes, such focus in the genetic basis of cardiovascular disease. as generation of red blood cells. Errors in the proteins involved in iron distribution can cause a range of disease He trained at the University of Sydney, Royal Prince states, such as cancer and anemia (reduced levels of Alfred Hospital, and Harvard Medical School. A red blood cells). By understanding membrane protein focus area of his research is in the investigation and anatomy, structure and function, A/Prof Jormakka hopes prevention of sudden cardiac death in the young, to facilitate a structure-based drug discovery. particularly amongst children and young adults. He has an established research program at the Centenary Studies have also shown that 30-80% of cancer patients, Institute and is at the interface of basic science, clinical 25-50% of chronic kidney disease patients, and between research and public health, with the ultimate goal to 20-90% of acute and chronic infections are associated prevent the complications of genetic heart diseases in with anemia. Every day his research comes one step our community. closer to finding a cure. He is progressing his aim for the “perfect” drug to treat ACD, with the development of He has published over 150 peer-reviewed scientific pharmaceutical compounds. publications, in the highest-ranking cardiovascular and general medical journals. He is also been the primary supervisor of over 30 PhD, honours, and medical honours students since 2003, and is an active member Professor Warwick Britton AO of the mentoring program at the University of Sydney. Head of Tuberculosis Research Program He uses an integrated translational approach in human families, murine models, and cell culture systems. Additional roles: His research has elucidated the genetic causes of Bosch Professor of Medicine and Professor of Immunology cardiomyopathies and sudden death, identified key Medicine Central Clinical School, University of Sydney signaling pathways involved in development of disease, Research Director, Sydney Local Health District and provided a platform for this knowledge to be directly Warwick Britton has been an international leader in the translated to cardiovascular medicine by improved study of mycobacterial infections, he has built a thriving diagnostic and risk stratification strategies. His research research and teaching program at the University of has led to the reduction of both mortality and morbidity in Sydney and has been at the forefront of clinical research, families with genetic heart diseases. education and clinical care for more than four decades.
Recently, he initiated new collaborative research Associate Professor Mika programs in Vietnam on improving the control of Jormakka tuberculosis and on immunogenetics of tuberculosis. Head of Structural Biology Program Since 1997 his group has used an aerosol model of infection with virulent M. tuberculosis in a dedicated Mika Jormakka is widely recognised as a leader in the PC3 facility in the Centenary Institute. This has allowed field for membrane proteins. them to analyse the cellular and cytokine control of
Student Research Projects for 2020
10 M. tuberculosis infection in the lungs using genetically Laboratory Heads modified mice and to develop novel subunit and recombinant BCG vaccines to prevent infection with M. Dr Renjing Liu tuberculosis. In addition his group has identified a new secreted enzyme of M. tuberculosis, which is a novel Head of Agnes Ginges target for drug development. He also has a longstanding Laboratory for Diseases of the research interest in the epidemiology and immunology Aorta of asthma, and established a long running cohort on childhood asthma in 1982. Renjing Liu has held many prestigious Fellowships and Awards from the USA and Australia in the field of cardiovascular research.
Professor Jennifer Gamble Her laboratory has identified a new stem cell mediated Head of Vascular Biology pathway in the regulation of smooth muscle cells. She Program is focused on the epigenetic regulation of miRNAs in cardiovascular diseases, looking at the identification Additional roles: of a novel biomarker for the earlier detection of Wenkart Chair of Endothelium cardiovascular events and deciphering the role of a novel Medicine, Central Clinical School, University of Sydney gene in protecting against aortic aneurysms. Jennifer Gamble is an internationally recognised research leader in the field of endothelial cell function Recent advanced work demonstrating the ability to and holds the Inaugural Wenkart Chair of the turn adult cells to stem cells has opened up exciting Endothelium and leads the Vascular Biology Program. avenues for disease modelling. This is particularly true for the study of diseases where tissue samples are Her interests lie in understanding endothelial cell near-impossible to obtain for research. Utilising this function particularly in the area of inflammation and how technique, she will derive patient-specific stem cells to dysfunction can influence disease. Her initial publication study complex diseases in the cardiovascular system. in this area established the endothelium as a dynamic These resultant cell lines will represent a unique cellular organ, central to the control of inflammatory processes. source for modelling complex diseases that can faithfully Diseases being investigated by her program include capture human disease and provide the first steps to cancer, atherosclerosis, metabolic disease, oedema and improved understanding of the cause of many disease thoracic aortic aneurysms. and its potential treatments.
The current studies in the Vascular Biology Program are Clinical Associate Professor under four broad areas: Understanding ageing of the endothelium and its impact on vascular function; Novel Devanshi Seth regulators of angiogenesis; MicroRNA regulation of Head of Alcoholic Liver oedema and angiogenesis; and Diseases of the Disease Laboratory Aorta focussing on thoracic aortic aneurysms which Additional roles: affect 1:500 to 1:1000 people and which can result in Principal Scientist, Drug Health Services, Royal Prince Alfred sudden death. Hospital Clinical Associate Professor, Clinical Medicine & Addiction Medi- cine, University of Sydney (USYD) Devanshi Seth established this liver diseasea research program as a response to this often neglected area of human health. She is an internationally known leader in the alcohol/liver field, and she leads the NIH/NIAAA-funded study on genetics of alcoholic liver cirrhosis (ALC) using genome/exome sequencing.
Student Research Projects for 2020
11 MEET OUR RESEARCHERS
She is the founder and leader of the multinational Associate Professor Jodie GenomALC Consortium which has established the Ingles world’s largest database and bio-bank of thousands of chronic heavy drinkers, a signficant resource for current Head of Clinical Cardiac and future research in the field of alcohol/liver research. Genetics Laboratory
Additional roles: Recently she was elected as Treasurer of the Research National Coordinator, Australian Genetic Heart Disease Registry Society on Alcoholism (RSoA), a unique association in the world on alcohol research. Dr Seth is also an Jodie Ingles is an NHMRC Career Development Executive member of the University of Sydney Human Fellow and is a cardiac genetic counsellor, Cardiology Research Ethics Committee (HREC 1). She is also on Department Royal Prince Alfred Hospital Sydney, and the Research Executive Committee at the Drug Health, Associate Professor, Faculty of Medicine and Health, RPAH and is the lead investigator on a UK Biobank University of Sydney. project with access to UK Biobank one of the largest databases of genetic and clinical information on 500,000 She has more than 15 years experience working with patients. patients and families with genetic heart diseases. Her research focuses on the clinical, genetic and psychosocial aspects of care of these families, and she has more than 100 publications in these areas. She Dr Xiangjian Zheng co-leads two important national initiatives, the Australian Head of Cell Signalling Genetic Heart Disease Registry and the Australian Laboratory Cardiac Genetic Testing Network. She was recently awarded the Cardiovascular Research Network (CVRN) Xiangjian Zheng is a member of the Faculty of Medicine Rising Star Ministerial Award and an NHMRC Excellence at the University of Sydney and obtained his PhD in Award for the top ranked career development fellowship Molecular Medicine from Medical College of Georgia, in 2018 (clinical, level 1). where he studied lipid signalling in skin biology and endocrine control of blood pressure control. Dr Ulf Schmitz He continued his research in lipid signalling as a Research Fellow, then used the combination of zebrafish Head of Computational modelling and lipidomics approaches to investigate BioMedicine lipid-mediated signalling in angiogenesis and cancer biology. After that he became more focused on human Ulf Schmitz has an appointment as Conjoint Senior vascular diseases. Lecturer at the Sydney Medical School.
His current research focuses on molecular mechanisms His laboratory develops integrative workflows combining of cardiovascular development and diseases. His various computational disciplines with experimentation laboratory in exploring how blood vessels and hearts to address questions around non-coding RNAs, post- form and how they maintain their function at molecular transcriptional gene regulation and cancer biology. and cellular levels. Using machine learning, mathematical modelling, This has important implications in many human disease and molecular dynamics simulations he investigates states such as congenital vascular diseases, stroke, mechanisms of post-transcriptional gene regulation. He cancer, wound healing, diabetic complications, coronary found that synergistic target regulation by microRNAs artery diseases and vascular dementia. is a widespread phenomenon of post-transcriptional gene regulation – a mechanism that can be exploited to sensitize aggressive tumour cells to chemotherapy.
He also develops multi-omics data analysis pipelines to investigate patterns of alternative splicing and other
Student Research Projects for 2020
12 forms of gene regulation in normal biology and in moving to Sydney to start an independent laboratory at various cancers. the Centenary Institute.
He has also identified intron retention as a well He primarily seeks to understand how pathology- conserved form of alternative splicing that mediates associated changes to the vasculature affect cell-specific gene regulation. Aberrant intron retention inflammation. He has an extensive publication record in has been described in multiple human cancers. He the fields of mycobacterial infection and inflammatory aims to identify regulators and consequences of intron bowel disease, with additional interests in atherogenesis retention as well as cross-talk with other forms of post- and diseases with a shared granuloma-like pathotype. transcriptional gene regulation. Associate Professor Anthony Dr Mainthan Palendira Don Head of Human Viral Head of Lipid Metabolism and and Cancer Immunology Neurochemistry Laboratory Laboratory Anthony Don leads has an interest in the modern field of Mainthan Palendira is a Senior Lecturer in the chemical biology. After completing a PhD in biochemistry Department of Infectious Diseases and Immunology at and molecular pathology at UNSW Sydney in 2004, the University of Sydney. he then undertook postdoctoral research at Scripps Research Institute, California. His laboratory focuses on human immunology research with a particular interest in cancers and viral infections. His laboratory uses sophisticated mass spectrometry He is interested in understanding how the human methods in combination with genetic models to immune system normally controls Epstein Barr Virus, investigate how lipid signalling molecules control and to what extent it contributes to disease. Effective myelination in normal development and normal control of infections and cancers relies on coordinated ageing, and how these processes are dysregulated trafficking of T cells into tissues. in neurodegenerative diseases, such as Alzheimer’s Disease, Frontotemporal Dementia, and Multiple His recent work has not only identified resident Sclerosis. Modern research is increasingly showing memory T cells in different human tissues, but has also that changes to brain lipid metabolism are causative demonstrated that there is strategic retention of these in age-related dementia. His research is generating a cells at sites of possible reinfection. Understanding greater understanding of how lipid signalling molecules how T cells are retained within tissues, at the sites of and myelin lipid metabolism regulates healthy brain continuing exposure to viruses, is critical not only for function and how the signalling metabolite sphingosine future vaccine strategies, but also for the prevention of T 1-phosphate will drive the development of new cell mediated immunopathology. therapeutics to promote remyelination and restore brain function in neurodegenerative conditions.
Dr Stefan Oehlers His research group is the first in the world to have developed potent and specific inhibitors of specific Head of Immune-vascular ceramide synthase enzymes, which are the enzymes Interactions Laboratory that catalyse ceramide synthesis. He is creating these inhibitors to open up the international research Stefan Oehlers is currently a University of Sydney Fellow community’s understanding of a key aspect of with the Marie Bashir Institute and a holder of a NSW physiological metabolism, and with a view to creating Health Early-Mid Career Fellowship. new drugs to treat obesity and diabetes.
He trained with zebrafish as a model of human immunity at the University of Auckland (PhD) and Duke before
Student Research Projects for 2020
13 Honours Projects
Take your first step into a career in medical research with Centenary. Housing state of the art imaging, cytometry and animal facilities, you will hone new skills and learn the latest techniques from internationally renowned researchers whilst building the foundations for a future that could see you make breakthroughs that save lives.
“You go into the lab not knowing what’s going to work. Nine times out of 10 it doesn’t work, but then the one time it does, it really hits you and it’s what keeps you hooked. But even when it’s wrong, that helps steer you in the right direction.”
Stuart Cook Former Honours Student Research Assistant, Melanoma Oncology & Immunology Program
Stuart started at Centenary at the beginning of 2017 as an Honours Student, and is now a Research Assistant in Professor Peter Hersey’s Melanoma Oncology & Immunology Program.
centenary.org.au/students genetically deleted at high rates in the most aggressive Dr Bijay Dhungel and deadly types of endometrial cancer (Marshall, Gene & Stem Cell Therapy: John Rasko et al., 2017). CTCF deletion predominantly occurs in [email protected] the Type II serous subtype of endometrial cancer and 0404867910 is associated with poorer overall survival in patients with serous tumours. Additionally we have shown that ●●Identification of host factors involved in CTCF deletions also occur in the clear cell subtype AAV transduction and this may be associated with tumour relapse and/ or metastasis. Our culturing of endometrial cancer Adeno associated viruses are the most widely used gene cell-lines as 3D spheroids has shown that a functional therapy vectors at the moment with approval for use in consequence of CTCF deletion in results in a loss of cell humans from multiple regulatory authorities. Although polarity – an early event in endometrial cancer pathology. we have a basic understanding of how AAV interacts Analysis of gene expression data in CTCF heterozygous with the host and expresses encoded transgene, there endometrial tumours has revealed a widespread are lots of unanswered questions. This project will be dysregulation of transcription. In this project we will undertaken in the lab of Australian gene therapy pioneer those examine genes and biochemical pathways that Prof John Rasko and will be aimed at filling the gaps are dysregulated in CTCF mutant endometrial cancers in our current understanding of the process of AAV including tumour suppressor genes and hormone- transduction. responsive genes.
Multiple genome-wide gain and loss of function studies School at USyd: Pathology have identified several host factors that play an essential role in AAV transduction. Using a range of molecular Keywords: Mammalian cell culture, spheroid culture, and cell biological techniques, this project will identify retroviral gene transfer, RT-qPCR, cell biology assays, what step of AAV transduction is affected by these shRNA knockdown or CRISPR/Cas9 gene editing, flow host factors. Additionally, strategies will be designed to cytometry, Western blotting, mouse work (Ctcf+/- mice), modulate expression levels of these factors and effect on immunofluorescence AAV transduction will be examined. Furthermore, novel genome-wide screening approaches will be applied in a ●●The role of MGA mutation in chronic range of cell types to identify novel determinants of AAV transduction. lymphocytic leukaemia (CLL) Chronic lymphocytic leukaemia (CLL) is the most School at USyd: Pathology common leukaemia in senior Australians. Every year nearly 1000 Australians are diagnosed with CLL and Keywords: Gene therapy, Adeno associated virus, typically 80% of all new diagnoses are in patients over the age of 60 years. CLL is a slow developing cancer affecting B cells. Genetic mutations acquired in these B cells result in their transformation into cancerous cells that can live longer and grow faster than normal B cells. Genetic alterations in CLL can be heterogeneous, and include point mutations, chromosomal deletions, Dr Chuck Bailey amplifications and rearrangements. Recent reports have Gene & Stem Cell Therapy: John Rasko identified the gene encoding the transcription factor Max [email protected] Gene Associated (MGA) to be recurrently deleted in 02 95656171 CLL. MGA inactivation through chromosomal deletion (del15q15) or point mutation occurs in 4% of CLL, but ●●Understanding the role of CTCF genetic this increases to 16% as CLL disease progresses to deletion in aggressive endometrial cancer chemotherapy resistance. Our hypothesis is that genetic inactivation of MGA promotes chronic lymphocytic CTCF is an essential gene for the normal organisation leukaemia disease progression. We will test this of DNA in cells. Our team has discovered that CTCF is hypothesis by analysing how acquired genetic lesions in
Research Projects for 2020
15 HONORS PROJECTS
MGA alter the proliferation, differentiation and survival of CLL cells and contribute to cellular transformation and Dr Dannel Yeo chemoresistance. Gene & Stem Cell Therapy: John Rasko [email protected] School at USyd: Pathology 95656286
Keywords: Cloning, mammalian cell culture, ●●Circulating Tumour Cells in Cancer Patients retroviral gene transfer, cell biology assays, flow Our Program is focused on new cell therapies (CAR-T cytometry, Western blotting, immunofluorescence, cell immunotherapies) for two of the most deadly immunoprecipitation, CRISPR/Cas9, RT-qPCR, next cancers, pancreatic cancer and mesothelioma, which generation sequencing, mouse handling have 5-year survival rates of less than 10%. Circulating tumour cells (CTCs) are cells that have been released ●●Receptor identification of AAV capsids from the primary tumour tissue into the bloodstream used in gene therapy and undergo a migratory process to form metastases. Recombinant adeno-associated virus (rAAV) has Capturing and analysing these rare cells is now possible gained widespread use as a gene delivery vector for using our newly established RareCyte® platform. We corrective gene therapies due to its ability to safely are able to identify, isolate and culture CTCs. Hence, this and efficiently deliver a genetic payload into a broad platform has the potential to provide ‘real-time’ cancer range of tissues. World-first clinical trials, conducted by monitoring throughout all stages of a patient’s cancer a team of clinicians including Professor Rasko, used journey and identify potentially effective treatments. rAAVs carrying the Factor IX gene to successfully infuse haemophilia B patients (George, et al., 2017). Recent Possible research topics: Characterising CTCs using efforts have improved the transduction efficiency of genetic, cellular and imaging techniques; Evaluating rAAV vectors by engineering capsids with higher affinity the ability of circulating tumour cells to predict patient or cell-specific tropism and increased resistance to the response; Evaluating cellular therapies to patient-derived host immune system. Yet, a third avenue for increasing CTC cultures; Evaluating circulating ‘precursor tumour’ AAV-mediated therapeutic efficacy remains unexplored: cells as a possible diagnostic marker to improve early modulation of the receptors to increase AAV entry. It is detection. this third approach with vast potential that we will focus on in this project. We will use structural, biochemical, Skills/tools: Mammalian cell culture (3D), cell biology genetic and proteomic strategies to functionally assays, western blot, microscopy, single cell sequencing, characterise the host determinants that permit entry drug assay/screening, mouse models. of human liver-specific AAV capsids. The overall goal is to test the hypothesis that modulation of receptor School at USyd: Pathology expression can improve gene transfer efficiency in clinically relevant circumstances. Keywords: Cancer, Liquid Biopsy, Circulating Tumour cells, CAR-T cell therapy School at USyd: Pathology
Keywords: Mammalian cell culture, retroviral gene transfer, cell biology assays, CRISPR/Cas9 gene editing, flow cytometry, confocal imaging, Western blotting, immunofluorescence, RT-qPCR, mass spectrometry
Research Projects for 2020
16 ageing and the age-associated genes on the function of Dr Jaesung Peter Choi endothelial cells and on the initiation and progression of Centre for Inflammation: Phil Hansbro Alzheimer’s Disease. [email protected] 0410588161 Techniques: High resolution imaging, animal models, molecular and cell biology techniques, isolation of cells ●●Finding safe and effective therapies from brain blood vessels, single cell transcriptomics, targeting sex hormones and the microbiome single cell proteomics for stroke in cerebral cavernous malformation School at USyd: Pathology Cerebral cavernous malformation (CCM) is a disease of the brain blood vessels and is one of the major Keywords: Alzheimer’s Disease, Heart Disease, causes of stroke in young individuals. Interestingly, CCM Vascular, Single cell RNA sequencing burden is greater in the male population, suggesting a previously under-appreciated role of sex hormones in its pathogenesis. My research program aims to understand the role of sex hormones in CCM pathogenesis and identify new druggable targets for patients with CCM.
School at UTS: School of Life Sciences A/Prof Jodie Ingles Molecular Cardiology: Jodie Ingles Keywords: Stroke, sex hormones, microbiome, [email protected] inflammation, mouse 02 95656293
●●Genotype-phenotype correlations in inherited heart diseases Genetic testing for inherited heart diseases is increasingly used. The current knowledge of the full Prof Jenny Gamble phenotype-spectrum of inherited heart diseases is Vascular Biology: Jenny Gamble incompletely understood. The Agnes Ginges Centre for [email protected] Molecular Cardiology is a world-leader in understanding 02 9565 6225 clinical, genetic and psychosocial aspects of these diseases. This project seeks to define the clinical ●●Alzheimer’s Disease and Endothelial Cell characteristics of patients with certain underlying genetic diagnoses, including describing the clinical course, Ageing interpretation of genetic variants, analysis of the location The evidence is now strong, both from animal and of the variant and familial inheritance. The project will human studies, that breakdown of the Blood Brain involve contact with patients and families enrolled in Barrier (BBB) is a causative factor in Alzheimer’s the Australian Genetic Heart Disease Registry, learning Disease, with the disruption of the BBB and changes in principles of interpreting genetic variants and clinical the blood vessels preceding cognitive decline. data analysis.
Endothelial cells are the first-line of the BBB and are also School at USyd: Pathology essential for maintaining the barrier integrity of blood vessels. When we age, endothelial cells change their Keywords: genetic, heart disease, inheritance, barrier characteristics. We have identified major changes genotype, phenotype. in the genes of ‘aged’ endothelial cells, with many of these genes linked to Alzheimer’s Disease.
The project will involve understanding the impact of
Research Projects for 2020
17 HONORS PROJECTS
●●Patient-Centred approaches to care for to thrombosis. Understanding how platelet activation is families with inherited heart diseases controlled will lead to development of novel therapies for treatment of thrombosis and related diseases. We have Uncertainty is a key aspect of cardiac genetics at present. discovered a novel redox switch in a platelet receptor While in many cases we aim to minimise uncertainty, that controls platelet activation and clot formation. increasingly there is greater need for improved ways Using cell-based assays, flow cytometry, fluorescence to communicate with patients allowing more informed microscopy and mass spectrometry, this project will decision making. The Agnes Ginges Centre for Molecular determine how this redox switch controls protein-protein Cardiology is a world-leader in understanding clinical, interactions and signaling events in clot formation. genetic and psychosocial aspects of these diseases. Two important areas of clinical importance at present are: School at USyd: Pathology (1) communicating genetic information to patients and facilitating subsequent communication to at-risk relatives, Keywords: blood clot, cardiovascular diseases, and (2) for those deemed to be an increased of sudden inflammation, platelet, cell signaling, proteomics, flow cardiac death, conveying this risk information in a way cytometry, FRET/BRET analysis that allows balanced discussion of the benefits and harms of treatment options can be a challenge. This project ●● will involve contact with patients and families enrolled in Live imaging the effects of an integrin the Australian Genetic Heart Disease Registry, learning disulphide switch in whole animal models of principles of shared-decision making and assessing thrombosis interventions in the clinical setting, and clinical data (Joint supervision with Dr Elinor Hortle from the Oehlers lab) analysis. Our body relies on cell surface receptors to convey external stimuli to cellular responses. Integrins are cell Pathology School at USyd: surface adhesion molecules that connect extracellular environment to intracellular signalling. Integrins are Heart disease, cardiac genetics, cardiology, Keywords: crucial in virtually all biological processes including clinical data analysis wound healing, inflammation, cell migration, and embryonic development. Therapeutics have been developed to block integrin function for treatment of cancer, multiple sclerosis, rheumatoid arthritis, and heart diseases. However, many of these therapeutics are toxic with severe side effects Understanding how integrin Dr Joyce Chiu function is regulated will enable precision targeting of ACRF Translational Cancer Research: ACRF specific integrins. We have identified a disulphide bond in an integrin that controls its activation and subsequent Phil Hogg cell adhesion. Using zebrafish genetics, intravital [email protected] microscopy and mass spectrometry, this project will 02 8627 4852 elucidate how this disulphide bond controls cell adhesion in zebrafish thrombocytes. You will also have the ●●Redox regulation of platelet receptors in opportunity to perform drug screen that target integrin clot formation function in zebrafish embryos using the thrombocyte adhesion assay developed in this project. The formation of blood clots is a physiological process essential for wound healing upon injury. However, School at USyd: Pathology in thrombosis, clot formation inside a blood vessel can obstruct blood flow to the downstream tissue. Keywords: integrin, cancer, inflammation, drug screen, Thrombosis is the precipitating event in heart attacks, zebrafish, live imaging, proteomics ischaemic stroke and coronary heart syndrome. Platelets are effector cells for blood clotting. Upon injury, resting platelets become active and aggregate to form a clot at the site of injury. Hyperactivation of platelets can lead
Research Projects for 2020
18 2. Pathogenesis of chronic liver injury from any cause. Prof Mark Gorrell with Dr Emma Zhang Liver Enzymes in Metabolism & 3. Understanding and better treatment of liver cirrhosis Inflammation: Mark Gorrell and cancer. [email protected] 61295656152 4. Protein biochemistry and inhibitors of DPP4 family proteases. ●●Liv DPP9 in Liver Disease and Cancer. TRAINING: We use sophisticated techniques in Primary liver cancer is the 3rd leading cause of cancer immunohistochemistry, flow cytometry, qPCR, related deaths and there is an urgent need to develop immunoblotting, protease assays, ELISA and confocal improved medical therapy. Proteases are important microscopy. Projects can be in mouse models or with in cancer pathogenesis and suit drug development. specimens from RPA hospital. Dipeptidyl peptidase (DPP) 9 is a rapidly emerging cancer associated protease that is expressed in School at USyd: Pathology hepatocytes and macrophages. DPP9 inhibition has shown anti-cancer actions in AML[1] and lung cancer. Keywords: cirrhosis, NASH, cancer, liver, DPP4, We made the first DPP9 gene knockout mice and we fibrosis, mouse, human use liver cancer models [2]. We will use new ways to understand, treat and study liver cancer [3].
TRAINING: The student will use sophisticated techniques in immunohistochemistry, flow cytometry, qPCR, immunoblotting, protease assays and confocal microscopy. A/Prof Patrick Bertolino Liver Immunology: Patrick Bertolino REFERENCES: [email protected] 02 9565 6186 1. Johnson et al 2018 DPP8/DPP9 inhibitor-induced pyroptosis for treatment of acute myeloid leukemia. Nat ●●Role of CD4 help in shaping the response Med 24:1151-6 of CD8 T cells recognising a liver-expressed 2. Henderson et al 2018 Multiple liver insults synergize antigen to accelerate experimental hepatocellular carcinoma. Sci Our group is recognised internationally for its Rep 8:10283 contributions to liver immunology. Using a variety of transgenic mouse models, we were the first to 3. Wilson et al 2019 Non-invasive fluorescent monitoring demonstrate that high affinity naïve CD8 and CD4 T of ovarian cancer in an immunocompetent mouse model. cells can be directly activated in the liver independently Cancers 11:E32 of lymphoid tissues, a unique process that promotes tolerance. This property might explain why liver School at USyd: Pathology transplants are spontaneously accepted in many animal models and why pathogens infecting the liver, Keywords: Liver diseases, inflammation, cancer, mice such as the hepatitis B and C viruses evade immune responses, leading to chronic infection and inflammation. ●●Liver and Enzymes To understand how CD4 and CD8 T cells recognising We discuss with each student their interests, skills and an antigen in the liver “talk” to each other and whether aspirations in order to design a suitable project within low affinity CD8 T cells are more dependent on CD4 these topics. help than high affinity CD8 T cells, we have generated several recombinant adeno-associated viral vectors 1. Liver complications of diabetes and chronic fatty liver. (rAAV) specifically targeting different proportions of hepatocytes to express wild type and mutant forms of the
Research Projects for 2020
19 HONORS PROJECTS
model antigen ovalbumin (OVA) with or without a CD4 epitope. The aim of this project is to use these vectors Dr Sj Sijie Shen to determine how cognate CD4 help and CD8 T cell Centre for Inflammation: Phil Hansbro affinity influence the development of CD8 T cells towards [email protected] tolerance or memory 0295656198
School at USyd: Pathology ●●Modulating microbiome during lung inflammation Keywords: T cells, CD4 T cell help, T cells, immunity, liver pathogens, hepatocytes, tolerance. A full understanding of the immune responses and progressions of many lung diseases, including severe steroid resistant (SSR) asthma, and lung cancer is still lacking. Recent studies suggest the bacterial community in the gut (gut microbiome) and lungs (lung microbiome) may play important roles in modulating inflammatory diseases. Indeed, there is growing interest in the gut-lung Dr Richard Bagnall axis, and how modulating the gut environment can alter Molecular Cardiology: Bioinformatics and the progression of lung diseases. However, the specific Molecular Genetics changes in microbiome and whether certain bacteria can alter disease progression is yet to be fully elucidated. [email protected] 0422141374 Prof Phil Hansbro recently established the Centre for Inflammation at Centenary Institute. He has extensive ●●Genetic Basis of Inherited Heart Disease expertise in using a clinically relevant smoking model to The inherited heart diseases are a collection of heart recapitulate lung cancer pathology in mice, in addition to muscle diseases and electrical rhythm disorders. They the use of a mouse model of SSR asthma. Our research can affect people of any age and can lead to heart aims to improve diagnostics and treatments for lung failure or even sudden cardiac death. The inherited heart inflammation. The project examines: 1) changes to the diseases are caused by changes, or variants, in our DNA gut and lung microbiome following lung inflammation; 2) that can be passed from parent to child. While major interplay between the microbiome and immune cells in advances have been made in identifying the genetic lung inflammation; and 3) modulating the gut microbiome causes of inherited heart diseases, current genetic to influence the progression of lung diseases. testing approaches fail to identify a cause of disease for many families. School at UTS: School of Life Sciences
This project seeks to identify novel genetic causes of Keywords: allergy, asthma, cancer, gut, lung, inherited heart disease. Computational approaches will inflammation, microbiome, mucosal immunity be used to search genome sequencing data for variants that directly cause the disease. Identified variants will be validated in the laboratory using standard clinical genetic testing approaches. The genetic findings will be interpreted in the context of available clinical data on family members. You will learn the basic principles of how clinical genetic testing is performed, from bench to bedside, within the world-leading Molecular Cardiology Program.
School at USyd: Pathology
Keywords: Genetic Testing; Bioinformatics; Cardiac Disease
Research Projects for 2020
20 tuberculosis infection. You will use the zebrafish infection Dr Stefan Oehlers model to study the expression and consequences of Mycobacterial: Stefan Oehlers tumour-like gene expression around granulomas. You [email protected] get to test the translational potential of your observations 0295656114 by performing drug intervention experiments.
●●Imaging atherogenesis in a zebrafish School at USyd: Pathology model Atherosclerosis and complications from atherosclerotic plaques are a leading cause of death and disability in Australia. The paradigm of foamy macrophages and lipid accumulation in the walls of blood vessels is well known. However, our understanding of the basic cellular Dr Ulf Schmitz dynamics that take place in atherogenesis has been Gene & Stem Cell Therapy: Ulf Schmitz limited by our ability to image the vessels in which these [email protected] processes take place with appropriate resolution. 02 95656209
The zebrafish model of atherosclerosis is a visually ●●Intron retention-mediated microRNA accessible model of an intact animal that forms spontaneous atheromas. Using live imaging and sponging in cancer experimental tools that have transformed our In a phylogenetic study of intron retention in vertebrate understanding of the tuberculosis granuloma, this project species we have identified a potential role of retained will specifically study the immune cell interactions that introns to act as conserved microRNA (miRNA) sponges occur during early atherosclerosis. You will test novel that are involved in the fine-tuning of global gene therapies. expression regulation (Schmitz et al., 2017).
School at USyd: Infectious Diseases and Immunology miRNAs have dozens to hundreds of targets and intron retention (IR) can affect hundreds or even thousands ●●The immunology of non-immune of expressed genes, depending on cell/tissue type and interventions in the tuberculosis granuloma condition. Both miRNA-induced translation repression or target degradation and IR-induced nonsense-mediated Tuberculosis is now the deadliest bacterial disease decay are concurrent mechanisms of gene expression affecting the world. Our research group uses the control. In addition to that, we have predicted a density of zebrafish model system to complement traditional mouse >100 miRNA response elements per kilobase in retained models of tuberculosis infection by providing a live introns (in human granulocytes). It is therefore important imaging platform to study bacterial pathogenesis. to analyse concurrent and competitive gene expression regulation including the effects of IR/miRNA sponging on Mycobacterial infection results in the formation of a global level. complex aggregates of immune cells known as granulomas, and these can be readily visualised In this project we will identify gene-regulatory network in zebrafish. We have shown granulomas behave modules using a data integration approach to determine like tumours in many ways. We have shown patterns of competitive post-transcriptional gene that angiogenesis (http://dx.doi.org/10.1038/ regulation. Toward this, we will integrate expression nature13967),vascular permeability (http://dx.doi. profiles of miRNAs and genes, IR pattern and predicted org/10.1093/infdis/jiw355), and haemostasis (http:// miRNA–gene interactions, TF–gene interactions, and IR- dx.doi.org/10.1093/infdis/jiz110) aid mycobacterial miRNA sponge interactions. For a selected sub network growth in zebrafish infection models. we will construct a mathematical model of competitive post-transcriptional gene regulation. We will parameterise You will have the opportunity to “Robin Hood” this model using data from in vitro time series experiments additional cutting edge cancer therapies for use against
Research Projects for 2020
21 HONORS PROJECTS
School at USyd: Pathology visualization, database design
Keywords: gene regulation, alternative splicing, ●●A comprehensive alternative splicing competing endogenous RNA, regulatory network analysis in vertebrate species analysis, bioinformatics, systems biology In a phylogenetic study of intron retention in vertebrate species we have identified conserved patterns of intron ●●Development of an Intron Retention retention-mediated gene regulation in granulocytes database (Schmitz et al., 2017). In a large-scale analysis of alternative splicing across 2,500 human tissue samples and cell lines we generated The data generated in this study provide ample a wealth of data regarding gene-, cell type-, tissue-, opportunities for further discoveries in vertebrate and disease-specific intron-retention events (Middleton transcriptomes through the analysis of gene (co)- et al., 2017). This data is in parts accessible through expression, and other forms of alternative splicing. a rudimentary web interface (http://mimirna.centenary. org.au/irfinder/database/). In this project we will develop In this project we will analyse mRNA-sequencing data a sophisticated database and web interface design to form human, mouse, dog, chicken, and zebrafish provide an efficient and rich user experience facilitating granulocytes to determine phylogenetically conserved a rapid success in the hunt for information about intron- and diverging patterns of gene expression and retention. The new IRBase 2.0 will provide data in alternative splicing (including differential exon usage, interactive graphs and customized data retrieval options. mutually exclusive exons, and alternative 3’ and 5’ splice sites). The impact of changes to highly conserved School at USyd: Pathology alternative splicing events in granulopoiesis will be determined in wet lab experiments using gene editing Keywords: alternative splicing, database design, techniques. graphical user interface, data integration, data visualization School at USyd: Pathology
●●A structured analysis of aberrant splicing Keywords: phylogenetics, alternative splicing, pattern in cancer identification, gene editing, molecular biology assays, gene regulation In this project we will retrieve and integrate data from public cancer databases (TCGA, COSMIC, and ICGC). ●●Cooperating microRNAs for cancer The data will be mined for alternative splicing events and associated correlations to gene expression, copy number therapy - a systems medicine approach variations, mutations, as well as clinical data, such as Drug resistance remains one of the most significant therapy response and survival. Analysis results will be problems in cancer therapy and requires a systematic richly annotated by incorporating additional sources of therapeutic approach. In this project, we use an information such as the Gene Ontology, and KEGG, established systems biology approach to design a etc. We will implement an advanced machine learning therapeutic strategy to tackle chemoresistance in approach (deep neuronal networks) for the prediction of aggressive tumours (Lai et al., 2018). We will utilize pairs disease outcomes based on alternative splicing patterns. of cooperating microRNAs as co-adjuvants to sensitize We will disseminate our results in a freely accessible tumour cells to existing anti-cancer drugs. online database of alternative splicing in cancer with a highly effective relational MySQL-based database We will use secondary structure prediction, 3D docking system in the backend. and molecular dynamics simulations as well as kinetic modelling to identify cooperating microRNA pairs School at USyd: Pathology and their synergistic potential in regulating drivers of chemoresistance. We will validate our predictions Keywords: alternative splicing, data integration, experimentally using adenoviral vector-based machine learning, disease outcome prediction, data microRNA transfection, qRT-qPCR, luciferase assays,
Research Projects for 2020
22 western blotting and/or ELISA assays. We will test this strategy by applying a genotoxic drug and a pair of Prof Warwick Britton, Dr Mainthain cooperating microRNAs that repress the expression of Palendira and Dr Diana Quan chemoresistance-genes in order to overcome resistance Tuberculosis Research Program: Warwick in aggressive tumour cell populations. Britton [email protected] Pathology School at USyd: 0414981003
Keywords: systems medicine, chemoresistance, pattern ●● identification, gene editing, molecular biology, gene How granulomas develop during infection regulation, bioinformatics, structural biology, molecular and checkpoint inhibitor therapy? biology assays Tuberculosis, sarcoidosis and leprosy are all characterised by the formation of granulomatous lesions, aggregates ●●Modelling and experimentally perturbing of immune cells which act as a protective response on chemoresistance networks behalf of the host. In the case of TB and leprosy, these contain the mycobacterial infection, while in sarcoidosis, Drug resistance remains one of the most significant the granulomas are an auto-immune inflammatory problems in cancer therapy and requires a systematic response to an unknown trigger. The recent introduction of therapeutic approach. checkpoint inhibitor therapy for cancer that unleashes anti- tumoiur T cells has been associated with immune-adverse In this project, we use a systems biology approach to advents, including the formation of granulomatous design a therapeutic strategy to tackle chemoresistance lesions resembling sarcoidosis. This project will compare in aggressive tumours. We will reconstruct granuloma formation in response to checkpoint inhibitor chemoresistance pathway networks for various therapy and in patients with tuberculosis, sarcoidosis aggressive tumour types by integrating knowledge from and different forms of leprosy to examine the role of the literature and public databases. Using algorithms different pro-inflammatory and regulatory T cell subsets in from graph theory, systems biology we will determine granulomas of different origin. The analysis of granuloma the regulatory cores of our resistance networks as in architecture and immunology will be conducted using two our recently published article in Nature Communications new and powerful techniques, multiparameter immune- (Khan et al., 2017). fluorescence staining and immune-mass cytometry (IMC) using antibodies to cell surface markers and receptors. For the regulatory core networks we will derive The detailed imaging information will be compared by multi-valued logic models that enable us to simulate quantitative statistical analysis. network responses to drug administration (including chemoresistance). The models will be calibrated using School at USyd: Infectious Diseases and Immunology previously generated and publically accessible data on reaction rates characterizing the dynamic interplay of Keywords: Granulomas, Tuberculosis, Leprosy, the components in the network. Time-series proteomics Checkpoint inhibitor therapy experiments will be used to further calibrate our model. Finally, the model will be used to identify molecules that can be used as therapeutic targets to sensitize tumour cells to anti-cancer drugs. In interactive cycles, model predictions will be validated, while new experimental data will be used to further calibrate the model.
School at USyd: Pathology
Keywords: systems biology, mathematical modelling, network modelling (graph theory), mass-spectrometry, immunoblotting
Research Projects for 2020
23 Masters Projects
Progress your research career by taking the next step with a Masters degree through the Centenary Institute. With state-of-the- art equipment, and an internal support system consisting of world- renowned scientists, the Centenary Institute can be the foundation for your promising career.
Our Masters program is designed as a perfect gateway to your PhD and enables you to further your skills on cutting edge flow and imaging machines, while working side by side with researchers at the top of their field. Whatever you desire for your future in science, Centenary can empower you to achieve your goal and help you to get where you want to be.
“It was very exciting to be involved in a project that was at the cutting edge and to work alongside so many inspiring people. But it was not smooth sailing all the way – more often than not, things did not work out the way I expected. Now at the other end of that journey, I can say that I'm more confident in my research abilities and the knowledge that sometimes solutions can be found in the most expected of places.”
Veronika Petrova Former Masters Student Research Assistant, Computational BioMedicine Lab, Gene and Stem Cell Therapy Program
centenary.org.au/students Dr Bijay Dhungel Dr Dannel Yeo Gene & Stem Cell Therapy: John Rasko Gene & Stem Cell Therapy: John Rasko [email protected] [email protected] 0404867910 95656286
●●Identification of host factors involved in ●●Circulating Tumour Cells in Cancer Patients AAV transduction Our Program is focused on new cell therapies (CAR-T Adeno associated viruses are the most widely used gene cell immunotherapies) for two of the most deadly therapy vectors at the moment with approval for use in cancers, pancreatic cancer and mesothelioma, which humans from multiple regulatory authorities. Although have 5-year survival rates of less than 10%. Circulating we have a basic understanding of how AAV interacts tumour cells (CTCs) are cells that have been released with the host and expresses encoded transgene, there from the primary tumour tissue into the bloodstream are lots of unanswered questions. This project will be and undergo a migratory process to form metastases. undertaken in the lab of Australian gene therapy pioneer Capturing and analysing these rare cells is now possible Prof John Rasko and will be aimed at filling the gaps using our newly established RareCyte® platform. We in our current understanding of the process of AAV are able to identify, isolate and culture CTCs. Hence, this transduction. platform has the potential to provide ‘real-time’ cancer monitoring throughout all stages of a patient’s cancer Multiple genome-wide gain and loss of function studies journey and identify potentially effective treatments. have identified several host factors that play an essential role in AAV transduction. Using a range of molecular Possible research topics: Characterising CTCs using and cell biological techniques, this project will identify genetic, cellular and imaging techniques; Evaluating what step of AAV transduction is affected by these the ability of circulating tumour cells to predict patient host factors. Additionally, strategies will be designed to response; Evaluating cellular therapies to patient-derived modulate expression levels of these factors and effect on CTC cultures; Evaluating circulating ‘precursor tumour’ AAV transduction will be examined. Furthermore, novel cells as a possible diagnostic marker to improve early genome-wide screening approaches will be applied in a detection. range of cell types to identify novel determinants of AAV transduction. Skills/tools: Mammalian cell culture (3D), cell biology assays, western blot, microscopy, single cell sequencing, School at USyd: Pathology drug assay/screening, mouse models.
Keywords: Gene therapy, Adeno associated virus, School at USyd: Pathology
Keywords: Cancer, Liquid Biopsy, Circulating Tumour cells, CAR-T cell therapy
Student Research Projects for 2020
25 MASTERS PROJECTS
variants and clinical data analysis. Dr Jaesung Peter Choi Centre for Inflammation: Phil Hansbro School at USyd: Pathology [email protected] 0410588161 Keywords: genetic, heart disease, inheritance, genotype, phenotype, ●●Finding safe and effective therapies targeting sex hormones and the microbiome ●●Patient-Centred approaches to care for for stroke in cerebral cavernous malformation families with inherited heart diseases Cerebral cavernous malformation (CCM) is a disease Uncertainty is a key aspect of cardiac genetics at of the brain blood vessels and is one of the major present. While in many cases we aim to minimise causes of stroke in young individuals. Interestingly, CCM uncertainty, increasingly there is greater need for burden is greater in the male population, suggesting a improved ways to communicate with patients allowing previously under-appreciated role of sex hormones in its more informed decision making. The Agnes Ginges pathogenesis. My research program aims to understand Centre for Molecular Cardiology is a world-leader in the role of sex hormones in CCM pathogenesis and understanding clinical, genetic and psychosocial aspects identify new druggable targets for patients with CCM. of these diseases. Two important areas of clinical importance at present are: (1) communicating genetic School at UTS: School of Life Sciences information to patients and facilitating subsequent communication to at-risk relatives, and (2) for those Keywords: Stroke, sex hormones, microbiome, deemed to be an increased of sudden cardiac death, inflammation, mouse conveying this risk information in a way that allows balanced discussion of the benefits and harms of treatment options can be a challenge. This project will involve contact with patients and families enrolled in the Australian Genetic Heart Disease Registry, learning principles of shared-decision making and assessing interventions in the clinical setting, and clinical data A/Prof Jodie Ingles analysis. Molecular Cardiology: Jodie Ingles [email protected] School at USyd: Pathology 02 95656293 Keywords: Heart disease, cardiac genetics, cardiology, ●●Genotype-phenotype correlations in clinical data analysis inherited heart diseases Genetic testing for inherited heart diseases is increasingly used. The current knowledge of the full phenotype-spectrum of inherited heart diseases is incompletely understood. The Agnes Ginges Centre for Molecular Cardiology is a world-leader in understanding Dr Joyce Chiu clinical, genetic and psychosocial aspects of these ACRF Translational Cancer Research: ACRF diseases. This project seeks to define the clinical Phil Hogg characteristics of patients with certain underlying [email protected] genetic diagnoses, including describing the clinical 02 8627 4852 course, interpretation of genetic variants, analysis of the location of the variant and familial inheritance. The ●●Redox regulation of platelet receptors in project will involve contact with patients and families enrolled in the Australian Genetic Heart Disease clot formation Registry, learning principles of interpreting genetic The formation of blood clots is a physiological process
Student Research Projects for 2020
26 essential for wound healing upon injury. However, perform drug screen that target integrin function in in thrombosis, clot formation inside a blood vessel zebrafish embryos using the thrombocyte adhesion can obstruct blood flow to the downstream tissue. assay developed in this project. Thrombosis is the precipitating event in heart attacks, ischaemic stroke and coronary heart syndrome. School at USyd: Pathology Platelets are effector cells for blood clotting. Upon injury, resting platelets become active and aggregate Keywords: integrin, cancer, inflammation, drug screen, to form a clot at the site of injury. Hyperactivation of zebrafish, live imaging, proteomics platelets can lead to thrombosis. Understanding how platelet activation is controlled will lead to development of novel therapies for treatment of thrombosis and related diseases. We have discovered a novel redox switch in a platelet receptor that controls platelet activation and clot formation. Using cell-based assays, flow cytometry, fluorescence microscopy and mass Prof Mark Gorrell with Dr Emma Zhang spectrometry, this project will determine how this Liver Enzymes in Metabolism & redox switch controls protein-protein interactions and Inflammation: Mark Gorrell signaling events in clot formation. [email protected] 61295656152 School at USyd: Pathology ●●Liv DPP9 in Liver Disease and Cancer. Keywords: blood clot, cardiovascular diseases, inflammation, platelet, cell signaling, proteomics, flow Primary liver cancer is the 3rd leading cause of cancer cytometry, FRET/BRET analysis related deaths and there is an urgent need to develop improved medical therapy. Proteases are important in cancer pathogenesis and suit drug development. ●●Live imaging the effects of an integrin Dipeptidyl peptidase (DPP) 9 is a rapidly emerging disulphide switch in whole animal models of cancer associated protease that is expressed in thrombosis (Joint supervision with Dr Elinor hepatocytes and macrophages. DPP9 inhibition has Hortle from the Oehlers lab) shown anti-cancer actions in AML[1] and lung cancer. We made the first DPP9 gene knockout mice and we Our body relies on cell surface receptors to convey use liver cancer models [2]. We will use new ways to external stimuli to cellular responses. understand, treat and study liver cancer [3]. Integrins are cell surface adhesion molecules that TRAINING: The student will use sophisticated connect extracellular environment to intracellular techniques in immunohistochemistry, flow cytometry, signalling. Integrins are crucial in virtually all biological qPCR, immunoblotting, protease assays and confocal processes including wound healing, inflammation, cell microscopy. migration, and embryonic development. Therapeutics have been developed to block integrin function for REFERENCES: treatment of cancer, multiple sclerosis, rheumatoid arthritis, and heart diseases. However, many of 1. Johnson et al 2018 DPP8/DPP9 inhibitor-induced these therapeutics are toxic with severe side effects pyroptosis for treatment of acute myeloid leukemia. Nat Understanding how integrin function is regulated will Med 24:1151-6 enable precision targeting of specific integrins. We have identified a disulphide bond in an integrin that 2. Henderson et al 2018 Multiple liver insults synergize controls its activation and subsequent cell adhesion. to accelerate experimental hepatocellular carcinoma. Sci Using zebrafish genetics, intravital microscopy and Rep 8:10283 mass spectrometry, this project will elucidate how this disulphide bond controls cell adhesion in zebrafish 3. Wilson et al 2019 Non-invasive fluorescent monitoring thrombocytes. You will also have the opportunity to
Student Research Projects for 2020
27 MASTERS PROJECTS
of ovarian cancer in an immunocompetent mouse model. known. However, our understanding of the basic cellular Cancers 11:E32 dynamics that take place in atherogenesis has been limited by our ability to image the vessels in which these School at USyd: Pathology processes take place with appropriate resolution.
Keywords: Liver diseases, inflammation, cancer, mice The zebrafish model of atherosclerosis is a visually accessible model of an intact animal that forms ●●Liver and Enzymes spontaneous atheromas. Using live imaging and experimental tools that have transformed our We discuss with each student their interests, skills and understanding of the tuberculosis granuloma, this project aspirations in order to design a suitable project within will specifically study the immune cell interactions that these topics. occur during early atherosclerosis. You will test novel therapies 1. Liver complications of diabetes and chronic fatty liver.
School at USyd: Infectious Diseases and Immunology 2. Pathogenesis of chronic liver injury from any cause.
3. Understanding and better treatment of liver cirrhosis ●●The immunology of non-immune and cancer. interventions in the tuberculosis granuloma Tuberculosis is now the deadliest bacterial disease 4. Protein biochemistry and inhibitors of DPP4 family affecting the world. Our research group uses the proteases. zebrafish model system to complement traditional mouse models of tuberculosis infection by providing a live TRAINING: We use sophisticated techniques in imaging platform to study bacterial pathogenesis. immunohistochemistry, flow cytometry, qPCR, immunoblotting, protease assays, ELISA and confocal Mycobacterial infection results in the formation of microscopy. Projects can be in mouse models or with complex aggregates of immune cells known as specimens from RPA hospital. granulomas, and these can be readily visualised in zebrafish. We have shown granulomas behave School at USyd: Pathology like tumours in many ways. We have shown that angiogenesis (http://dx.doi.org/10.1038/ Keywords: cirrhosis, NASH, cancer, liver, DPP4, nature13967),vascular permeability (http://dx.doi. fibrosis, mouse, human org/10.1093/infdis/jiw355), and haemostasis (http:// dx.doi.org/10.1093/infdis/jiz110) aid mycobacterial growth in zebrafish infection models.
You will have the opportunity to “Robin Hood” additional cutting edge cancer therapies for use against Dr Stefan Oehlers tuberculosis infection. You will use the zebrafish infection model to study the expression and consequences of Mycobacterial: Stefan Oehlers tumour-like gene expression around granulomas. You [email protected] get to test the translational potential of your observations 0295656114 by performing drug intervention experiments.
●●Imaging atherogenesis in a zebrafish School at USyd: Pathology model Atherosclerosis and complications from atherosclerotic plaques are a leading cause of death and disability in Australia. The paradigm of foamy macrophages and lipid accumulation in the walls of blood vessels is well
Student Research Projects for 2020
28 ●●Development of an Intron Retention Dr Ulf Schmitz database Gene & Stem Cell Therapy: Ulf Schmitz In a large-scale analysis of alternative splicing across [email protected] 2,500 human tissue samples and cell lines we generated 02 95656209 a wealth of data regarding gene-, cell type-, tissue-, ●● and disease-specific intron-retention events (Middleton Intron retention-mediated microRNA et al., 2017). This data is in parts accessible through sponging in cancer a rudimentary web interface (http://mimirna.centenary. In a phylogenetic study of intron retention in vertebrate org.au/irfinder/database/). In this project we will develop species we have identified a potential role of retained a sophisticated database and web interface design to introns to act as conserved microRNA (miRNA) sponges provide an efficient and rich user experience facilitating that are involved in the fine-tuning of global gene a rapid success in the hunt for information about intron- expression regulation (Schmitz et al., 2017). retention. The new IRBase 2.0 will provide data in interactive graphs and customized data retrieval options. miRNAs have dozens to hundreds of targets and intron retention (IR) can affect hundreds or even thousands School at USyd: Pathology of expressed genes, depending on cell/tissue type and condition. Both miRNA-induced translation repression or Keywords: alternative splicing, database design, target degradation and IR-induced nonsense-mediated graphical user interface, data integration, data decay are concurrent mechanisms of gene expression visualization control. In addition to that, we have predicted a density of >100 miRNA response elements per kilobase in retained ●●A structured analysis of aberrant splicing introns (in human granulocytes). It is therefore important in cancer to analyse concurrent and competitive gene expression In this project we will retrieve and integrate data from regulation including the effects of IR/miRNA sponging on public cancer databases (TCGA, COSMIC, and ICGC). a global level. The data will be mined for alternative splicing events and associated correlations to gene expression, copy number In this project we will identify gene-regulatory network variations, mutations, as well as clinical data, such as modules using a data integration approach to determine therapy response and survival. Analysis results will be patterns of competitive post-transcriptional gene richly annotated by incorporating additional sources of regulation. Toward this, we will integrate expression information such as the Gene Ontology, and KEGG, profiles of miRNAs and genes, IR pattern and predicted etc. We will implement an advanced machine learning miRNA–gene interactions, TF–gene interactions, and approach (deep neuronal networks) for the prediction of IR-miRNA sponge interactions. For a selected sub disease outcomes based on alternative splicing patterns. network we will construct a mathematical model of We will disseminate our results in a freely accessible competitive post-transcriptional gene regulation. We will online database of alternative splicing in cancer with parameterise this model using data from in vitro time a highly effective relational MySQL-based database series experiments system in the backend. School at USyd: Pathology School at USyd: Pathology Keywords: gene regulation, alternative splicing, Keywords: alternative splicing, data integration, competing endogenous RNA, regulatory network machine learning, disease outcome prediction, data analysis, bioinformatics, systems biology visualization, database design
Student Research Projects for 2020
29 MASTERS PROJECTS
●●Cooperating microRNAs for cancer multi-valued logic models that enable us to simulate therapy - a systems medicine approach network responses to drug administration (including chemoresistance). The models will be calibrated using Drug resistance remains one of the most significant previously generated and publically accessible data on problems in cancer therapy and requires a systematic reaction rates characterizing the dynamic interplay of therapeutic approach. In this project, we use an the components in the network. Time-series proteomics established systems biology approach to design a experiments will be used to further calibrate our model. therapeutic strategy to tackle chemoresistance in Finally, the model will be used to identify molecules that aggressive tumours (Lai et al., 2018). We will utilize pairs can be used as therapeutic targets to sensitize tumour of cooperating microRNAs as co-adjuvants to sensitize cells to anti-cancer drugs. In interactive cycles, model tumour cells to existing anti-cancer drugs. predictions will be validated, while new experimental data will be used to further calibrate the model. We will use secondary structure prediction, 3D docking and molecular dynamics simulations as well as kinetic School at USyd: Pathology modelling to identify cooperating microRNA pairs and their synergistic potential in regulating drivers Keywords: systems biology, mathematical modelling, of chemoresistance. We will validate our predictions network modelling (graph theory), mass-spectrometry, experimentally using adenoviral vector-based immunoblotting microRNA transfection, qRT-qPCR, luciferase assays, western blotting and/or ELISA assays. We will test this strategy by applying a genotoxic drug and a pair of cooperating microRNAs that repress the expression of chemoresistance-genes in order to overcome resistance in aggressive tumour cell populations. Prof Warwick Britton, Dr Mainthain School at USyd: Pathology Palendira and Dr Diana Quan Tuberculosis Research Program: Warwick Keywords: systems medicine, chemoresistance, pattern identification, gene editing, molecular biology, gene Britton regulation, bioinformatics, structural biology, molecular [email protected] biology assays 0414981003
●●Modelling and experimentally perturbing ●●Title: How granulomas develop during chemoresistance networks infection and checkpoint inhibitor therapy? Drug resistance remains one of the most significant Tuberculosis, sarcoidosis and leprosy are all problems in cancer therapy and requires a systematic characterised by the formation of granulomatous lesions, therapeutic approach. aggregates of immune cells which act as a protective response on behalf of the host. In the case of TB and In this project, we use a systems biology approach to leprosy, these contain the mycobacterial infection, while design a therapeutic strategy to tackle chemoresistance in sarcoidosis, the granulomas are an auto-immune in aggressive tumours. We will reconstruct inflammatory response to an unknown trigger. The chemoresistance pathway networks for various recent introduction of checkpoint inhibitor therapy for aggressive tumour types by integrating knowledge from cancer that unleashes anti-tumoiur T cells has been the literature and public databases. Using algorithms associated with immune-adverse advents, including from graph theory, systems biology we will determine the formation of granulomatous lesions resembling the regulatory cores of our resistance networks as in sarcoidosis. This project will compare granuloma our recently published article in Nature Communications formation in response to checkpoint inhibitor therapy and (Khan et al., 2017). in patients with tuberculosis, sarcoidosis and different forms of leprosy to examine the role of different pro- For the regulatory core networks we will derive inflammatory and regulatory T cell subsets in granulomas
Student Research Projects for 2020
30 of different origin. The analysis of granuloma architecture and immunology will be conducted using two new and powerful techniques, multiparameter immune- fluorescence staining and immune-mass cytometry (IMC) using antibodies to cell surface markers and receptors. The detailed imaging information will be compared by quantitative statistical analysis.
School at USyd: Infectious Diseases and Immunology
Keywords: Granulomas, Tuberculosis, Leprosy, Checkpoint inhibitor therapy
Student Research Projects for 2020
31 PhD Projects
Embrace the independence to pursue your desire of discovery. With state-of-the-art facilities, and an internationally renowned reputation, the Centenary Institute offers you the support and means to realise your dreams through pioneering breakthroughs and advancing the fight to find a cure.
The Centenary Institute has supported PhD candidates that have gone on to revolutionise medical practice and saving countless lives.
“I had many opportunities to present at a number of scientific meetings locally and abroad, and was successful in gaining awards and prizes for my presentations as well as competitive travel grants to attend these meetings.”
Dr Philip Tong Former PhD Student, Immune Imaging Program
centenary.org.au/students Dr Dannel Yeo Dr Jaesung Peter Choi Gene & Stem Cell Therapy: John Rasko Centre for Inflammation: Phil Hansbro [email protected] [email protected] 95656286 0410588161
●●Circulating Tumour Cells in Cancer Patients ●●Finding safe and effective therapies Our Program is focused on new cell therapies (CAR-T targeting sex hormones and the microbiome cell immunotherapies) for two of the most deadly for stroke in cerebral cavernous malformation cancers, pancreatic cancer and mesothelioma, which Cerebral cavernous malformation (CCM) is a disease have 5-year survival rates of less than 10%. Circulating of the brain blood vessels and is one of the major tumour cells (CTCs) are cells that have been released causes of stroke in young individuals. Interestingly, CCM from the primary tumour tissue into the bloodstream burden is greater in the male population, suggesting a and undergo a migratory process to form metastases. previously under-appreciated role of sex hormones in its Capturing and analysing these rare cells is now possible pathogenesis. My research program aims to understand using our newly established RareCyte® platform. We the role of sex hormones in CCM pathogenesis and are able to identify, isolate and culture CTCs. Hence, this identify new druggable targets for patients with CCM. platform has the potential to provide ‘real-time’ cancer monitoring throughout all stages of a patient’s cancer School at UTS: School of Life Sciences journey and identify potentially effective treatments. Keywords: Stroke, sex hormones, microbiome, Possible research topics: Characterising CTCs using inflammation, mouse genetic, cellular and imaging techniques; Evaluating the ability of circulating tumour cells to predict patient response; Evaluating cellular therapies to patient-derived CTC cultures; Evaluating circulating ‘precursor tumour’ cells as a possible diagnostic marker to improve early detection. Prof Jenny Gamble Skills/tools: Mammalian cell culture (3D), cell biology Vascular Biology: Jenny Gamble assays, western blot, microscopy, single cell sequencing, [email protected] drug assay/screening, mouse models. 02 9565 6225
School at USyd: Pathology ●●Alzheimer’s Disease and Endothelial Cell Keywords: Cancer, Liquid Biopsy, Circulating Tumour Ageing cells, CAR-T cell therapy The evidence is now strong, both from animal and human studies, that breakdown of the Blood Brain Barrier (BBB) is a causative factor in Alzheimer’s Disease, with the disruption of the BBB and changes in the blood vessels preceding cognitive decline.
Endothelial cells are the first-line of the BBB and are also essential for maintaining the barrier integrity of blood vessels. When we age, endothelial cells change their barrier characteristics. We have identified major changes in the genes of ‘aged’ endothelial cells, with many of these genes linked to Alzheimer’s Disease.
The project will involve understanding the impact of
Student Research Projects for 2020
33 PhD PROJECTS
ageing and the age-associated genes on the function of endothelial cells and on the initiation and progression of A/Prof Jodie Ingles Alzheimer’s Disease. Molecular Cardiology: Jodie Ingles [email protected] Techniques: High resolution imaging, animal models, 02 95656293 molecular and cell biology techniques, isolation of cells from brain blood vessels, single cell transcriptomics, ●●Undiagnosed Genetic Heart Disease single cell proteomics Program
School at USyd: Pathology Genetic testing for inherited heart diseases is increasingly used. The current knowledge of the full Keywords: Alzheimer’s Disease, Heart Disease, phenotype-spectrum of inherited heart diseases is Vascular, Single cell RNA sequencing incompletely understood. The Agnes Ginges Centre for Molecular Cardiology is a world-leader in understanding clinical, genetic and psychosocial aspects of these ●●Age and Aortic Valve Calcification diseases. This project seeks to define the clinical Calcific aortic valve disease (CAVD) is the most common characteristics of patients with certain underlying genetic valvular heart disease in developed countries. The diagnoses, including describing the clinical course, incidence of CAVD increases with age. Even moderate to interpretation of genetic variants, analysis of the location severe cases of the disease increase the risks for heart of the variant and familial inheritance. The project will failure and sudden death. involve contact with patients and families enrolled in the Australian Genetic Heart Disease Registry, learning At present there are no drug therapies available for principles of interpreting genetic variants and clinical this disease and we have a limited understanding of data analysis. the underlying molecular and cellular mechanisms of calcification that may help in the development of School at USyd: Pathology therapeutics. The project is aimed at identifying the role of ageing on the endothelial cells and the impact on the Keywords: Genetic testing, heart disease, diagnosis calcification of the valve. ●●Patient-Centred approaches to care for Techniques: in vitro model of ageing and of disease, establishment of animal models of disease. families with inherited heart diseases Uncertainty is a key aspect of cardiac genetics at Analysis of human tissue. Isolation of endothelial cells present. While in many cases we aim to minimise and application to single cell RNA sequencing, Molecular uncertainty, increasingly there is greater need for biology and cell biology, High resolution imaging. improved ways to communicate with patients allowing more informed decision making. School at USyd: Pathology The Agnes Ginges Centre for Molecular Cardiology is Keywords: heart disease, ageing, single cell a world-leader in understanding clinical, genetic and transcriptomics, vascular biology psychosocial aspects of these diseases.
Two important areas of clinical importance at present are: (1) communicating genetic information to patients and facilitating subsequent communication to at-risk relatives, and (2) for those deemed to be an increased of sudden cardiac death, conveying this risk information in a way that allows balanced discussion of the benefits and harms of treatment options can be a challenge. This project will involve contact with patients and families enrolled in the Australian Genetic Heart Disease
Student Research Projects for 2020
34 Registry, learning principles of shared-decision making and assessing interventions in the clinical setting, and Prof Mark Gorrell with Dr Emma Zhang clinical data analysis. Liver Enzymes in Metabolism & Inflammation: Mark Gorrell School at USyd: Pathology [email protected] 61295656152 Keywords: Heart disease, cardiac genetics, cardiology, clinical data analysis ●●Liv DPP9 in Liver Disease and Cancer. Primary liver cancer is the 3rd leading cause of cancer related deaths and there is an urgent need to develop improved medical therapy. Proteases are important in cancer pathogenesis and suit drug development. Dipeptidyl peptidase (DPP) 9 is a rapidly emerging Dr Joyce Chiu cancer associated protease that is expressed in ACRF Translational Cancer Research: ACRF hepatocytes and macrophages. DPP9 inhibition has Phil Hogg shown anti-cancer actions in AML[1] and lung cancer. We made the first DPP9 gene knockout mice and we [email protected] use liver cancer models [2]. We will use new ways to 02 8627 4852 understand, treat and study liver cancer [3].
●●Redox regulation of platelet receptors in TRAINING: The student will use sophisticated clot formation techniques in immunohistochemistry, flow cytometry, The formation of blood clots is a physiological process qPCR, immunoblotting, protease assays and confocal essential for wound healing upon injury. However, microscopy. in thrombosis, clot formation inside a blood vessel can obstruct blood flow to the downstream tissue. REFERENCES: Thrombosis is the precipitating event in heart attacks, ischaemic stroke and coronary heart syndrome. Platelets 1. Johnson et al 2018 DPP8/DPP9 inhibitor-induced are effector cells for blood clotting. Upon injury, resting pyroptosis for treatment of acute myeloid leukemia. Nat platelets become active and aggregate to form a clot at Med 24:1151-6 the site of injury. Hyperactivation of platelets can lead to thrombosis. Understanding how platelet activation is 2. Henderson et al 2018 Multiple liver insults synergize controlled will lead to development of novel therapies for to accelerate experimental hepatocellular carcinoma. Sci treatment of thrombosis and related diseases. We have Rep 8:10283 discovered a novel redox switch in a platelet receptor that controls platelet activation and clot formation. 3. Wilson et al 2019 Non-invasive fluorescent monitoring Using cell-based assays, flow cytometry, fluorescence of ovarian cancer in an immunocompetent mouse model. microscopy and mass spectrometry, this project will Cancers 11:E32 determine how this redox switch controls protein-protein interactions and signaling events in clot formation. School at USyd: Pathology
School at USyd: Pathology Keywords: Liver diseases, inflammation, cancer, mice
Keywords: blood clot, cardiovascular diseases, inflammation, platelet, cell signaling, proteomics, flow cytometry, FRET/BRET analysis
Student Research Projects for 2020
35 PhD PROJECTS
●●Liver and Enzymes to mammalian health and improve health care and We discuss with each student their interests, skills and agriculture outcomes. aspirations in order to design a suitable project within these topics. School at UTS: School of Life Sciences
1. Liver complications of diabetes and chronic fatty liver. ●●Development of new therapies for COPD Emphysema is a major cause of illness and death and 2. Pathogenesis of chronic liver injury from any cause. there are no good treatments. It is caused by smoking that induces lung inflammation and disease. Cellular 3. Understanding and better treatment of liver cirrhosis respiration can become defective causing oxidative and cancer. stress and inflammation and we think that these may drive emphysema. We have developed new treatments 4. Protein biochemistry and inhibitors of DPP4 family that restore cell respiration and stop oxidative stress. proteases. We will assess altered respiration and oxidative stress in emphysema and stop and/or reverse these changes with TRAINING: We use sophisticated techniques in our new therapies. immunohistochemistry, flow cytometry, qPCR, immunoblotting, protease assays, ELISA and confocal School at UTS: School of Life Sciences microscopy. Projects can be in mouse models or with specimens from RPA hospital. ●●Developing new treatments for chronic lung diseases. School at USyd: Pathology Currently, we have 3x full-time postgraduate scholarships Keywords: cirrhosis, NASH, cancer, liver, DPP4, available for suitably qualified candidates with a strong fibrosis, mouse, human Honours degree (or equivalent) in biomedical science, pharmacology, chemistry, biomedical engineering or pharmacy to undertake research studies leading to a PhD.
You will work in an established expert and high profile team that is internationally renowned for their studies of respiratory disease and have much support from Prof Phil Hansbro Post-doctoral fellows, research assistants and technical Centre for Inflammation officers, etc. [email protected] 0427263084 PROJECTS
●●Elucidating the roles of steroid receptors in The main aims of the work involves investigating the pathogenesis and developing new treatments for mitochondria severe asthma and COPD and could involve the study This project aims to elucidate the roles of newly of epigenetic (acetylation, methylation - 2 projects), discovered steroid receptors in the functions of single cell sequencing/RNAseq and multi-omics, roles mitochondria. We will characterise their impact on of innate immunity (Toll-like receptors IFNs, mast cells, cellular respiration, oxidative stress, and the induction inflammasomes). of inflammation. We will define these processes in the healthy state and in response to common environmental The data generated in this study provide ample challenges of infection and smoke exposure. As a opportunities for further discoveries in vertebrate result we will characterise the fundamental biology of transcriptomes through the analysis of gene (co)- entirely new processes of how normal body hormones expression, and other forms of alternative splicing. and administered steroids may function. This may eventually lead to new and more effective ways to School at UTS: School of Life Sciences control inflammation that will have significant benefits
Student Research Projects for 2020
36 Dr Sj Sijie Shen Dr Stefan Oehlers Centre for Inflammation: Phil Hansbro Mycobacterial: Stefan Oehlers [email protected] [email protected] 0295656198 0295656114
●●Modulating microbiome during lung ●●Imaging atherogenesis in a zebrafish inflammation model A full understanding of the immune responses and Atherosclerosis and complications from atherosclerotic progressions of many lung diseases, including severe plaques are a leading cause of death and disability in steroid resistant (SSR) asthma, and lung cancer is still Australia. The paradigm of foamy macrophages and lacking. Recent studies suggest the bacterial community lipid accumulation in the walls of blood vessels is well in the gut (gut microbiome) and lungs (lung microbiome) known. However, our understanding of the basic cellular may play important roles in modulating inflammatory dynamics that take place in atherogenesis has been diseases. Indeed, there is growing interest in the gut-lung limited by our ability to image the vessels in which these axis, and how modulating the gut environment can alter processes take place with appropriate resolution. the progression of lung diseases. However, the specific changes in microbiome and whether certain bacteria can The zebrafish model of atherosclerosis is a visually alter disease progression is yet to be fully elucidated. accessible model of an intact animal that forms spontaneous atheromas. Using live imaging and Prof Phil Hansbro recently established the Centre for experimental tools that have transformed our Inflammation at Centenary Institute. He has extensive understanding of the tuberculosis granuloma, this project expertise in using a clinically relevant smoking model to will specifically study the immune cell interactions that recapitulate lung cancer pathology in mice, in addition to occur during early atherosclerosis. You will test novel the use of a mouse model of SSR asthma. therapies
Our research aims to improve diagnostics and School at USyd: Infectious Diseases and Immunology treatments for lung inflammation. The project examines: 1) changes to the gut and lung microbiome following lung ●●The immunology of non-immune inflammation; 2) interplay between the microbiome and interventions in the tuberculosis granuloma immune cells in lung inflammation; and 3) modulating the gut microbiome to influence the progression of lung Tuberculosis is now the deadliest bacterial disease diseases. affecting the world. Our research group uses the zebrafish model system to complement traditional mouse School at UTS: School of Life Sciences models of tuberculosis infection by providing a live imaging platform to study bacterial pathogenesis. Keywords: allergy, asthma, cancer, gut, lung, inflammation, microbiome, mucosal immunity Mycobacterial infection results in the formation of complex aggregates of immune cells known as granulomas, and these can be readily visualised in zebrafish. We have shown granulomas behave like tumours in many ways. We have shown that angiogenesis (http://dx.doi.org/10.1038/ nature13967),vascular permeability (http://dx.doi. org/10.1093/infdis/jiw355), and haemostasis (http:// dx.doi.org/10.1093/infdis/jiz110) aid mycobacterial growth in zebrafish infection models.
You will have the opportunity to “Robin Hood” additional cutting edge cancer therapies for use against
Student Research Projects for 2020
37 PhD PROJECTS
tuberculosis infection. You will use the zebrafish infection School at USyd: Pathology model to study the expression and consequences of tumour-like gene expression around granulomas. You Keywords: gene regulation, alternative splicing, get to test the translational potential of your observations competing endogenous RNA, regulatory network by performing drug intervention experiments. analysis, bioinformatics, systems biology
School at USyd: Pathology ●●A structured analysis of aberrant splicing in cancer In this project we will retrieve and integrate data from public cancer databases (TCGA, COSMIC, and ICGC). The data will be mined for alternative splicing events and associated correlations to gene expression, copy number Dr Ulf Schmitz variations, mutations, as well as clinical data, such as Gene & Stem Cell Therapy: Ulf Schmitz therapy response and survival. Analysis results will be [email protected] richly annotated by incorporating additional sources of 02 95656209 information such as the Gene Ontology, and KEGG, etc. We will implement an advanced machine learning approach (deep neuronal networks) for the prediction of ●●Intron retention-mediated microRNA disease outcomes based on alternative splicing patterns. sponging in cancer We will disseminate our results in a freely accessible In a phylogenetic study of intron retention in vertebrate online database of alternative splicing in cancer with species we have identified a potential role of retained a highly effective relational MySQL-based database introns to act as conserved microRNA (miRNA) sponges system in the backend. that are involved in the fine-tuning of global gene expression regulation (Schmitz et al., 2017). School at USyd: Pathology miRNAs have dozens to hundreds of targets and intron Keywords: alternative splicing, data integration, retention (IR) can affect hundreds or even thousands machine learning, disease outcome prediction, data of expressed genes, depending on cell/tissue type and visualization, database design condition. Both miRNA-induced translation repression or target degradation and IR-induced nonsense-mediated ●●Title: Modelling and experimentally decay are concurrent mechanisms of gene expression perturbing chemoresistance networks control. In addition to that, we have predicted a density of >100 miRNA response elements per kilobase in retained Drug resistance remains one of the most significant introns (in human granulocytes). It is therefore important problems in cancer therapy and requires a systematic to analyse concurrent and competitive gene expression therapeutic approach. regulation including the effects of IR/miRNA sponging on a global level. In this project, we use a systems biology approach to design a therapeutic strategy to tackle chemoresistance In this project we will identify gene-regulatory network in aggressive tumours. We will reconstruct modules using a data integration approach to determine chemoresistance pathway networks for various patterns of competitive post-transcriptional gene aggressive tumour types by integrating knowledge from regulation. Toward this, we will integrate expression the literature and public databases. Using algorithms profiles of miRNAs and genes, IR pattern and predicted from graph theory, systems biology we will determine miRNA–gene interactions, TF–gene interactions, and the regulatory cores of our resistance networks as in IR-miRNA sponge interactions. For a selected sub our recently published article in Nature Communications network we will construct a mathematical model of (Khan et al., 2017). competitive post-transcriptional gene regulation. We will parameterise this model using data from in vitro time For the regulatory core networks we will derive series experiments multi-valued logic models that enable us to simulate
Student Research Projects for 2020
38 network responses to drug administration (including chemoresistance). The models will be calibrated using previously generated and publically accessible data on reaction rates characterizing the dynamic interplay of the components in the network. Time-series proteomics experiments will be used to further calibrate our model. Finally, the model will be used to identify molecules that can be used as therapeutic targets to sensitize tumour cells to anti-cancer drugs. In interactive cycles, model predictions will be validated, while new experimental data will be used to further calibrate the model.
School at USyd: Pathology
Keywords: systems biology, mathematical modelling, network modelling (graph theory), mass-spectrometry, immunoblotting
Student Research Projects for 2020
39 Where to find Centenary Institute
Centenary Institute
OUR OFFICIAL ADDRESS IS Building 93, RPA Hospital Missenden Road Camperdown 2050
BUT THE EASIEST WAY TO FIND US IS Follow Johns Hopkins Drive, off Missenden Road Or, walk through USyd, we’re next to the Charles Perkins Centre
Student Research Projects for 2020
40 www.centenary.org.au 1800 677 977