Honours, Masters and PhD Student Projects 2021

Cover

The Centenary Institute is located in the Camperdown-Ultimo health precinct with the University of , The and Royal Prince Alfred Hospital as our neighbours.

This booklet contains the projects that will be supervised at Centenary Institute in 2021.

If you have any questions of a general nature, please contact our Student Recruitment Officer.

Email: [email protected] Phone: +61 2 9565 6100

Using this booklet

Projects listed are run through the following Disciplines at the or University of Technology Sydney.

● Discipline of Infectious Disease and Immunology, University of Sydney ● Discipline of Pathology, University of Sydney ● School of Medical Sciences, University of Sydney ● School of Life Sciences, University of Technology Sydney

Contents

About Centenary...... 4-5 Novel treatments of alpha-1 antitrypsin gene deficiency induced Functional strategies to mitigate or eliminate PFAS from human Alzheimer’s Disease: How age effects the blood vessels in the brain chronic obstructive pulmonary disease – Dr Gang Liu...... 26 and animal tissue – Dr Daniel Hesselson...... 37 – Professor Jennifer Gamble...... 49 Facilities and Equipment...... 6 How the cornea responds to UV radiation Understanding the role of extracellular matrix proteins in Calcified aortic valve disease: the role of the ageing Research Programs...... 7 – Associate Professor Guy Lyons...... 27 regulating lung fibrosis – Dr Gang Liu...... 38 – Professor Jennifer Gamble...... 49 Research Laboratories...... 8 Genes and cell-cell interactions in tumour progression Novel treatments of alpha-1 antitrypsin gene deficiency induced Alzheimer’s Disease: How age effects the blood vessels in the – Associate Professor Guy Lyons...... 27 chronic obstructive pulmonary disease – Dr Gang Liu...... 38 Project Supervisors...... 9-17 brain – Professor Jennifer Gamble...... 50

Bidirectional interaction between the cardiovascular system and How the cornea responds to UV radiation Proteases in the pathogenesis of chronic liver injury and cancer Honours...... 18 infectious diseases – Dr Stefan Oehlers...... 28 – Associate Professor Guy Lyons...... 39 – Professor Mark Gorrell...... 50 Molecular modeling of cancer-associated mutations in tumour Characterizing fusion transcripts in cancer and normal cells Genes and cell-cell interactions in tumour progression Blocking follistatin in ovarian cancer to prevent chemoresistance suppressor genes – Dr Chuck Bailey...... 19 – Dr Ulf Schmitz...... 28 – Associate Professor Guy Lyons...... 39 and recurrence – Dr Daniel Hesselson...... 51 Understanding the role of CTCF genetic deletion in aggressive Deciphering the cross-talk between microRNAs and retained Bidirectional interaction between the cardiovascular system and Functional strategies to mitigate or eliminate PFAS from human endometrial cancer – Dr Chuck Bailey...... 19 introns in cancer gene regulation – Dr Ulf Schmitz...... 29 infectious diseases – Dr Stefan Oehlers...... 40 and animal tissue – Dr Daniel Hesselson...... 51 The role of MGA mutation in chronic lymphocytic leukaemia Mirtron synthesis and expression in leukemia – Dr Ulf Schmitz...... 29 Characterizing fusion transcripts in cancer and normal cells Understanding the role of extracellular matrix proteins in (CLL) – Dr Chuck Bailey...... 20 – Dr Ulf Schmitz...... 40 Core transcriptional networks in cell trans-differentiation regulating lung fibrosis – Dr Gang Liu...... 52 Modulation of host entry factors to improve AAV-mediated gene – Dr Ulf Schmitz...... 30 Deciphering the cross-talk between microRNAs and retained Novel treatments of alpha-1 antitrypsin gene deficiency induced therapy – Dr Chuck Bailey...... 20 introns in cancer gene regulation – Dr Ulf Schmitz...... 41 Role of lipid metabolism in alcohol-induced liver cirrhosis chronic obstructive pulmonary disease – Dr Gang Liu...... 52 Investigating the role of monocyte-derived macrophages in liver – Clinical Associate Professor Devanshi Seth...... 30 Mirtron synthesis and expression in leukemia – Dr Ulf Schmitz...... 41 How the cornea responds to UV radiation structure and homeostasis – Associate Professor Patrick Bertolino Modulating the gut microbiome to influence the progression of Core transcriptional networks in cell trans-differentiation and Associate Professor David Bowen...... 21 – Associate Professor Guy Lyons...... 53 lung diseases – Dr Sj Sijie Shen...... 31 – Dr Ulf Schmitz...... 42 How does silica dust make TB worse? Genes and cell-cell interactions in tumour progression Circulating tumour cells to monitor cancer patients Modulating the gut microbiome to influence the progression of – Professor Warwick Britton AO...... 21 – Associate Professor Guy Lyons...... 53 – Dr Dannel Yeo...... 31 lung diseases – Dr Sj Sijie Shen...... 42 Finding safe and effective therapies targeting sex hormones and Bidirectional interaction between the cardiovascular system and Investigating CAR-T therapy for pancreatic cancer Proteases in liver cancer – Dr Hui Emma Zhang...... 43 the microbiome for the commonest cause of stroke in children: infectious diseases – Dr Stefan Oehlers...... 54 – Dr Dannel Yeo...... 32 cerebral cavernous malformation (CCM) – Dr Jaesung Peter Choi.. 22 PhD...... 44 Deciphering the cross-talk between microRNAs and retained Proteases in liver cancer – Dr Hui Emma Zhang...... 32 Imaging transcription at single molecule resolution in a living cell introns in cancer gene regulation – Dr Ulf Schmitz...... 54 Molecular modeling of cancer-associated mutations in tumour – Associate Professor Mathias Francois...... 22 Masters...... 33 suppressor genes – Dr Chuck Bailey...... 45 Core transcriptional networks in cell trans-differentiation Molecular and cellular basis of lymphatic vascular development – Dr Ulf Schmitz...... 55 Molecular modeling of cancer-associated mutations in tumour Understanding the role of CTCF genetic deletion in aggressive – Associate Professor Mathias Francois...... 23 suppressor genes – Dr Chuck Bailey...... 34 endometrial cancer – Dr Chuck Bailey...... 45 Role of lipid metabolism in alcohol-induced liver cirrhosis – Clinical Associate Professor Devanshi Seth...... 55 Alzheimer’s Disease: Determining the role of aged perivascular Understanding the role of CTCF genetic deletion in aggressive The role of MGA mutation in chronic lymphocytic leukaemia (CLL) macrophages in blood-brain barrier dysfunction endometrial cancer – Dr Chuck Bailey...... 34 – Dr Chuck Bailey...... 46 Why do only some drinkers develop liver cirrhosis? – Professor Jennifer Gamble...... 23 Risk stratification of drinkers using genomics+clinical risk factors The role of MGA mutation in chronic lymphocytic leukaemia (CLL) Modulation of host entry factors to improve AAV-mediated gene – Clinical Associate Professor Devanshi Seth...... 56 Alzheimer’s Disease: How age effects the blood vessels in the – Dr Chuck Bailey...... 35 therapy – Dr Chuck Bailey...... 46 brain – Professor Jennifer Gamble...... 24 Modulating the gut microbiome to influence the progression of Modulation of host entry factors to improve AAV-mediated gene How does silica dust make TB worse? Proteases in the pathogenesis of chronic liver injury and cancer therapy – Dr Chuck Bailey...... 35 – Professor Warwick Britton AO...... 47 lung diseases – Dr Sj Sijie Shen...... 56 – Professor Mark Gorrell...... 24 Finding safe and effective therapies targeting sex hormones and Finding safe and effective therapies targeting sex hormones and Circulating tumour cells to monitor cancer patients Blocking follistatin in ovarian cancer to prevent chemoresistance the microbiome for the commonest cause of stroke in children: the microbiome for the commonest cause of stroke in children: – Dr Dannel Yeo...... 57 and recurrence – Dr Daniel Hesselson...... 25 cerebral cavernous malformation (CCM) – Dr Jaesung Peter Choi.. 36 cerebral cavernous malformation (CCM) – Dr Jaesung Peter Choi.. 47 Investigating CAR-T therapy for pancreatic cancer Functional strategies to mitigate or eliminate PFAS from human Proteases in the pathogenesis of chronic liver injury and cancer Imaging transcription at single molecule resolution in a living cell – Dr Dannel Yeo...... 57 and animal tissue – Dr Daniel Hesselson...... 25 – Professor Mark Gorrell...... 36 – Associate Professor Mathias Francois...... 48 Proteases in liver cancer – Dr Hui Emma Zhang...... 58 Understanding the role of extracellular matrix proteins in Blocking follistatin in ovarian cancer to prevent chemoresistance Molecular and cellular basis of lymphatic vascular development regulating lung fibrosis – Dr Gang Liu...... 26 and recurrence – Dr Daniel Hesselson...... 37 – Associate Professor Mathias Francois...... 48 Map...... 59

Student Research Projects for 2021 Student Research Projects for 2021

2 3 ABOUT CENTENARY

At the Centenary Institute, researchers are Campus life is close at hand with our building on the Life at Centenary Centenary Postgraduate Network bringing renewed health and hope to border of the University of Sydney and next door to the We have a collegiate approach to student engagement The Postgraduate Network is a group built by, and for, Australians and people around the world. Charles Perkins Centre, a multidisciplinary research and offer a number of initiatives to improve, encourage Centenary PhD students that aims to identify issues centre committed to improving global health outcomes. and support the education of our students. and activities of importance to postgraduate students, and to find and generate resources. We are home to world-leading researchers in cancer, inflammation and cardiovascular disease. At Centenary you will be at the centre of the latest Education Committee and most-up-to-date medical research taking place in The Education Committee’s general purpose is to Meeting once a month to share information, discuss technical, organisational, and other issues, and to offer As an independent and internationally recognised , our geography facilitating potential linkages provide advice on the education strategy for the support to members. Masters and Honours students Medical Research Institute the Centenary Institute and collaboration opportunities - plus you’ll be close to Institute. It also plans, coordinates and implements pursuing PhD studies are invited to participate. has state-of-the-art facilities and researchers at the all of the advantages that University life has to offer. activities that assist in the continuing education and top of their field. Centenary offers a perfect balance of development of Centenary researchers and support challenge and support that will enable you to expand Affiliation staff. Social Committee The Social Committee organises events to encourage your skills and knowledge as you consider your future Centenary is also closely affiliated with the Royal Prince intra-institutional relationships within the Centenary in science. Alfred Hospital, the University of Sydney and University The Education Committee coordinates the regular of Technology Sydney. Many of our researchers are seminar series within the Institute, develops and Institute. Notably the Centenary Institute has a long history of specialist clinicians at the hospital and lecturers at the delivers public lectures and also helps organise helping students graduate with 1st Class Honours, Universities. Colloquia and Symposiums. an extensive PhD program and Post-doctorate opportunities for those who wish to further develop their This provides Centenary students and post-doctorates Inclusion and Gender Equity Program research skills. with a ready-made network of some of the brightest Our Inclusion and Gender Equity Program provides a minds in basic, applied and clinical medical research. forum for staff to raise and discuss issues relating to inclusion and gender equity and champions initiatives Location that will help support and progress equity at Centenary. There are other benefits to joining Centenary and At Centenary we know that connection and the first is location. We are located in the heart of the collaboration is key - both to success in the present and Student Committee Camperdown-Ultimo health and education precinct - to a successful future too. Benefit from the knowledge, The Student Committee advises on student related consisting of an active and geographically condensed the contacts and the professional expertise that our issues, coordinates events and engages with hub of research, teaching, training and industry leading researchers can provide. supervisors and potential students to promote student organisations specialising in medicine and healthcare. opportunities and recruitment at Centenary.

Student Research Projects for 2021 Student Research Projects for 2021

4 5 ABOUT CENTENARY MEET OUR RESEARCHERS

Research Programs

Professor Phil Hansbro Professor Peter Hersey Centenary Deputy Director Head - Melanoma Oncology and Director - Centenary UTS Centre for Immunology Program Inflammation

Professor Phil Hogg Associate Professor Jodie Centenary Depty Director Ingles Head - ACRF Centenary Cancer Research Head - Cardio Genomics Program Centre

Professor Chris Semsarian AM Associate Professor Mika Centenary Deputy Director Jormakka Head - Molecular Cardiology Program Head - Structural Biology Program

Facilities Intravital Microscopy At Centenary you will be able to access state-of-the- Our most advanced microscopes available are three art research equipment. Hands-on as well as theory LaVision Biotech multi-photon imaging stations that can Associate Professor Patrick Professor Geoff McCaughan training is provided to all Honours, Masters and PhD be used for deep tissue image in vitro or in vivo. These Bertolino Head - Liver Injury and Cancer Program students by experienced facility staff. systems are the only ones in Australia that can utilise Joint Head - Liver Immunology Program up to three different femto-second laser sources. Flow Cytometry Our many BD Analysers allow you to take quantitative Software measurements of thousands of individual cells or For the analysis of flow cytometry data, we provide Professor Warwick Britton AO Professor John Rasko AO particles. The 10-Laser LSR can even differentiate up access to the FlowJo Single Cell Analysis Software. Head - Tuberculosis Research Program Head - Gene and Stem Cell Therapy to 20 different parameters within a single cell, which Images are used to analyse and observations quantified Program is something only very few labs in the world are able in order to generate meaningful outcomes. We provide to do. We also have the CyTOF which is a mass access to a wide range of Image Analysis softwares. cytometer - the first instrument of its kind in Australia. Animal House Associate Professor Mathias Professor Wolfgang Weninger Imaging Cytometry The Animal Facility is responsible for providing quality Head - Immune Imaging Program animals for research. Comprised of highly skilled staff Francois The advantage of using the Imaging Cytometry is Head - David Richmond Laboratory for who perform routine husbandry and welfare checks, to analyse a large amount of cells (high throughout) Cardiovascular Development: Gene in a consistent and unbiased manner. The AMNIS as well as procedures training and researcher service Regulation and Editing Program ImageStream X Mk2 allows many hundreds of cell requests. images to be captured per second. Professor Mark Gorrell Dr Justin Wong Zebrafish Facility Head - Liver Enzymes in Metabolism and Head - Epigenetics and RNA Biology Microscopy Our 100 tank zebrafish facility is stocked with a range Inflammation Program Program Our imaging systems include the Leica SP8 Confocal, of transgenic and mutant zebrafish concentrated on the the LAS Matrix Screener software and a water investigation of inflammation and vascular biology. immersion pump allow for high content screening even when performing long-term live cell imaging. The other Professor Jennifer Gamble imaging systems are equipped with high precision Head - Vascular Biology Program stages, high quality objectives, and some are equipped with cameras.

Visit our website to learn more about our Programs and staff – www.centenary.org.au/our-researchers

Student Research Projects for 2021 Student Research Projects for 2021

6 7 MEET OUR RESEARCHERS

Research Laboratories Project Supervisors

Dr Richard Bagnall Dr Mainthan Palendira Dr Chuck Bailey Associate Professor Patrick Head - Bioinformatics and Molecular Head - Human Viral and Cancer Gene and Stem Cell Therapy Program Bertolino and Associate Genetics Laboratory Immunology Laboratory Professor David Bowen

Liver Immunology Program

Dr David Bowen Dr Yanfei (Jacob) Qi Joint Head - Liver Immunology Program Head - Lipid Cell Biology Laboratory Chuck Bailey trained as a molecular and cellular Patrick Bertolino is considered one of the leading biologist and has nearly 20 years experience in experts in Liver Immunology internationally, and is studying molecular mechanisms of normal biology, acknowledged as the leader in this field in Australia. genetic disease and cancer. In 2001 he joined the Gene and Stem Cell Therapy Program headed by Professor He has worked in the same field for the last 20 years Associate Professor Anthony Dr Ulf Schmitz John Rasko at the Centenary Institute studying the in internationally recognised research institutes, and molecular genetics of human amino acid transporter Don Head - Computational BioMedicine has been trained by first class immunologists. During disorders. His work lead to the discovery of the genetic this time, he has developed unique transgenic mouse Head - Lipid Metabolism and Laboratory causes of 3-of-5 principal inherited amino acid transport Neurochemistry Laboratory models and has acquired a leading reputation in liver disorders in humans. immunology.

Dr Daniel Hesselson Clinical Associate Professor He was appointed as a Senior Research Fellow in 2007 This reputation derives from original landmark Head - Directed Evolution Laboratory and now leads a group within the Program in studying papers that have transformed the field, and are Devanshi Seth the role of transcription factors in cancer causation. now part of current paradigms. These include the Head - Alcoholic Liver Disease Laboratory By understanding fundamental gene regulatory first demonstration of naïve CD8 T cell activation mechanisms in normal biology, he is applying this in the liver, the first evidence of direct interaction knowledge to elucidating aberrant transcription factor between circulating T cells and hepatocytes, the role function in cancer. Dr Stefan Oehlers Dr Xiangjian Zheng of intrahepatic T cell activation in tolerance, and the discovery that liver-activated T cells are deleted in the Head - Immune-vascular Interactions Head - Cell Signalling Laboratory Dr Bailey uses the latest molecular, cellular, genetic Laboratory lysosomes of hepatocytes. and proteomic techniques in his research. Recently, he is applying this approach to improve the gene therapy efficiency of adeno-associated viral vectors. He is examining the pathway of AAV uptake into the cell to identify host entry factors that may participate in this process.

Visit our website to learn more about our Laboratories and staff – www.centenary.org.au/our-researchers

Student Research Projects for 2021 Student Research Projects for 2021

8 9 MEET OUR RESEARCHERS

Associate Professor Patrick Professor Warwick Britton AO Dr Jaesung Peter Choi Associate Professor Mathias Bertolino and Associate Tuberculosis Research Program Centenary UTS Centre for Inflammation Francois Professor David Bowen David Richmond Laboratory for

Liver Immunology Program Car diovascular Development: Gene Regulation and Editing Program

David Bowen is a Gastroenterologist and Hepatologist Warwick Britton is Emeritus Professor of Medicine Peter Choi is an emerging researcher in the field of Mat Francois, heads the David Richmond Laboratory at the AW Morrow Gastroenterology and Liver Centre at the University of Sydney, head of the Tuberculosis cardiovascular research. He received his PhD from the for Cardiovascular Development: Gene Regulation and and the Australian National Liver Transplanation Unit, Research Program at the Centenary Institute, and University of Sydney in 2016 and joined UTS in 2020 Editing at the Centenary Institute. He leads a research RPAH, and the Head of the MD Research Program at Research Director for Sydney Local Health District and with Chancellor’s Postdoctoral Research Fellowship. team with a focus on identifying new and innovative . RPAH. His research focuses on identifying therapeutic therapeutic approaches targeting vascular diseases. targets for the commonest stroke in children: Cerebral His research program is helping to improve our He has longstanding research in the immunology of Cavernous Malformation (CCM). The research activity of the laboratory focuses on the understanding of the liver and its impact on immune mycobacterial infections and the control of tuberculosis transcriptional control of endothelial cell specification responses, both wanted and unwanted. Although and leprosy, including the development of novel His recent work includes development of a novel micro- during vascular development in different organs (heart, the liver’s tolerogenic effects are beneficial in protective vaccines and drugs against TB. He is CT imaging, identified the gut microbiome as a critical skin) during embryogenesis and also during cancer transplantation, they can be detrimental during principal investigator on the NHMRC-funded Centre for stimulant of CCM and repurposed an-FDA approved metastasis. infections such as hepatitis B, hepatitis C and malaria. Research Excellence in Tuberculosis Control on both drug to treat experimental CCM. These diseases can use the liver as a means of sides of the border that promotes TB research and The group is developing a novel approach combining persisting, which can often lead to chronic infection. collaborations, training and translation within Australia developmental genetics (mouse and fish model and the Asia-Pacific, including Vietnam, Indonesia and system), biochemistry, genomics and biophysics Dr Bowen’s work is also providing some important Papua New Guinea. He is involved in ongoing research (molecular imaging using super resolution microscopy) clues to improve the success of human gene therapy in Vietnam and a new MRFF funded project to control to understand and target transcription factors mode and improve outcomes in liver transplantation. Having drug resistant and latent TB in the Pacific (PEARL). of action with small molecule inhibitors. One direct already shown that the liver, like the lymph nodes, outcome of the current research activity is the discovery can activate T cells, a key cell of the immune system, Professor Britton has received continuous research and development of a new class of anti-angiogenic he is now investigating how the liver induces immune funding from the National Health and Medical Research drugs. tolerance and how immunity can be enhanced in this Council of Australia since 1991 and has published 289 organ. papers with >15,000 citations. He has supervised and co-supervised 27 PhD, 2 Masters and 30 Honours David Bowen additional roles research students and mentored 24 post-doctoral scientists on his laboratory. Associate Professor Medicine, Central Clinical School, University of Sydney and Head MD Research Program, Warwick Britton additional roles Sydney Medical School. Research Director, Sydney Local Health District

Emeritus Professor of Medicine, Central Clinical School, University of Sydney

Student Research Projects for 2021 Student Research Projects for 2021

10 11 MEET OUR RESEARCHERS

Professor Jennifer Gamble Professor Mark Gorrell Dr Daniel Hesselson Dr Gang Liu Vascular Biology Program Liver Enzymes in Metabolism and Directed Evolution Laboratory Centenary UTS Centre for Inflammation Inflammation Program

Jennifer Gamble is an internationally recognised Mark Gorrell trained in cell biology, protein Daniel Hesselson heads the Directed Evolution Gang Liu is the leader of fibrosis programme in Centre research leader in the field of endothelial cell function. biochemistry, virology, parasitology and immunology at Laboratory. He trained in Molecular Genetics in Alberta, for Inflammation at Centenary Institute and University She holds the Inaugural Wenkart Chair of the Australian National University, University of Melbourne Canada before completing his PhD in Wisconsin, US. of Technology Sydney (UTS). He is also a lecturer Endothelium and leads the Vascular Biology Program. and Johns Hopkins University. in School of Life Science at UTS to teach year 2 He was a postdoctoral fellow at the University of Immunology Her interests lie in understanding endothelial cell His research is focussed upon liver scarring and California before moving to the Garvan Institute in 2012. function particularly in the area of inflammation and how cancer prevention and treatment, chronic liver disease There his work pursued the experimental advantages of Dr Liu obtained his PhD in immunology and dysfunction can influence disease. Her initial publication pathogenesis, diabetes, and protein and enzyme the zebrafish model system to develop new approaches microbiology at Hunter Medical Research Institute in this area established the endothelium as a dynamic biochemistry and cell biology related to the proteases for tackling the growing diabetes epidemic as laboratory and the University of Newcastle (UoN) in 2016. His organ, central to the control of the inflammatory DPP4, DPP9 and fibroblast activation protein (FAP). Head. PhD study is on tissue remodelling and fibrosis in processes. lung disorders. He did his first postdoc training in the His research was important in the development of He also held the position of Conjoint Lecturer, St same group on mast cell regulate inflammation/airway The current studies in the Vascular Biology Program are DPP4 - targetted therapies for type 2 diabetes, which Vincent’s Clinical School, Faculty of Medicine, UNSW remodelling in COPD. He then started his postdoc under the broad area of “Understanding ageing of the are now used to treat millions of patients. His research Sydney. fellow position from 2017-2019 in priority research endothelium and its impact on vascular function”. One experience includes small RNA viruses, transcriptomics centre for digestive health and nurogastroenterology at of the major diseases being investigated is Alzheimer’s and proteomics. He current research includes SARS- UoN. His research was focusing on understanding of Disease. It is known that changes in the blood brain CoV-2 protein biochemistry. gut-lung axis in mucosal diseases and how microbiota barrier occur early in disease progression with one of changes affects gut diseases, such as inflammatory the changes seen in both humans and mouse models Inside the Centenary Institute, he chairs the bowel disease. of Alzheimer’s Disease (AD) being vascular leak. Her postgraduate research committee, is an Academic team is investigating endothelial cell ageing and how Leader Research Education and is a Commercialisation His current research is to understand the mechanism of this may influence the integrity of the blood brain barrier Committee member. tissue remodelling and fibrosis in different lung diseases and AD progression, with the hope of exposing new and identify novel therapeutic targets of lung fibrotic therapeutic targets. Outside the Centenary Institute, he is active diseases. He also extends the fibrotic studies to the in the International Proteolysis Society, the diseases in other organs, such as liver, kidney and gut. Jennifer Gamble additional roles Gastroenterological Society of Australia, NHMRC grant reviews, and editorial boards of journals including Wenkart Chair of Endothelium Medicine, Central Scientific Reports. Clinical School, University of Sydney.

Student Research Projects for 2021 Student Research Projects for 2021

12 13 MEET OUR RESEARCHERS

Associate Professor Guy Lyons Dr Stefan Oehlers Clinical Associate Professor Dr Ulf Schmitz Immune Imaging Program Immune-vascular Interactions Laboratory Devanshi Seth Computational BioMedicine Laboratory Alcoholic Liver Disease Laboratory

Guy Lyons is a cell biologist who has appointments Stefan Oehlers trained with the zebrafish as a model Devanshi Seth is an internationally recognised Ulf Schmitz has an appointment as Conjoint Senior with the Centenary Institute, University of Sydney and of human immunity at the University of Auckland (PhD) leader in alcohol and liver research. She is a Principal Lecturer at the Sydney Medical School. RPA Hospital. and Duke University (postdoc, supported by an NHMRC Scientist at the Royal Prince Alfred Hospital (RPAH) CJ Martin Fellowship) before moving to Sydney to start and Centenary Institute. In 2008 she established a His laboratory develops integrative workflows His research aims to understand the pathogenesis an independent lab at the Centenary Institute. unique Alcohol-Liver Disease Research Program combining various computational disciplines with of diseases that affect the stratified epithelial tissues in Australia to focus on this critical human health experimentation to address questions around non- that protect us from our environment, including those His Immune-Vascular Interactions Laboratory primarily area using multiple approaches (genetics, clinical, coding RNAs, post-transcriptional gene regulation and that cover the mouth, skin and eye. The mechanisms seeks to understand how pathology-associated cellular, molecular). Dr Seth has >175 publications/ cancer biology. that regulate and enable these epithelial cells to form changes to the vasculature affect inflammation. He presentations, is the recipient of several awards, a multilayered structure are poorly understood, but has an extensive publication record in the fields media releases and radio interviews, funding of >AU$ Using machine learning, mathematical modelling, important to a range of diseases. of mycobacterial infection and inflammatory bowel 6.5mil, including the prestigious National Institutes of and molecular dynamics simulations he investigates disease, with additional interests in atherogenesis and Health (NIH)/National Institute on Alcohol Abuse and mechanisms of post-transcriptional gene regulation. He He has a particular interest in the mechanisms by which diseases with a shared granuloma-like pathotype. Alcoholism (NIAAA), USA and Australia India Strategic found that synergistic target regulation by microRNAs sunlight makes these tissues susceptible to conditions Research Fund (AISRF). is a widespread phenomenon of post-transcriptional such as cancer, corneal blindness and viral infections. Dr Oehlers is currently a University of Sydney Fellow gene regulation – a mechanism that can be exploited to He uses microscopy of living tissues and advanced with the Marie Bashir Institute and a holder of a NSW Dr Seth is the founder and leader of the multinational sensitize aggressive tumour cells to chemotherapy. image analysis methods to investigate these diseases Health Early-Mid Career Fellowship. GenomALC Consortium at the forefront of research in in combination with genetic and molecular analyses. this field. With her leadership, GenomALC established He also develops multi-omics data analysis pipelines the world’s largest database and bio-bank of thousands to investigate patterns of alternative splicing and other of drinkers, a significant global resource for future forms of gene regulation in normal biology and in alcohol/liver research. The group has recently published various cancers. novel genetic and clinical risk factors associated with alcohol-induced cirrhosis in drinkers. He has also identified intron retention as a well conserved form of alternative splicing that mediates Dr Seth champions the Equity Diversity and Inclusion at cell-specific gene regulation. Aberrant intron retention the Centenary Institute (founder & ex-Chair of Gender has been described in multiple human cancers. He Equity Program, current member; USYD (SAGE-SAT aims to identify regulators and consequences of intron member), Research Society on Alcoholism, USA retention as well as cross-talk with other forms of post- (Diversity and Inclusion Committee) and Franklin transcriptional gene regulation. Women (Peer Advisory Committee).

Student Research Projects for 2021 Student Research Projects for 2021

14 15 MEET OUR RESEARCHERS

Dr Sj Sijie Shen Dr Dannel Yeo Dr Hui Emma Zhang Centenary UTS Centre for Inflammation Gene and Stem Cell Therapy Program Liver Enzymes in Metabolism and Inflammation Program

Sj Sijie Shen is a research officer as part of Prof. Philip Dannel Yeo heads the Li Ka Shing Cell and Hui Emma Zhang received a Master of Applied Hansbro’s group at the Centenary Institute/University Gene Therapy Initiative Group which investigates Science in Australian Centre of Microscopy and of Technology Sydney Centre for Inflammation. His liquid biopsies in cancer and undertakes cellular Microanalysis and a PhD in protease and cancer research of interest is in respiratory and gastrointestinal immunotherapy clinical trials in solid cancers. The biology in the University of Sydney. She has over tract diseases, with a major focus on the interaction lab focuses on improving patient management and ten years’ biomedical research experience in various between host immunity and microbiomes. Dr Shen investigating novel treatments using patient samples fields such as Alzheimer’s disease, diabetes, cancer has a special interest in the role diet plays in immune from a range of solid cancers including pancreatic, lung and liver diseases. She trained in cell biology, protein responses and disease progression. and mesothelioma. biochemistry, cancer biology and immunology.

The focus of Dr Shen’s research is on the investigation Dannel received his PhD from the University of Her research seeks to understand the pathogenesis of how the gut and lung crosstalks and communicates Melbourne in cancer cell biology and cancer mouse of liver cancer and to medically exploit the protease- under normal homeostasis and during disease. In models in pancreatic cancer. He then undertook a based approach for the treatment of liver cancer. particular, he wishes to understand how the community postdoctoral position under the direction of Prof Sean She has studied the unique protease named DPP9 of gut bacteria (gut microbiome) affects chronic Grimmond at the University of Melbourne Centre for for eight years and has published many novel and respiratory diseases including severe asthma and Cancer Research where he generated and utilised significant discoveries on DPP9. Her lab has developed chronic obstructive pulmonary disease (COPD). 3D culture organoids from pancreatic cancer patient genetically modified mouse strains and cell lines Furthermore, his research will explore how the gut resected tissue and biopsies for precision and targeting DPP9. Her lab has also established new microbiome can be modified to protect against or treat personalised medicine. liver cancer mouse models to recapitulate human liver these respiratory diseases. cancer development. Dannel also has appointments at the University of Dr Shen’s prior studies have culminated in his current Sydney, Royal Prince Alfred Hospital and Chris O’Brien Hui Emma Zhang has an appointment as Conjoint research. He examined the effects of dietary fibre and Lifehouse. Lecturer at the Faculty of Medicine and Health in the short-chain fatty acids in Allergic Bronchopulmonary University of Sydney. Aspergillosis and Eosinophilic Oesophagitis as part of B.Biomes.Sci (Honours) (Monash University, 2014). In extension, his PhD research assessed the interplay between the gut microbiome and neutrophils in a mouse model of colitis (Monash University, 2019).

Student Research Projects for 2021 Student Research Projects for 2021

16 17 Supervisor: Dr Chuck Bailey Supervisor: Dr Chuck Bailey Gene and Stem Cell Therapy Program: Head - Professor Gene and Stem Cell Therapy Program: Head - Professor Honours John Rasko AO John Rasko AO Projects E: [email protected] E: [email protected] P: +61 2 9565 6171 P: +61 2 9565 6171

● Molecular modeling of cancer-associated ● Understanding the role of CTCF genetic mutations in tumour suppressor genes deletion in aggressive endometrial cancer Take your first step into a career in medical research with the The ‘master weaver’ protein CTCF, is mutated in CTCF is essential for the normal organisation of Centenary Institute. endometrial cancer, as well as colorectal, stomach, DNA in cells. Our team has discovered that CTCF is breast and haemopoietic cancers. Our group was the genetically deleted at high rates in the most aggressive Housing state-of-the-art imaging, cytometry and animal facilities, you will hone new first to demonstrate that the ubiquitous zinc finger and deadly types of endometrial cancer (Marshall, et skills and learn the latest techniques from internationally renowned researchers (ZF) protein CTCF acts as a tumour suppressor gene. al., 2017). CTCF deletion predominantly occurs in the whilst building the foundations for a future that could see you make breakthroughs Missense mutations in CTCF are enriched in the DNA- Type II serous subtype of endometrial cancer and is that save lives. binding ZF region. associated with poorer overall survival in patients with serous tumours. Additionally, we have shown that We have shown that mutations in the ZF region can CTCF deletions also occur in the clear cell subtype result in a loss- or gain-of-function in CTCF, which has and this may be associated with tumour relapse and/or implications for cancer development. We are currently metastasis. modelling ‘hotspot’ mutations on published CTCF ZF structures to assess the impact of those mutations. Our culturing of endometrial cancer cell-lines as 3D In addition, we will develop homology models for the spheroids has shown that a functional consequence of ZF domain of CTCF-Like protein (CTCFL, also known CTCF deletion results in a loss of cell polarity – an early as BORIS). CTCFL which shares 80% homology with event in endometrial cancer pathology. Our analysis CTCF within its ZF domain is aberrantly expressed of gene expression data in CTCF heterozygous in more than half of all cancers. Both factors have endometrial tumours has revealed a widespread overlapping and unique DNA binding characteristics. dysreguation of transcription.

We will examine which residues are critical for binding In this project we will examine those genes and of CTCF and CTCFL to the same DNA target sites and biochemical pathways that are dysregulated in CTCF which ZF residues confer DNA binding specificity. This mutant endometrial cancers. We will investigate the will provide important insight into the sibling rivalry that impact of these genes on cell polarity in 3D spheroids exists between CTCF and CTCFL in normal biology and which will give us important insights into early cancer. pathophysiological events underlying endometrial “Centenary Institute is like a big family, people are very welcoming and friendly cancer. here. During an experiment, you may need to visit different labs for various School at: Pathology equipment, which provides chances to chat with colleagues and make friends. It is School at: Pathology very well organised. I am very happy to be part of it.” Keywords: protein structure, mutation, cancer, transcription factor Keywords: endometrial cancer, mutation, mouse “Centenary is a great place to further explore your interest in science. Research models, cell biology can be challenging, but there’s always someone to help you out at Centenary.”

Carrie Huang, Honours Student and Cecy Xi, PhD Student Liver Enzymes in Metabolism and Inflammation Program

Alphabetical by supervisor surname.

centenary.org.au/students Student Research Projects for 2021

19 HONOURS PROJECTS

Supervisor: Dr Chuck Bailey Supervisor: Dr Chuck Bailey Supervisor: Associate Professor Patrick Supervisor: Professor Warwick Britton AO Gene and Stem Cell Therapy Program: Head - Professor Gene and Stem Cell Therapy Program: Head - Professor Bertolino and Associate Professor David Mycobacterial Program: Head - Professor Warwick John Rasko AO John Rasko AO Bowen Britton AO

Liver Immunology Program: Heads - Associate Professor Patrick Bertolino and Associate Professor David Bowen E: [email protected] E: [email protected] E: [email protected] E: [email protected] P: +61 2 9565 6171 P: +61 2 9565 6171 P: 0402 850 402 P: 0414 981 003

● The role of MGA mutation in chronic ● Modulation of host entry factors to ● Investigating the role of monocyte- ● How does silica dust make TB worse? lymphocytic leukaemia (CLL) improve AAV-mediated gene therapy derived macrophages in liver structure and The lung is one of the most important organs exposed homeostasis Chronic lymphocytic leukaemia (CLL) is the most Recombinant adeno-associated virus (rAAV) has to environmental pollution and pathogens. Lung inflammation and disease is a leading cause of death common leukaemia in senior Australians. Every year gained widespread use as a gene delivery vector for Macrophages play a key immune role but are also and disability globally, and an overlooked area is the nearly 1000 Australians are diagnosed with CLL and corrective gene therapies due to its lack of association considered as key regulators of pathology and healing intersection of silicosis and tuberculosis (TB). typically 80% of all new diagnoses are in patients over with any human disease and its ability to safely and responses as they secrete factors promoting or the age of 60 years. efficiently deliver a genetic payload into a broad range inhibiting inflammation and tissue fibrosis. of tissues. Well-known as a disease of miners and stonemasons, silicosis has resurged in the sandstone basin which CLL is a slow developing cancer affecting B cells. Liver resident macrophages include Kupffer cells (KCs) cups the Sydney region and continues to afflict millions Genetic mutations acquired in these B cells result For liver-specific genetic diseases, current rAAV as well as “liver capsular macrophages” (“LCMs”) of workers in hazardous occupations around the world. in their transformation into cancerous cells that can modalities have not provided the necessary high-level recently discovered by the host laboratory. KCs Silicosis predisposes to TB and patients with silicosis live longer and grow faster than normal B cells. transduction efficiencies and humoral neutralisation and LCMs have a distinct phenotype and ontogeny. who develop active TB have poor outcomes. As 25% of Similar to many blood cancers, genetic alterations properties necessary for curative outcomes in diverse While LCMs are CX3CR1+ and derived from blood the world’s population is infected with Mycobacterium in CLL can be heterogeneous, and include point patient groups. monocytes, KCs are embryonically derived and tuberculosis, this is a serious problem. mutations, chromosomal deletions, amplifications CX3CR1-. LCMs form a network that is intimately and rearrangements. Recent reports have identified Improved transduction efficiency of rAAV vectors has related to the collagen framework of the liver capsule, The mechanisms by which silicosis impacts the body’s the gene encoding the transcription factor Max Gene been achieved by engineering capsids with higher and play a potential role in its integrity. Advancing defenses against mycobacteria are poorly understood. Associated (MGA) to be recurrently deleted in CLL. affinity or cell-specific tropism and increased resistance our knowledge on the role of these two types of This project will use a mouse model of silicosis and MGA inactivation through chromosomal deletion or to neutralising antibodies. Increasing AAV-mediated macrophages in normal liver tissue, and in mediating mycobacterial infection to examine how silicosis point mutation occurs in 4% of CLL, but this increases therapeutic efficacy by modulating host entry factors inflammation and fibrosis during pathology is critical for affects innate (dendritic cell and macrophage) and to 16% as CLL disease progresses to chemotherapy remains unexplored. the development of new treatments. resistance. adaptive immune responses. The student will be part of a stimulating research team and develop skills in KIAA0319L was recently shown to be an essential This project aims to characterise the role of immunology, cellular biology and flow cytometry. Our hypothesis is that genetic inactivation of MGA host entry factor for most AAV serotypes, however the macrophages in the structure of the liver using a unique promotes chronic lymphocytic leukaemia disease biology and normal function of KIAA0319L is poorly mouse line recently generated by the group. This line School at: School of Medical Sciences progression. We will test this hypothesis by analysing understood. In this project, we will use a combination selectively lacks monocyte-derived macrophages and how acquired genetic lesions in MGA alter the of biochemical, genetic and proteomic strategies to displays abnormal liver development. proliferation, differentiation and survival of CLL cells functionally characterise the host determinants that Keywords: immunology, infectious diseases, tuberculosis, environment, inflammation and contribute to cellular transformation. regulate KIAA0319L expression and distribution. Techniques: high resolution confocal microscopy, state of the art imaging, and flflow cytometric techniques. School at: Pathology School at: Pathology School at: Infectious Diseases and Immunology Keywords: leukaemia, mutation, transcription factor, Keywords: gene therapy, adeno-associated virus, host mouse models factor, KIAA0319L Keywords: macrophages, liver, T cells, inflammation

Alphabetical by supervisor surname.

Student Research Projects for 2021 Student Research Projects for 2021

20 21 HONOURS PROJECTS

Supervisor: Dr Jaesung Peter Choi Supervisor: Associate Professor Mathias Supervisor: Associate Professor Mathias Supervisor: Professor Jennifer Gamble Centenary UTS Centre for Inflammation: Head - Professor Francois Francois Vascular Biology Program: Head - Professor Jennifer Phil Hansbro David Richmond Laboratory for Cardiovascular David Richmond Laboratory for Cardiovascular Gamble Development: Gene Regulation and Editing Program: Development: Gene Regulation and Editing Program: Head - Associate Professor Mathias Francois Head - Associate Professor Mathias Francois E: [email protected] E: [email protected] E: [email protected] E: [email protected] P: +61 2 9565 6203 P: +61 2 8627 9497 P: +61 2 8627 9497

● Finding safe and effective therapies ● Imaging transcription at single molecule ● Molecular and cellular basis of lymphatic ● Alzheimer’s Disease: Determining the targeting sex hormones and the microbiome resolution in a living cell vascular development role of aged perivascular macrophages in for the commonest cause of stroke in blood-brain barrier dysfunction children: cerebral cavernous malformation The primary objective of this project is to develop The primary objective of this project is to develop a research study with general and specific in vitro a research study with general and specific in vivo (CCM) Alzheimer’s Disease (AD) is an age-related disease techniques in stem cells and in vivo approaches in early techniques in mouse or zebrafish model system to that affects brain function. Breakdown of the blood-brain stage mouse embryo to study the molecular basis of study the molecular and cellular biology of vascular barrier (BBB) results in neuroinflammation involved in Cerebral cavernous malformations (CCMs) are vascular cell fate decision during embryogenesis. development during embryogenesis. cognitive decline, a feature of AD. lesions of the central nervous system that affect 1 in 200 people. CCM lesions are prone to bleeds and are This work will take advantage of cutting edge The biological question is centred around the molecular In a mouse model of AD, we have identified aged the major cause of stroke and sudden death in children. approaches based on single molecule approaches control of cell fate during lymphatic endothelial cell vascular cells. These cells are thought to be Current treatment for CCM is limited to high-risk to study the role of different components of the specification by a novel transcriptional effector. perivascular macrophages, which are known to regulate neurosurgery. As such there is an urgent need for novel transcriptional machinery in stem cells. Two types of The work will involve wet and dry lab approach to BBB permeability and neuroinflammation. non-invasive, druggable treatment options. complementary approaches will be used in parallel understand how this new gene modulates the program either based on live imaging methods or on fixed cells of lymphatic endothelial cell differentiation on a genome The project aims to: Just as men have earlier onset and more severe with super resolution microscopy. Further the work wide scale. Techniques used will cover a broad range cardiovascular diseases than women, recent clinical will be complemented by genomic and transcriptomic of skills from phenotyping vascular networks using 1. Confirm the identity of aged (senescent) perivascular observations and our preliminary data in mouse models approaches to correlate changes in gene output with confocal microscopy to gene editing with crispr/cas9 macrophages in AD. demonstrate a greater CCM burden in males. The male molecular activity imaged in a cell. and genomics and transcriptomics approaches. predisposition to CCM is likely to reflect an impact of 2. Investigate the consequence of the senescent sex hormones in its pathogenesis. Furthermore, we The David Richmond (DR) program for cardio-vascular The David Richmond (DR) program for cardio-vascular perivascular macrophages on BBB function. recently identified the gut microbiome as a critical development welcomes only a limited number of development welcomes only a limited number of stimulant of CCM. Interestingly, gut microbiota differs Honours / PhD candidates to ensure high quality Honours / PhD candidates to ensure high quality Scientist associated with this project: Dr Kaka Ting between males and females and microbiota influence supervision is provided to the student. Usually students supervision is provided to the student. Usually student sex hormone metabolism and action. work on their own project but embedded in a team with work on their own project but embedded in a team with E: [email protected]: P: + 61 2 9565 6227 a post doc and research assistant.The DR laboratory a post doc and research assistant.The DR laboratory Hence, the project aims to elucidate the role that sex is physically located at the CPC and therefore benefits is physically located at the CPC and therefore benefits School at: Infectious Diseases and Immunology hormones and the microbiome play in the prominent from a great scientific environment from both the from a great scientific environment from both the CI and sex difference in CCM. This could reveal a potential Centenary Institute and the CPC. the CPC. Keywords: alzheimer's disease, macrophages, aged use of steroids, precision antibiotics/probiotics, and immune response repurposing existing drugs as non-invasive therapeutic School at: School of Medical Sciences School at: School of Medical Sciences options for CCM. Keywords: gene regulation, molecular imaging, Keywords: transcription factor, molecular genetics, in School at: UTS School of Life Sciences transcription factors, stem cell, super resolution imaging vivo model, mouse and fish transgenics, live imaging

Keywords: stroke, cardiovascular diseases, mouse, microbiome, cerebral cavernous malformation

Alphabetical by supervisor surname.

Student Research Projects for 2021 Student Research Projects for 2021

22 23 HONOURS PROJECTS

Supervisor: Professor Jennifer Gamble Supervisor: Professor Mark Gorrell Supervisor: Dr Daniel Hesselson Supervisor: Dr Daniel Hesselson Vascular Biology Program: Head - Professor Jennifer Liver Enzymes in Metabolism and Inflammation Program: ACRF Centenary Cancer Centre: Head - Professor Phil ACRF Centenary Cancer Centre: Head - Professor Phil Gamble Head - Professor Mark Gorrell Hogg, Directed Evolution Laboratory: Head - Dr Dan Hogg, Directed Evolution Laboratory: Head - Dr Dan Hesselson Hesselson

E: [email protected] E: [email protected] E: [email protected] E: [email protected] P: + 61 2 9565 6152 P: 0404 456 830 P: 0404 456 830

● Alzheimer's Disease: How age effects the ● Proteases in the pathogenesis of chronic ● Blocking follistatin in ovarian cancer to ● Functional strategies to mitigate or blood vessels in the brain liver injury and cancer prevent chemoresistance and recurrence eliminate PFAS from human and animal tissue Ageing is one of the greatest risk factors for Primary liver cancer is the 4th leading cause of cancer In the Directed Evolution laboratory, we harness the cardiovascular disease including Alzheimer's Disease. related deaths. We are addressing the urgent need to power of Darwinian selection to evolve proteins with Per- and poly-fluoroalkyl substances (PFAS) are Cellular ageing, referred to as cellular senescence develop a greater understanding of pathogenesis for new therapeutic activities. We have discovered that synthetic chemicals that resist heat and water, and have is an irreversible process activated in response to improved therapeutics. The pathogenesis of chronic blocking follistatin activity could increase the sensitivity been widely used since the 1940s. Importantly, these stress that is characterised by permanent cell cycle liver injury and cancer is driven by chronic cell death of ovarian cancer to primary chemotherapeutics. compounds are highly stable in the environment and in arrest, an active metabolic state and in changes to the and proliferation and inflammation. Cirrhosis generally However, existing anti-follistatin antibodies lack the some areas have penetrated ground water putting rural inflammatory phenotype of the cell. precedes cancer in the liver. potency to fully neutralise follistatin activity in vivo. populations at risk of continued chronic exposure.

Endothelial cells are unique in showing both pro- Proteases are important in cancer pathogenesis and Thus, we will evolve high affinity single-domain This project is part of a larger program to provide inflammatory and anti-inflammatory senescence suit drug development. We primarily study fibroblast antibodies (nanobodies) against follistatin, to disrupt clear and experimentally validated evidence and phenotypes. We have evidence to suggest that this activation protein (FAP) and DPP9 as proteases its signalling. This work will pave the way for new meta-evidence for how PFAS exposure impacts dual phenotype maybe regulated through changes in associated with cancer pathogenesis. adjunctive therapies which could enhance the efficacy human health, its biological mechanisms of action, the metabolic state of the cell. of primary chemotherapeutics in a wide range of and importantly how to treat individuals exposed to I discuss with each student their interests, skills and cancers. hazardous levels of PFAS. This project will investigate this possibility and uncover aspirations in order to design a suitable project within the molecular pathway that controls the metabolic these topics: School at: School of Medical Sciences Developing zebrafish embryos absorb PFAS from switch. their aqueous environment and bioaccumulate these 1. Liver complications of diabetes and chronic fatty liver. Keywords: directed evolution, cancer, chemicals. We’ve discovered that embryos loaded Associated Scientist: Dr Paul Coleman 2. Liver cirrhosis and cancer. chemoresistance with PFAS continue to endure toxic effects even once moved to an uncontaminated environment providing a E: [email protected] P: +61 2 9565 6229 3. Protein biochemistry and inhibitors of FAP and high-throughput experimental system to identify small DPP9. molecule treatments that stimulate PFAS elimination School at: School of Medical Sciences 4. Diagnosis of fibrosis in chronic liver disease and at the organism level. In this project we will perform predicting treatable patients. unbiased small molecule screens to identify and Keywords: ageing, metabolism, inflammation validate novel potential treatments for PFAS exposure 5. Potential therapies for cancer and NASH. in humans. Training: We use sophisticated techniques in School at: School of Medical Sciences immunohistochemistry, flow cytometry, qPCR, immunoblotting, protease assays, ELISA and confocal Keywords: environmental determinants of human microscopy. Projects can be in cell lines, mouse models health and treatment strategies or with specimens from RPA hospital.

School at: School of Medical Sciences

Keywords: cirrhosis, NASH, cancer, liver, DPP4, fibrosis, mouse, human Alphabetical by supervisor surname.

Student Research Projects for 2021 Student Research Projects for 2021

24 25 HONOURS PROJECTS

Supervisor: Dr Gang Liu Supervisor: Dr Gang Liu Supervisor: Associate Professor Guy Lyons Supervisor: Associate Professor Guy Lyons Centenary UTS Centre for Inflammation: Head - Professor Centenary UTS Centre for Inflammation: Head - Professor Immune Imaging Program: Head - Professor Wolfgang Immune Imaging Program: Head - Professor Wolfgang Phil Hansbro Phil Hansbro Weninger Weninger

E: [email protected] E: [email protected] E: [email protected] E: [email protected] P: +61 2 9565 6198 P: +61 2 9565 6198 P: +61 2 9565 6127 P: +61 2 9565 6127

● Understanding the role of extracellular ● Novel treatments of alpha-1 antitrypsin ● How the cornea responds to UV radiation ● Genes and cell-cell interactions in tumour matrix proteins in regulating lung fibrosis gene deficiency induced chronic progression obstructive pulmonary disease The cornea is covered by a multi-layered (stratified) Lung fibrosis is a progressive, debilitating, and severe sheet of clear epithelial cells, which protects it from Cancer cells within a tumour often have different pathogens and the environment. Like the skin, the lung disease, which is characterised by damage to Chronic obstructive pulmonary disease (COPD) is a mutations from neighbouring cells. This genetic cornea is exposed to damaging ultraviolet radiation lung tissues, and idiopathic pulmonary fibrosis (IPF) is progressive pulmonary disease defined by emphysema heterogeneity enables novel cell-cell interactions (UVR) from sunlight. one of the major lung fibrosis diseases in humans. It is and severe breathing difficulties. It is the 3rd to occur that are not possible in homogenous characterised by lung tissue remodelling and fibrosis, commonest cause of chronic morbidity and death. tumours. This opens up exciting new possibilities where normal lung tissue is interspersed with interstitial This project will investigate how UVR affects for understanding the pathogenesis of cancer and stratification of the corneal epithelium and its barrier fibrosis, honeycomb cysts and fibroblast foci. Alpha 1 anti-trypsin (A1AT) deficiency is the major strategies for treating it. function against viruses such as coronaviruses. It will genetic predisposition to COPD. Endogenous proteases use advanced microscopy and image analysis methods In lung injury, extracellular matrix (ECM) proteins are function to clear debris and damaged tissues from the To explore these interactions between cancer cells, we to visualise the epithelial cells of living corneas as they secreted into the connective tissue to serve as scaffolds lungs. However, when not properly controlled they have have identified clones of cells that interact to promote divide, migrate and stratify. for tissue repair and regeneration. However, ECM aberrant activity degrading elastin and various forms of cancer cell growth in an experimental model of oral proteins continue to be produced and deposited in lung collagen leading to lung damage. cancer. tissues in IPF, and the process becomes irreversible. The corneas from novel reporter strains of genetically modified mice will be used to locate and measure Current treatments to lung fibrosis have limited effect to It is well-known that deficiencies in A1AT lead to an This project will investigate the molecular genetic basis signalling responses in the living tissue, and probed reduce and inhibit lung fibrosis development in IPF. imbalance in protease-anti-protease activity resulting in for this interaction, using cell culture, image analysis, with pathway-specific drugs to determine their tissue damage and emphysema. More than 80% of the deep sequencing and mouse models. importance. Our recent studies have identified some key ECM human genome produces RNAs that are not translated, proteins that targeting these proteins can reduce lung and many of them are long non-coding (lnc) RNAs. School at: Pathology fibrosis and inflammation in an experimental model School at: Pathology of lung fibrosis. In this research project, we aim to In this project, we aim to understand how lncRNA Keywords: cancer, oral, skin, microscopy Keywords: eye, cancer, COVID-19, UV radiation, understand the mechanism of the ECM proteins regulates A1AT deficiency-induced COPD and explore microscopy regulate lung fibrosis in IPF. a potential treatment.

School at: UTS School of Life Sciences School at: UTS School of Life Sciences

Keywords: lung fibrosis, idiopathic pulmonary fibrosis, Keywords: Alpha-1 antitrypsin, COPD, PCR, CRISPR animal models, extracellular matrix proteins

Alphabetical by supervisor surname.

Student Research Projects for 2021 Student Research Projects for 2021

26 27 HONOURS PROJECTS

Supervisor: Dr Stefan Oehlers Supervisor: Dr Ulf Schmitz Supervisor: Dr Ulf Schmitz Supervisor: Dr Ulf Schmitz Mycobacterial Program: Head - Professor Warwick Britton Gene and Stem Cell Therapy Program: Head - Professor Gene and Stem Cell Therapy Program: Head - Professor Gene and Stem Cell Therapy Program: Head - Professor AO, Immune-Vascular Interactions Laboratory: Head - Dr John Rasko AO, Computational BioMedicine Laboratory: John Rasko AO, Computational BioMedicine Laboratory: John Rasko AO, Computational BioMedicine Laboratory: Stefan Oehlers Head - Dr Ulf Schmitz Head - Dr Ulf Schmitz Head - Dr Ulf Schmitz

E: [email protected] E: [email protected] E: [email protected] E: [email protected] P: +61 2 9565 6114 P: +61 2 9565 6209 P: +61 2 9565 6209 P: +61 2 9565 6209

● Bidirectional interaction between the ● Characterizing fusion transcripts in ● Deciphering the cross-talk between ● Mirtron synthesis and expression in cardiovascular system and infectious cancer and normal cells microRNAs and retained introns in cancer leukemia diseases gene regulation DNA rearrangement leading to fusion genes is a In a large-scale analysis of alternative splicing across Our research group uses the zebrafish model system to hallmark of cancer. A number of these fusions are Perturbations to the highly calibrated system of gene 2,500 human tissue samples and cell lines we better understand and treat this disease. The zebrafish used as biomarkers and therapeutic targets in different regulation can have severe consequences and cause generated a wealth of data regarding gene-, cell type-, is an emerging model for the study of infectious cancer types; prominent examples include BCR-ABL1 diseases including cancer. MicroRNAs can regulate tissue-, and disease-specific intron-retention events . diseases that complements existing mouse infection for chronic myeloid leukemia and MYC-IGH for Burkitt's dozens of target genes and intron retention has been This data is in parts accessible through a rudimentary models in the Tuberculosis Research Program at the lymphoma. found to be another mechanism of post-transcriptional web interface: http://mimirna.centenary.org.au/irfinder/ Centenary Institute. gene regulation affecting hundreds of genes. database/. Traditionally, DNA rearrangement and gene fusion Mycobacterial infection results in the formation of was attributed largely to chromosomal translocations. In this project we will identify gene-regulatory network In this project we will develop a sophisticated database complex aggregates of immune cells known as However, recent years have produced conclusive modules using a data integration approach to determine and web interface design to provide an efficient and granulomas, and these can be readily visualised in evidences that two or more transcripts can fuse at patterns of competitive post-transcriptional gene rich user experience facilitating a rapid success in the zebrafish. These granulomas behave similarly to the transcription level irrespective of chromosomal regulation. hunt for information about intron retention. The new tumours in many ways including the way they recruit translocations. IRBase 2.0 will provide data in interactive graphs and leaky blood vessels to the site of infection. We have Toward this, we will integrate expression profiles of customized data retrieval options. shown that angiogenesis (http://dx.doi.org/10.1038/ In this project, we will analyse long-read sequencing microRNAs and genes, intron retention profiles and nature13967),vascular permeability (http://dx.doi. and single-cell sequencing data from tumour samples predicted gene-regulatory interactions between (i) School at: School of Medical Sciences org/10.1093/infdis/jiw355), and haemostasis (http:// and healthy tissue to identify known and novel fusion microRNAs and target genes, (ii) transcription factors dx.doi.org/10.1093/infdis/jiz110) aid mycobacterial transcripts and determine their (cancer) cell-type and target genes, and (iii) microRNA-intron retention Keywords: alternative splicing, database design, growth in zebrafish infection models. specific expression profiles. interactions. For a selected sub network relevant in graphical user interface, data integration, data cancer we will construct a mathematical model of visualisation This project will expand these findings by determining School at: School of Medical Sciences competitive post-transcriptional gene regulation. the effects of vascularisation on host and bacterial physiology using a combination of in vitro cell culture Keywords: bioinformatics, trans-splicing, single cell School at: School of Medical Sciences assays, zebrafish infection experiments and mouse sequencing, long read sequencing, big data, cancer models of pulmonary TB. biology Keywords: microRNA, alternative splicing, bioinformatics, systems biology School at: Infectious Diseases and Immunology

Keywords: infection & immunity, cardiovascular & respiratory diseases, vascular biology, zebrafish

Alphabetical by supervisor surname.

Student Research Projects for 2021 Student Research Projects for 2021

28 29 HONOURS PROJECTS

Supervisor: Dr Ulf Schmitz Supervisor: Clinical Associate Professor Supervisor: Dr Sj Sijie Shen Supervisor: Dr Dannel Yeo Gene and Stem Cell Therapy Program: Head - Professor Devanshi Seth Centenary UTS Centre for Inflammation: Head - Professor Gene and Stem Cell Therapy Program: Head - Professor John Rasko AO, Computational BioMedicine Laboratory: Liver Injury and Cancer Program: Head - Professor Geoff Phil Hansbro John Rasko AO Head - Dr Ulf Schmitz McCaughan, Alcoholic Liver Disease Laboratory: Head - Clinical Associate Professor Devanshi Seth E: [email protected] E: [email protected] E: [email protected] E: [email protected] P: +61 2 9565 6209 T: +61 2 9565 6268 P: 0466 574 995 P: +61 2 9565 6286

● Core transcriptional networks in cell ● Role of lipid metabolism in alcohol- ● Modulating the gut microbiome to ● Circulating tumour cells to monitor trans-differentiation induced liver cirrhosis influence the progression of lung diseases cancer patients

Core transcriptional networks are essential drivers Risky drinking continues to be a major concern in Dr Shen is a postdoctoral researcher in Professor Circulating tumour cells (CTCs) are tumour cells that and determinants of cell-fate transitions. To date, our Australia. The major medical consequence of risky Phil Hansbro’s group at the recently established UTS/ have been released from the primary tumour tissue to mechanistic understanding of these essential regulatory drinking is alcohol-induced liver cirrhosis (AC). Our Centenary Centre for Inflammation, based at the form metastases by travelling through the blood and layers is very limited, especially in the context of trans- discovery of novel variant in FAF2 gene (lipid droplet/ Centenary Institute. lymphatic system. Capturing and analysing these rare differentiation, despite being one of the most promising metabolism) associated with the risk of AC in drinkers, cells is now possible using our next generation liquid therapeutic cell replacement strategies in regenerative is significant because it fits well with the current His research aims to provide deeper insights into the biopsy platform. medicine. knowledge of other single nucleotide polymorphisms “gut-lung axis”. The project will explore how our lifestyle (SNPs) in genes (PNPLA3, TM6SF2 and HSD17B13) and environment alters the bacteria in the gut (the We are able to identify, capture and characterise these In this project, we will reconstruct gene-regulatory also linked to lipid biology. Build-up of lipid droplets in gut microbiome) to influence lung inflammation during CTCs. Hence, this platform has the potential to provide networks involving non-coding RNAs and mRNAs the liver due to heavy drinking can cause inflammation, severe asthma and chronic obstructive pulmonary ‘real-time’ cancer monitoring throughout all stages of a that drive trans-differentiation of human cells and leading to cirrhosis in some drinkers. disease (COPD). The major aim of this project is to patient’s cancer journey and identify potentially effective identify key alternative splicing events during cell-fate delve deep into understanding the mechanisms by treatments in cancers such as pancreatic cancer, lung transitions. My group is interested to understand the mechanisms which bacteria interacts with and influences host cancer, and mesothelioma. Potential research topics of action of these genes in the development of immune cells and responses in the gut, and how this include: School at: School of Medical Sciences cirrhosis. We will use our established zebrafish model modulates inflammation in the lungs. This project will of alcohol-induced liver injury. Function of risk genes utilise well-established animal models combined with 1. Evaluate CTCs to predict patient response and guide Keywords: bioinformatics, systems biology, next and their mechanisms driving disease development cutting-edge techniques for research. patient management. generation sequencing data analysis will be studied using gene-editing (Crispr-Cas9), 2. Characterise CTCs using genetic, cellular and transgenics and state-of-art imaging technology. It will Dr Shen received his PhD in medicine/immunology imaging techniques. advance knowledge on the role of lipid biology genes from Monash University in 2019. His research shows in chronicity of AC development. Importantly, it will that host immune and environmental factors change the 3. Establish and characterise patient-derived CTC generate a list of new drug targets. gut microbiome and alter colitis. organoid cultures. 4. Evaluate CTCs and other blood biomarkers as a School of Medical Sciences UTS School of Life Sciences School: School at: diagnostic marker to improve early detection.

cirrhosis, SNPs, lipid, alcohol, genetics, microbiome, gut, lung, respiratory, COPD, Keywords: Keywords: Skills/tools: Mammalian cell culture (3D), cell zebrafish, crispr bacteria, asthma biology assays, western blot, RT-qPCR, microscopy, immunofluorescence, cell picking, mouse models

School at: Pathology

Keywords: cancer, translational medicine, liquid biopsy, circulating tumour cells

Alphabetical by supervisor surname.

Student Research Projects for 2021 Student Research Projects for 2021

30 31 HONOURS PROJECTS

Supervisor: Dr Dannel Yeo Supervisor: Dr Hui Emma Zhang Gene and Stem Cell Therapy Program: Head - Professor Liver Enzymes in Metabolism and Inflammation Program: John Rasko AO Head - Professor Mark Gorrell Masters Projects E: [email protected] E: [email protected] P: +61 2 9565 6286 P: +61 2 9565 6115

● Investigating CAR-T therapy for pancreatic ● Proteases in liver cancer cancer Primary liver cancer is the 4th leading cause of cancer Progress your research career by taking the next step with a Masters Chimeric antigen receptor-engineered T-cell (CAR-T) related deaths and there is an urgent need to develop therapy is an exciting new cellular immunotherapy for improved medical therapy. Our team is the first to degree through the Centenary Institute. the treatment of cancer. find that the protease DPP9 is a druggable target in hepatocellular carcinoma (HCC). DPP9 inhibition has With state-of-the-art equipment, and an internal support system consisting of Isolated patient T-cells are modified to target a specific shown anti-cancer actions in acute myeloid leukaemia world-renowned scientists, the Centenary Institute can be the foundation for your tumour surface antigen and then injected back into and lung cancer. This project aims to better understand promising career. the patient. CAR-T therapy is now approved for blood the roles of DPP9 in the pathogenesis of HCC. cancers but the same success has not been observed Our Masters program is designed as a perfect gateway to your PhD and enables in solid cancers. Projects will be these, or similar based on student you to further your skills on cutting-edge flow and imaging machines, while working interests: side-by-side with researchers at the top of their field. Whatever you desire for your Novel CAR-T therapies will be evaluated in pancreatic future in science, Centenary can empower you to achieve your goal and help you cancer using the latest cancer model systems 1. To elucidate molecular mechanisms of DPP9 using to get where you want to be. including 2D cells, 3D organoids and mice models. liver cancer cell lines. To test the efficacy of CAR-T cells, cytotoxicity and 2. To generate cell-specific DPP9 depletion in mice to immune activation/persistence will be evaluated, and study the role of DPP9 in the immune system. mechanisms of resistance will be explored. 3. To measure growth of orthotopic tumours in DPP9 inhibitor treated mice. Skills/tools: mammalian cell culture, cell biology assays (including cellular impedance assays, live cell imaging), isolating T cells, lentivirus gene transfer, Skills that the student can learn: cell culture, immune phenotyping (by flow cytometry), RT-qPCR, histopathology, immunohistochemistry, immunoblotting, cytokine analysis (ELIZA), and mouse models. qPCR, flow cytometry, confocal microscopy.

Pathology School at: Pathology School at:

protease, liver cancer, inflammation, DNA Keywords: cancer, immunotherapy, CAR-T Keywords: repair

“I love the positive and supportive environment and the resources and laboratories are absolutely top-notch. The best thing? My supervisors help me a lot. They’re always willing to listen, to advise and to share the fantastic knowledge that they’ve gained over years of hard work and effort. I love working here!”

Darren Liu, Masters Student Lipid Cell Biology Laboratory

Student Research Projects for 2021 centenary.org.au/students

32 MASTERS PROJECTS

Supervisor: Dr Chuck Bailey Supervisor: Dr Chuck Bailey Supervisor: Dr Chuck Bailey Supervisor: Dr Chuck Bailey Gene and Stem Cell Therapy Program: Head - Professor Gene and Stem Cell Therapy Program: Head - Professor Gene and Stem Cell Therapy Program: Head - Professor Gene and Stem Cell Therapy Program: Head - Professor John Rasko AO John Rasko AO John Rasko AO John Rasko AO

E: [email protected] E: [email protected] E: [email protected] E: [email protected] P: +61 2 9565 6171 P: +61 2 9565 6171 P: +61 2 9565 6171 P: +61 2 9565 6171

● Molecular modeling of cancer-associated ● Understanding the role of CTCF genetic ● The role of MGA mutation in chronic ● Modulation of host entry factors to mutations in tumour suppressor genes deletion in aggressive endometrial cancer lymphocytic leukaemia (CLL) improve AAV-mediated gene therapy

The ‘master weaver’ protein CTCF, is mutated in CTCF is essential for the normal organisation of Chronic lymphocytic leukaemia (CLL) is the most Recombinant adeno-associated virus (rAAV) has endometrial cancer, as well as colorectal, stomach, DNA in cells. Our team has discovered that CTCF is common leukaemia in senior Australians. Every year gained widespread use as a gene delivery vector for breast and haemopoietic cancers. Our group was the genetically deleted at high rates in the most aggressive nearly 1000 Australians are diagnosed with CLL and corrective gene therapies due to its lack of association first to demonstrate that the ubiquitous zinc finger and deadly types of endometrial cancer (Marshall, et typically 80% of all new diagnoses are in patients over with any human disease and its ability to safely and (ZF) protein CTCF acts as a tumour suppressor gene. al., 2017). CTCF deletion predominantly occurs in the the age of 60 years. efficiently deliver a genetic payload into a broad range Missense mutations in CTCF are enriched in the DNA- Type II serous subtype of endometrial cancer and is of tissues. binding ZF region. associated with poorer overall survival in patients with CLL is a slow developing cancer affecting B cells. serous tumours. Additionally, we have shown that Genetic mutations acquired in these B cells result For liver-specific genetic diseases, current rAAV We have shown that mutations in the ZF region can CTCF deletions also occur in the clear cell subtype in their transformation into cancerous cells that can modalities have not provided the necessary high-level result in a loss- or gain-of-function in CTCF, which has and this may be associated with tumour relapse and/or live longer and grow faster than normal B cells. transduction efficiencies and humoral neutralisation implications for cancer development. We are currently metastasis. Similar to many blood cancers, genetic alterations properties necessary for curative outcomes in diverse modelling ‘hotspot’ mutations on published CTCF ZF in CLL can be heterogeneous, and include point patient groups. structures to assess the impact of those mutations. Our culturing of endometrial cancer cell-lines as 3D mutations, chromosomal deletions, amplifications In addition, we will develop homology models for the spheroids has shown that a functional consequence of and rearrangements. Recent reports have identified Improved transduction efficiency of rAAV vectors has ZF domain of CTCF-Like protein (CTCFL, also known CTCF deletion results in a loss of cell polarity – an early the gene encoding the transcription factor Max Gene been achieved by engineering capsids with higher as BORIS). CTCFL which shares 80% homology with event in endometrial cancer pathology. Our analysis Associated (MGA) to be recurrently deleted in CLL. affinity or cell-specific tropism and increased resistance CTCF within its ZF domain is aberrantly expressed of gene expression data in CTCF heterozygous MGA inactivation through chromosomal deletion or to neutralising antibodies. Increasing AAV-mediated in more than half of all cancers. Both factors have endometrial tumours has revealed a widespread point mutation occurs in 4% of CLL, but this increases therapeutic efficacy by modulating host entry factors overlapping and unique DNA binding characteristics. dysreguation of transcription. to 16% as CLL disease progresses to chemotherapy remains unexplored. resistance. We will examine which residues are critical for binding In this project we will examine those genes and KIAA0319L was recently shown to be an essential of CTCF and CTCFL to the same DNA target sites and biochemical pathways that are dysregulated in CTCF Our hypothesis is that genetic inactivation of MGA host entry factor for most AAV serotypes, however the which ZF residues confer DNA binding specificity. This mutant endometrial cancers. We will investigate the promotes chronic lymphocytic leukaemia disease biology and normal function of KIAA0319L is poorly will provide important insight into the sibling rivalry that impact of these genes on cell polarity in 3D spheroids progression. We will test this hypothesis by analysing understood. In this project, we will use a combination exists between CTCF and CTCFL in normal biology and which will give us important insights into early how acquired genetic lesions in MGA alter the of biochemical, genetic and proteomic strategies to cancer. pathophysiological events underlying endometrial proliferation, differentiation and survival of CLL cells functionally characterise the host determinants that cancer. and contribute to cellular transformation. regulate KIAA0319L expression and distribution. School at: Pathology School at: Pathology School at: Pathology School at: Pathology Keywords: protein structure, mutation, cancer, transcription factor Keywords: endometrial cancer, mutation, mouse Keywords: leukaemia, mutation, transcription factor, Keywords: gene therapy, adeno-associated virus, host models, cell biology mouse models factor, KIAA0319L

Alphabetical by supervisor surname.

Student Research Projects for 2021 Student Research Projects for 2021

34 35 MASTERS PROJECTS

Supervisor: Dr Jaesung Peter Choi Supervisor: Professor Mark Gorrell Supervisor: Dr Daniel Hesselson Supervisor: Dr Daniel Hesselson Centenary UTS Centre for Inflammation: Head - Professor Liver Enzymes in Metabolism and Inflammation Program: ACRF Centenary Cancer Centre: Head - Professor Phil ACRF Centenary Cancer Centre: Head - Professor Phil Phil Hansbro Head - Professor Mark Gorrell Hogg, Directed Evolution Laboratory: Head - Dr Dan Hogg, Directed Evolution Laboratory: Head - Dr Dan Hesselson Hesselson

E: [email protected] E: [email protected] E: [email protected] E: [email protected] P: +61 2 9565 6203 P: + 61 2 9565 6152 P: 0404 456 830 P: 0404 456 830

● Finding safe and effective therapies ● Proteases in the pathogenesis of chronic ● Blocking follistatin in ovarian cancer to ● Functional strategies to mitigate or targeting sex hormones and the microbiome liver injury and cancer prevent chemoresistance and recurrence eliminate PFAS from human and animal for the commonest cause of stroke in tissue children: cerebral cavernous malformation Primary liver cancer is the 4th leading cause of cancer In the Directed Evolution laboratory, we harness the related deaths. We are addressing the urgent need to power of Darwinian selection to evolve proteins with (CCM) Per- and poly-fluoroalkyl substances (PFAS) are develop a greater understanding of pathogenesis for new therapeutic activities. We have discovered that synthetic chemicals that resist heat and water, and have improved therapeutics. The pathogenesis of chronic blocking follistatin activity could increase the sensitivity been widely used since the 1940s. Importantly, these Cerebral cavernous malformations (CCMs) are vascular liver injury and cancer is driven by chronic cell death of ovarian cancer to primary chemotherapeutics. compounds are highly stable in the environment and in lesions of the central nervous system that affect 1 in and proliferation and inflammation. Cirrhosis generally However, existing anti-follistatin antibodies lack the some areas have penetrated ground water putting rural 200 people. CCM lesions are prone to bleeds and are precedes cancer in the liver. potency to fully neutralise follistatin activity in vivo. populations at risk of continued chronic exposure. the major cause of stroke and sudden death in children. Current treatment for CCM is limited to high-risk Proteases are important in cancer pathogenesis and Thus, we will evolve high affinity single-domain This project is part of a larger program to provide neurosurgery. As such there is an urgent need for novel suit drug development. We primarily study fibroblast antibodies (nanobodies) against follistatin, to disrupt clear and experimentally validated evidence and non-invasive, druggable treatment options. activation protein (FAP) and DPP9 as proteases its signalling. This work will pave the way for new meta-evidence for how PFAS exposure impacts associated with cancer pathogenesis. adjunctive therapies which could enhance the efficacy human health, its biological mechanisms of action, Just as men have earlier onset and more severe of primary chemotherapeutics in a wide range of and importantly how to treat individuals exposed to cardiovascular diseases than women, recent clinical I discuss with each student their interests, skills and cancers. hazardous levels of PFAS. observations and our preliminary data in mouse models aspirations in order to design a suitable project within demonstrate a greater CCM burden in males. The male these topics: School at: School of Medical Sciences Developing zebrafish embryos absorb PFAS from predisposition to CCM is likely to reflect an impact of their aqueous environment and bioaccumulate these sex hormones in its pathogenesis. Furthermore, we 1. Liver complications of diabetes and chronic fatty liver. Keywords: directed evolution, cancer, chemicals. We’ve discovered that embryos loaded recently identified the gut microbiome as a critical chemoresistance with PFAS continue to endure toxic effects even once stimulant of CCM. Interestingly, gut microbiota differs 2. Liver cirrhosis and cancer. moved to an uncontaminated environment providing a between males and females and microbiota influence 3. Protein biochemistry and inhibitors of FAP and DPP9. high-throughput experimental system to identify small sex hormone metabolism and action. 4. Diagnosis of fibrosis in chronic liver disease and molecule treatments that stimulate PFAS elimination at the organism level. In this project we will perform Hence, the project aims to elucidate the role that sex predicting treatable patients. unbiased small molecule screens to identify and hormones and the microbiome play in the prominent 5. Potential therapies for cancer and NASH. validate novel potential treatments for PFAS exposure sex difference in CCM. This could reveal a potential in humans. use of steroids, precision antibiotics/probiotics, and Training: We use sophisticated techniques in repurposing existing drugs as non-invasive therapeutic immunohistochemistry, flow cytometry, qPCR, School at: School of Medical Sciences options for CCM. immunoblotting, protease assays, ELISA and confocal microscopy. Projects can be in cell lines, mouse models Keywords: environmental determinants of human School at: UTS School of Life Sciences or with specimens from RPA hospital. health and treatment strategies Keywords: stroke, cardiovascular diseases, mouse, School at: School of Medical Sciences microbiome, cerebral cavernous malformation Keywords: cirrhosis, NASH, cancer, liver, DPP4, fibrosis, mouse, human

Alphabetical by supervisor surname.

Student Research Projects for 2021 Student Research Projects for 2021

36 37 MASTERS PROJECTS

Supervisor: Dr Gang Liu Supervisor: Dr Gang Liu Supervisor: Associate Professor Guy Lyons Supervisor: Associate Professor Guy Lyons Centenary UTS Centre for Inflammation: Head - Professor Centenary UTS Centre for Inflammation: Head - Professor Immune Imaging Program: Head - Professor Wolfgang Immune Imaging Program: Head - Professor Wolfgang Phil Hansbro Phil Hansbro Weninger Weninger

E: [email protected] E: [email protected] E: [email protected] E: [email protected] P: +61 2 9565 6198 P: +61 2 9565 6198 P: +61 2 9565 6127 P: +61 2 9565 6127

● Understanding the role of extracellular ● Novel treatments of alpha-1 antitrypsin ● How the cornea responds to UV radiation ● Genes and cell-cell interactions in tumour matrix proteins in regulating lung fibrosis gene deficiency induced chronic progression obstructive pulmonary disease The cornea is covered by a multi-layered (stratified) Lung fibrosis is a progressive, debilitating, and severe sheet of clear epithelial cells, which protects it from Cancer cells within a tumour often have different pathogens and the environment. Like the skin, the lung disease, which is characterised by damage to Chronic obstructive pulmonary disease (COPD) is a mutations from neighbouring cells. This genetic cornea is exposed to damaging ultraviolet radiation lung tissues, and idiopathic pulmonary fibrosis (IPF) is progressive pulmonary disease defined by emphysema heterogeneity enables novel cell-cell interactions (UVR) from sunlight. one of the major lung fibrosis diseases in humans. It is and severe breathing difficulties. It is the 3rd to occur that are not possible in homogenous characterised by lung tissue remodelling and fibrosis, commonest cause of chronic morbidity and death. tumours. This opens up exciting new possibilities where normal lung tissue is interspersed with interstitial This project will investigate how UVR affects for understanding the pathogenesis of cancer and stratification of the corneal epithelium and its barrier fibrosis, honeycomb cysts and fibroblast foci. Alpha 1 anti-trypsin (A1AT) deficiency is the major strategies for treating it. function against viruses such as coronaviruses. It will genetic predisposition to COPD. Endogenous proteases use advanced microscopy and image analysis methods In lung injury, extracellular matrix (ECM) proteins are function to clear debris and damaged tissues from the To explore these interactions between cancer cells, we to visualise the epithelial cells of living corneas as they secreted into the connective tissue to serve as scaffolds lungs. However, when not properly controlled they have have identified clones of cells that interact to promote divide, migrate and stratify. for tissue repair and regeneration. However, ECM aberrant activity degrading elastin and various forms of cancer cell growth in an experimental model of oral proteins continue to be produced and deposited in lung collagen leading to lung damage. cancer. tissues in IPF, and the process becomes irreversible. The corneas from novel reporter strains of genetically modified mice will be used to locate and measure Current treatments to lung fibrosis have limited effect to It is well-known that deficiencies in A1AT lead to an This project will investigate the molecular genetic basis signalling responses in the living tissue, and probed reduce and inhibit lung fibrosis development in IPF. imbalance in protease-anti-protease activity resulting in for this interaction, using cell culture, image analysis, with pathway-specific drugs to determine their tissue damage and emphysema. More than 80% of the deep sequencing and mouse models. importance. Our recent studies have identified some key ECM human genome produces RNAs that are not translated, proteins that targeting these proteins can reduce lung and many of them are long non-coding (lnc) RNAs. School at: Pathology fibrosis and inflammation in an experimental model School at: Pathology of lung fibrosis. In this research project, we aim to In this project, we aim to understand how lncRNA Keywords: cancer, oral, skin, microscopy Keywords: eye, cancer, COVID-19, UV radiation, understand the mechanism of the ECM proteins regulates A1AT deficiency-induced COPD and explore microscopy regulate lung fibrosis in IPF. a potential treatment.

School at: UTS School of Life Sciences School at: UTS School of Life Sciences

Keywords: lung fibrosis, idiopathic pulmonary fibrosis, Keywords: Alpha-1 antitrypsin, COPD, PCR, CRISPR animal models, extracellular matrix proteins

Alphabetical by supervisor surname.

Student Research Projects for 2021 Student Research Projects for 2021

38 39 MASTERS PROJECTS

Supervisor: Dr Stefan Oehlers Supervisor: Dr Ulf Schmitz Supervisor: Dr Ulf Schmitz Supervisor: Dr Ulf Schmitz Mycobacterial Program: Head - Professor Warwick Britton Gene and Stem Cell Therapy Program: Head - Professor Gene and Stem Cell Therapy Program: Head - Professor Gene and Stem Cell Therapy Program: Head - Professor AO, Immune-Vascular Interactions Laboratory: Head - Dr John Rasko AO, Computational BioMedicine Laboratory: John Rasko AO, Computational BioMedicine Laboratory: John Rasko AO, Computational BioMedicine Laboratory: Stefan Oehlers Head - Dr Ulf Schmitz Head - Dr Ulf Schmitz Head - Dr Ulf Schmitz

E: [email protected] E: [email protected] E: [email protected] E: [email protected] P: +61 2 9565 6114 P: +61 2 9565 6209 P: +61 2 9565 6209 P: +61 2 9565 6209

● Bidirectional interaction between the ● Characterizing fusion transcripts in ● Deciphering the cross-talk between ● Mirtron synthesis and expression in cardiovascular system and infectious cancer and normal cells microRNAs and retained introns in cancer leukemia diseases gene regulation DNA rearrangement leading to fusion genes is a In a large-scale analysis of alternative splicing across Our research group uses the zebrafish model system to hallmark of cancer. A number of these fusions are Perturbations to the highly calibrated system of gene 2,500 human tissue samples and cell lines we better understand and treat this disease. The zebrafish used as biomarkers and therapeutic targets in different regulation can have severe consequences and cause generated a wealth of data regarding gene-, cell type-, is an emerging model for the study of infectious cancer types; prominent examples include BCR-ABL1 diseases including cancer. MicroRNAs can regulate tissue-, and disease-specific intron-retention events . diseases that complements existing mouse infection for chronic myeloid leukemia and MYC-IGH for Burkitt's dozens of target genes and intron retention has been This data is in parts accessible through a rudimentary models in the Tuberculosis Research Program at the lymphoma. found to be another mechanism of post-transcriptional web interface: http://mimirna.centenary.org.au/irfinder/ Centenary Institute. gene regulation affecting hundreds of genes. database/. Traditionally, DNA rearrangement and gene fusion Mycobacterial infection results in the formation of was attributed largely to chromosomal translocations. In this project we will identify gene-regulatory network In this project we will develop a sophisticated database complex aggregates of immune cells known as However, recent years have produced conclusive modules using a data integration approach to determine and web interface design to provide an efficient and granulomas, and these can be readily visualised in evidences that two or more transcripts can fuse at patterns of competitive post-transcriptional gene rich user experience facilitating a rapid success in the zebrafish. These granulomas behave similarly to the transcription level irrespective of chromosomal regulation. hunt for information about intron retention. The new tumours in many ways including the way they recruit translocations. IRBase 2.0 will provide data in interactive graphs and leaky blood vessels to the site of infection. We have Toward this, we will integrate expression profiles of customized data retrieval options. shown that angiogenesis (http://dx.doi.org/10.1038/ In this project, we will analyse long-read sequencing microRNAs and genes, intron retention profiles and nature13967),vascular permeability (http://dx.doi. and single-cell sequencing data from tumour samples predicted gene-regulatory interactions between (i) School at: School of Medical Sciences org/10.1093/infdis/jiw355), and haemostasis (http:// and healthy tissue to identify known and novel fusion microRNAs and target genes, (ii) transcription factors dx.doi.org/10.1093/infdis/jiz110) aid mycobacterial transcripts and determine their (cancer) cell-type and target genes, and (iii) microRNA-intron retention Keywords: alternative splicing, database design, growth in zebrafish infection models. specific expression profiles. interactions. For a selected sub network relevant in graphical user interface, data integration, data cancer we will construct a mathematical model of visualisation This project will expand these findings by determining School at: School of Medical Sciences competitive post-transcriptional gene regulation. the effects of vascularisation on host and bacterial physiology using a combination of in vitro cell culture Keywords: bioinformatics, trans-splicing, single cell School at: School of Medical Sciences assays, zebrafish infection experiments and mouse sequencing, long read sequencing, big data, cancer models of pulmonary TB. biology Keywords: microRNA, alternative splicing, bioinformatics, systems biology School at: Infectious Diseases and Immunology

Keywords: infection & immunity, cardiovascular & respiratory diseases, vascular biology, zebrafish

Alphabetical by supervisor surname.

Student Research Projects for 2021 Student Research Projects for 2021

40 41 MASTERS PROJECTS

Supervisor: Dr Ulf Schmitz Supervisor: Dr Sj Sijie Shen Supervisor: Dr Hui Emma Zhang Gene and Stem Cell Therapy Program: Head - Professor Centenary UTS Centre for Inflammation: Head - Professor Liver Enzymes in Metabolism and Inflammation Program: John Rasko AO, Computational BioMedicine Laboratory: Phil Hansbro Head - Professor Mark Gorrell Head - Dr Ulf Schmitz

E: [email protected] E: [email protected] E: [email protected] P: +61 2 9565 6209 P: 0466 574 995 P: +61 2 9565 6115

● Core transcriptional networks in cell trans- ● Modulating the gut microbiome to ● Proteases in liver cancer differentiation influence the progression of lung diseases Primary liver cancer is the 4th leading cause of cancer Core transcriptional networks are essential drivers Dr Shen is a postdoctoral researcher in Professor related deaths and there is an urgent need to develop and determinants of cell-fate transitions. To date, our Phil Hansbro’s group at the recently established UTS/ improved medical therapy. Our team is the first to mechanistic understanding of these essential regulatory Centenary Centre for Inflammation, based at the find that the protease DPP9 is a druggable target in layers is very limited, especially in the context of trans- Centenary Institute. hepatocellular carcinoma (HCC). DPP9 inhibition has differentiation, despite being one of the most promising shown anti-cancer actions in acute myeloid leukaemia therapeutic cell replacement strategies in regenerative His research aims to provide deeper insights into the and lung cancer. This project aims to better understand medicine. “gut-lung axis”. The project will explore how our lifestyle the roles of DPP9 in the pathogenesis of HCC. and environment alters the bacteria in the gut (the In this project, we will reconstruct gene-regulatory gut microbiome) to influence lung inflammation during Projects will be these, or similar based on student networks involving non-coding RNAs and mRNAs severe asthma and chronic obstructive pulmonary interests: that drive trans-differentiation of human cells and disease (COPD). The major aim of this project is to identify key alternative splicing events during cell-fate delve deep into understanding the mechanisms by 1. To elucidate molecular mechanisms of DPP9 using transitions. which bacteria interacts with and influences host liver cancer cell lines. immune cells and responses in the gut, and how this 2. To generate cell-specific DPP9 depletion in mice to School at: School of Medical Sciences modulates inflammation in the lungs. This project will study the role of DPP9 in the immune system. utilise well-established animal models combined with 3. To measure growth of orthotopic tumours in DPP9 Keywords: bioinformatics, systems biology, next cutting-edge techniques for research. generation sequencing data analysis inhibitor treated mice. Dr Shen received his PhD in medicine/immunology from Monash University in 2019. His research shows Skills that the student can learn: cell culture, that host immune and environmental factors change the histopathology, immunohistochemistry, immunoblotting, gut microbiome and alter colitis. qPCR, flow cytometry, confocal microscopy.

Pathology School at: UTS School of Life Sciences School at:

protease, liver cancer, inflammation, DNA Keywords: microbiome, gut, lung, respiratory, COPD, Keywords: bacteria, asthma repair

Alphabetical by supervisor surname.

Student Research Projects for 2021 Student Research Projects for 2021

42 43 Supervisor: Dr Chuck Bailey Supervisor: Dr Chuck Bailey Gene and Stem Cell Therapy Program: Head - Professor Gene and Stem Cell Therapy Program: Head - Professor PhD John Rasko AO John Rasko AO Projects E: [email protected] E: [email protected] P: +61 2 9565 6171 P: +61 2 9565 6171

● Molecular modeling of cancer-associated ● Understanding the role of CTCF genetic mutations in tumour suppressor genes deletion in aggressive endometrial cancer Embrace the independence to pursue your desire of discovery. The ‘master weaver’ protein CTCF, is mutated in CTCF is essential for the normal organisation of endometrial cancer, as well as colorectal, stomach, DNA in cells. Our team has discovered that CTCF is With state-of-the-art facilities, and an internationally renowned reputation, the breast and haemopoietic cancers. Our group was the genetically deleted at high rates in the most aggressive Centenary Institute offers you the support and means to realise your dreams first to demonstrate that the ubiquitous zinc finger and deadly types of endometrial cancer (Marshall, et through pioneering breakthroughs and advancing the fight to find a cure. (ZF) protein CTCF acts as a tumour suppressor gene. al., 2017). CTCF deletion predominantly occurs in the Missense mutations in CTCF are enriched in the DNA- Type II serous subtype of endometrial cancer and is Centenary has supported PhD candidates that have gone on to revolutionise binding ZF region. associated with poorer overall survival in patients with medical practice and saving countless lives. serous tumours. Additionally, we have shown that We have shown that mutations in the ZF region can CTCF deletions also occur in the clear cell subtype result in a loss- or gain-of-function in CTCF, which has and this may be associated with tumour relapse and/or implications for cancer development. We are currently metastasis. modelling ‘hotspot’ mutations on published CTCF ZF structures to assess the impact of those mutations. Our culturing of endometrial cancer cell-lines as 3D In addition, we will develop homology models for the spheroids has shown that a functional consequence of ZF domain of CTCF-Like protein (CTCFL, also known CTCF deletion results in a loss of cell polarity – an early as BORIS). CTCFL which shares 80% homology with event in endometrial cancer pathology. Our analysis CTCF within its ZF domain is aberrantly expressed of gene expression data in CTCF heterozygous in more than half of all cancers. Both factors have endometrial tumours has revealed a widespread overlapping and unique DNA binding characteristics. dysreguation of transcription.

We will examine which residues are critical for binding In this project we will examine those genes and of CTCF and CTCFL to the same DNA target sites and biochemical pathways that are dysregulated in CTCF which ZF residues confer DNA binding specificity. This mutant endometrial cancers. We will investigate the will provide important insight into the sibling rivalry that impact of these genes on cell polarity in 3D spheroids exists between CTCF and CTCFL in normal biology and which will give us important insights into early cancer. pathophysiological events underlying endometrial “As a clinician, it has been a really interesting transition into the research world but cancer. with the support of an amazing group of experienced researchers in the lab, I am School at: Pathology thoroughly enjoying pursuing my PhD at Centenary.” School at: Pathology Keywords: protein structure, mutation, cancer, Dr Julia Isbister, PhD Student pictured with her Supervisor, Professor Chris transcription factor Keywords: endometrial cancer, mutation, mouse Semsarian AM, Head of the Molecular Cardiology Program models, cell biology

Alphabetical by supervisor surname.

centenary.org.au/students Student Research Projects for 2021

45 PhD PROJECTS

Supervisor: Dr Chuck Bailey Supervisor: Dr Chuck Bailey Supervisor: Professor Warwick Britton AO Supervisor: Dr Jaesung Peter Choi Gene and Stem Cell Therapy Program: Head - Professor Gene and Stem Cell Therapy Program: Head - Professor Mycobacterial Program: Head - Professor Warwick Centenary UTS Centre for Inflammation: Head - Professor John Rasko AO John Rasko AO Britton AO Phil Hansbro

E: [email protected] E: [email protected] E: [email protected] E: [email protected] P: +61 2 9565 6171 P: +61 2 9565 6171 P: 0414 981 003 P: +61 2 9565 6203

● The role of MGA mutation in chronic ● Modulation of host entry factors to ● How does silica dust make TB worse? ● Finding safe and effective therapies lymphocytic leukaemia (CLL) improve AAV-mediated gene therapy targeting sex hormones and the microbiome The lung is one of the most important organs exposed for the commonest cause of stroke in to environmental pollution and pathogens. Lung Chronic lymphocytic leukaemia (CLL) is the most Recombinant adeno-associated virus (rAAV) has children: cerebral cavernous malformation common leukaemia in senior Australians. Every year gained widespread use as a gene delivery vector for inflammation and disease is a leading cause of death nearly 1000 Australians are diagnosed with CLL and corrective gene therapies due to its lack of association and disability globally, and an overlooked area is the (CCM) typically 80% of all new diagnoses are in patients over with any human disease and its ability to safely and intersection of silicosis and tuberculosis (TB). the age of 60 years. efficiently deliver a genetic payload into a broad range Cerebral cavernous malformations (CCMs) are vascular of tissues. Well-known as a disease of miners and stonemasons, lesions of the central nervous system that affect 1 in CLL is a slow developing cancer affecting B cells. silicosis has resurged in the sandstone basin which 200 people. CCM lesions are prone to bleeds and are Genetic mutations acquired in these B cells result For liver-specific genetic diseases, current rAAV cups the Sydney region and continues to afflict millions the major cause of stroke and sudden death in children. in their transformation into cancerous cells that can modalities have not provided the necessary high-level of workers in hazardous occupations around the world. Current treatment for CCM is limited to high-risk live longer and grow faster than normal B cells. transduction efficiencies and humoral neutralisation Silicosis predisposes to TB and patients with silicosis neurosurgery. As such there is an urgent need for novel Similar to many blood cancers, genetic alterations properties necessary for curative outcomes in diverse who develop active TB have poor outcomes. As 25% of non-invasive, druggable treatment options. in CLL can be heterogeneous, and include point patient groups. the world’s population is infected with Mycobacterium mutations, chromosomal deletions, amplifications tuberculosis, this is a serious problem. Just as men have earlier onset and more severe and rearrangements. Recent reports have identified Improved transduction efficiency of rAAV vectors has cardiovascular diseases than women, recent clinical the gene encoding the transcription factor Max Gene been achieved by engineering capsids with higher The mechanisms by which silicosis impacts the body’s observations and our preliminary data in mouse models Associated (MGA) to be recurrently deleted in CLL. affinity or cell-specific tropism and increased resistance defenses against mycobacteria are poorly understood. demonstrate a greater CCM burden in males. The male MGA inactivation through chromosomal deletion or to neutralising antibodies. Increasing AAV-mediated This project will use a mouse model of silicosis and predisposition to CCM is likely to reflect an impact of point mutation occurs in 4% of CLL, but this increases therapeutic efficacy by modulating host entry factors mycobacterial infection to examine how silicosis sex hormones in its pathogenesis. Furthermore, we to 16% as CLL disease progresses to chemotherapy remains unexplored. affects innate (dendritic cell and macrophage) and recently identified the gut microbiome as a critical resistance. adaptive immune responses. The student will be part stimulant of CCM. Interestingly, gut microbiota differs KIAA0319L was recently shown to be an essential of a stimulating research team and develop skills in between males and females and microbiota influence Our hypothesis is that genetic inactivation of MGA host entry factor for most AAV serotypes, however the immunology, cellular biology and flow cytometry. sex hormone metabolism and action. promotes chronic lymphocytic leukaemia disease biology and normal function of KIAA0319L is poorly progression. We will test this hypothesis by analysing understood. In this project, we will use a combination School at: School of Medical Sciences Hence, the project aims to elucidate the role that sex how acquired genetic lesions in MGA alter the of biochemical, genetic and proteomic strategies to hormones and the microbiome play in the prominent proliferation, differentiation and survival of CLL cells functionally characterise the host determinants that Keywords: immunology, infectious diseases, sex difference in CCM. This could reveal a potential and contribute to cellular transformation. regulate KIAA0319L expression and distribution. tuberculosis, environment, inflammation use of steroids, precision antibiotics/probiotics, and repurposing existing drugs as non-invasive therapeutic School at: Pathology School at: Pathology options for CCM.

Keywords: leukaemia, mutation, transcription factor, Keywords: gene therapy, adeno-associated virus, host School at: UTS School of Life Sciences mouse models factor, KIAA0319L Keywords: stroke, cardiovascular diseases, mouse, microbiome, cerebral cavernous malformation

Alphabetical by supervisor surname.

Student Research Projects for 2021 Student Research Projects for 2021

46 47 PhD PROJECTS

Supervisor: Associate Professor Mathias Supervisor: Associate Professor Mathias Supervisor: Professor Jennifer Gamble Supervisor: Professor Jennifer Gamble Francois Francois Vascular Biology Program: Head - Professor Jennifer Vascular Biology Program: Head - Professor Jennifer David Richmond Laboratory for Cardiovascular David Richmond Laboratory for Cardiovascular Gamble Gamble Development: Gene Regulation and Editing Program: Development: Gene Regulation and Editing Program: Head - Associate Professor Mathias Francois Head - Associate Professor Mathias Francois E: [email protected] E: [email protected] E: [email protected] E: [email protected] P: +61 2 8627 9497 P: +61 2 8627 9497

● Imaging transcription at single molecule ● Molecular and cellular basis of lymphatic ● Alzheimer's Disease: How age effects the ● Calcified aortic valve disease: the role of resolution in a living cell vascular development blood vessels in the brain the ageing

The primary objective of this project is to develop The primary objective of this project is to develop Alzheimer’s Disease (AD) is an age-related disease Calcific aortic valve disease (CAVD) is the most a research study with general and specific in vitro a research study with general and specific in vivo that affects brain function. common valvular heart disease in developed countries. techniques in stem cells and in vivo approaches in early techniques in mouse or zebrafish model system to However, the molecular mechanisms or targets stage mouse embryo to study the molecular basis of study the molecular and cellular biology of vascular Ageing and its consequence to induce dysfunctional for nonsurgical treatments, to prevent or slow the cell fate decision during embryogenesis. development during embryogenesis. endothelial cells is one of the greatest risk factors for progression of CAVD, remain elusive. both AD and cardiovascular disease. This work will take advantage of cutting edge The biological question is centred around the molecular The incidence of CAVD increases with age, in an area approaches based on single molecule approaches control of cell fate during lymphatic endothelial cell We are studying the molecular consequences of ageing of the aorta where blood flow is disturbed. Disturbed to study the role of different components of the specification by a novel transcriptional effector. (cellular senescence) on endothelial cells and pericytes blood flow is associated with premature ageing of blood transcriptional machinery in stem cells. Two types of The work will involve wet and dry lab approach to using single cell RNAseq analysis of mouse brain cells. vessels and loss of the protective mechanisms against complementary approaches will be used in parallel understand how this new gene modulates the program The genes may expose novel insights into cellular inflammation in the aorta. either based on live imaging methods or on fixed cells of lymphatic endothelial cell differentiation on a genome ageing and potential targets for the development of with super resolution microscopy. Further the work wide scale. Techniques used will cover a broad range senolytics, drugs designed to eliminate senescent cells The project is directed to identification of changes in will be complemented by genomic and transcriptomic of skills from phenotyping vascular networks using and restore organ function. the aortic valve upon ageing using animal model and approaches to correlate changes in gene output with confocal microscopy to gene editing with crispr/cas9 human tissue and the molecular signalling pathways molecular activity imaged in a cell. and genomics and transcriptomics approaches. Scientist associated with this project: Dr Paul that are altered with age. Coleman The David Richmond (DR) program for cardio-vascular The David Richmond (DR) program for cardio-vascular Techniques: animal models, high resolution imaging, development welcomes only a limited number of development welcomes only a limited number of E: [email protected] P: +61 2 9565 6229 RNAseq gene analysis, tissue culture, Honours / PhD candidates to ensure high quality Honours / PhD candidates to ensure high quality supervision is provided to the student. Usually students supervision is provided to the student. Usually student School at: School of Medical Sciences School at: School of Medical Sciences work on their own project but embedded in a team with work on their own project but embedded in a team with a post doc and research assistant.The DR laboratory a post doc and research assistant.The DR laboratory Keywords: alzheimer's disease; age; single cell Keywords: calcified aortic valve disease; age: is physically located at the CPC and therefore benefits is physically located at the CPC and therefore benefits analysis cardiovascular disease from a great scientific environment from both the from a great scientific environment from both the CI and Centenary Institute and the CPC. the CPC.

School at: School of Medical Sciences School at: School of Medical Sciences

Keywords: gene regulation, molecular imaging, Keywords: transcription factor, molecular genetics, in transcription factors, stem cell, super resolution imaging vivo model, mouse and fish transgenics, live imaging

Alphabetical by supervisor surname.

Student Research Projects for 2021 Student Research Projects for 2021

48 49 PhD PROJECTS

Supervisor: Professor Jennifer Gamble Supervisor: Professor Mark Gorrell Supervisor: Dr Daniel Hesselson Supervisor: Dr Daniel Hesselson Vascular Biology Program: Head - Professor Jennifer Liver Enzymes in Metabolism and Inflammation Program: ACRF Centenary Cancer Centre: Head - Professor Phil ACRF Centenary Cancer Centre: Head - Professor Phil Gamble Head - Professor Mark Gorrell Hogg, Directed Evolution Laboratory: Head - Dr Dan Hogg, Directed Evolution Laboratory: Head - Dr Dan Hesselson Hesselson

E: [email protected] E: [email protected] E: [email protected] E: [email protected] P: + 61 2 9565 6152 P: 0404 456 830 P: 0404 456 830

● Alzheimer's Disease: How age effects the ● Proteases in the pathogenesis of chronic ● Blocking follistatin in ovarian cancer to ● Functional strategies to mitigate or blood vessels in the brain liver injury and cancer prevent chemoresistance and recurrence eliminate PFAS from human and animal tissue Ageing is one of the greatest risk factors for Primary liver cancer is the 4th leading cause of cancer In the Directed Evolution laboratory, we harness the cardiovascular disease including Alzheimer's Disease. related deaths. We are addressing the urgent need to power of Darwinian selection to evolve proteins with Per- and poly-fluoroalkyl substances (PFAS) are Cellular ageing, referred to as cellular senescence develop a greater understanding of pathogenesis for new therapeutic activities. We have discovered that synthetic chemicals that resist heat and water, and have is an irreversible process activated in response to improved therapeutics. The pathogenesis of chronic blocking follistatin activity could increase the sensitivity been widely used since the 1940s. Importantly, these stress that is characterised by permanent cell cycle liver injury and cancer is driven by chronic cell death of ovarian cancer to primary chemotherapeutics. compounds are highly stable in the environment and in arrest, an active metabolic state and in changes to the and proliferation and inflammation. Cirrhosis generally However, existing anti-follistatin antibodies lack the some areas have penetrated ground water putting rural inflammatory phenotype of the cell. precedes cancer in the liver. potency to fully neutralise follistatin activity in vivo. populations at risk of continued chronic exposure.

Endothelial cells are unique in showing both pro- Proteases are important in cancer pathogenesis and Thus, we will evolve high affinity single-domain This project is part of a larger program to provide inflammatory and anti-inflammatory senescence suit drug development. We primarily study fibroblast antibodies (nanobodies) against follistatin, to disrupt clear and experimentally validated evidence and phenotypes. We have evidence to suggest that this activation protein (FAP) and DPP9 as proteases its signalling. This work will pave the way for new meta-evidence for how PFAS exposure impacts dual phenotype maybe regulated through changes in associated with cancer pathogenesis. adjunctive therapies which could enhance the efficacy human health, its biological mechanisms of action, the metabolic state of the cell. of primary chemotherapeutics in a wide range of and importantly how to treat individuals exposed to I discuss with each student their interests, skills and cancers. hazardous levels of PFAS. This project will investigate this possibility and uncover aspirations in order to design a suitable project within the molecular pathway that controls the metabolic these topics: School at: School of Medical Sciences Developing zebrafish embryos absorb PFAS from switch. their aqueous environment and bioaccumulate these 1. Liver complications of diabetes and chronic fatty liver. Keywords: directed evolution, cancer, chemicals. We’ve discovered that embryos loaded Associated Scientist: Dr Paul Coleman 2. Liver cirrhosis and cancer. chemoresistance with PFAS continue to endure toxic effects even once moved to an uncontaminated environment providing a 3. Protein biochemistry and inhibitors of FAP and DPP9. E: [email protected] P: +61 2 9565 6229 high-throughput experimental system to identify small 4. Diagnosis of fibrosis in chronic liver disease and molecule treatments that stimulate PFAS elimination School at: School of Medical Sciences predicting treatable patients. at the organism level. In this project we will perform unbiased small molecule screens to identify and 5. Potential therapies for cancer and NASH. Keywords: ageing, metabolism, inflammation validate novel potential treatments for PFAS exposure in humans. Training: We use sophisticated techniques in immunohistochemistry, flow cytometry, qPCR, School of Medical Sciences immunoblotting, protease assays, ELISA and confocal School at: microscopy. Projects can be in cell lines, mouse models environmental determinants of human or with specimens from RPA hospital. Keywords: health and treatment strategies School at: School of Medical Sciences

Keywords: cirrhosis, NASH, cancer, liver, DPP4, fibrosis, mouse, human

Alphabetical by supervisor surname.

Student Research Projects for 2021 Student Research Projects for 2021

50 51 PhD PROJECTS

Supervisor: Dr Gang Liu Supervisor: Dr Gang Liu Supervisor: Associate Professor Guy Lyons Supervisor: Associate Professor Guy Lyons Centenary UTS Centre for Inflammation: Head - Professor Centenary UTS Centre for Inflammation: Head - Professor Immune Imaging Program: Head - Professor Wolfgang Immune Imaging Program: Head - Professor Wolfgang Phil Hansbro Phil Hansbro Weninger Weninger

E: [email protected] E: [email protected] E: [email protected] E: [email protected] P: +61 2 9565 6198 P: +61 2 9565 6198 P: +61 2 9565 6127 P: +61 2 9565 6127

● Understanding the role of extracellular ● Novel treatments of alpha-1 antitrypsin ● How the cornea responds to UV radiation ● Genes and cell-cell interactions in tumour matrix proteins in regulating lung fibrosis gene deficiency induced chronic progression obstructive pulmonary disease The cornea is covered by a multi-layered (stratified) Lung fibrosis is a progressive, debilitating, and severe sheet of clear epithelial cells, which protects it from Cancer cells within a tumour often have different pathogens and the environment. Like the skin, the lung disease, which is characterised by damage to Chronic obstructive pulmonary disease (COPD) is a mutations from neighbouring cells. This genetic cornea is exposed to damaging ultraviolet radiation lung tissues, and idiopathic pulmonary fibrosis (IPF) is progressive pulmonary disease defined by emphysema heterogeneity enables novel cell-cell interactions (UVR) from sunlight. one of the major lung fibrosis diseases in humans. It is and severe breathing difficulties. It is the 3rd to occur that are not possible in homogenous characterised by lung tissue remodelling and fibrosis, commonest cause of chronic morbidity and death. tumours. This opens up exciting new possibilities where normal lung tissue is interspersed with interstitial This project will investigate how UVR affects for understanding the pathogenesis of cancer and stratification of the corneal epithelium and its barrier fibrosis, honeycomb cysts and fibroblast foci. Alpha 1 anti-trypsin (A1AT) deficiency is the major strategies for treating it. function against viruses such as coronaviruses. It will genetic predisposition to COPD. Endogenous proteases use advanced microscopy and image analysis methods In lung injury, extracellular matrix (ECM) proteins are function to clear debris and damaged tissues from the To explore these interactions between cancer cells, we to visualise the epithelial cells of living corneas as they secreted into the connective tissue to serve as scaffolds lungs. However, when not properly controlled they have have identified clones of cells that interact to promote divide, migrate and stratify. for tissue repair and regeneration. However, ECM aberrant activity degrading elastin and various forms of cancer cell growth in an experimental model of oral proteins continue to be produced and deposited in lung collagen leading to lung damage. cancer. tissues in IPF, and the process becomes irreversible. The corneas from novel reporter strains of genetically modified mice will be used to locate and measure Current treatments to lung fibrosis have limited effect to It is well-known that deficiencies in A1AT lead to an This project will investigate the molecular genetic basis signalling responses in the living tissue, and probed reduce and inhibit lung fibrosis development in IPF. imbalance in protease-anti-protease activity resulting in for this interaction, using cell culture, image analysis, with pathway-specific drugs to determine their tissue damage and emphysema. More than 80% of the deep sequencing and mouse models. importance. Our recent studies have identified some key ECM human genome produces RNAs that are not translated, proteins that targeting these proteins can reduce lung and many of them are long non-coding (lnc) RNAs. School at: Pathology fibrosis and inflammation in an experimental model School at: Pathology of lung fibrosis. In this research project, we aim to In this project, we aim to understand how lncRNA Keywords: cancer, oral, skin, microscopy Keywords: eye, cancer, COVID-19, UV radiation, understand the mechanism of the ECM proteins regulates A1AT deficiency-induced COPD and explore microscopy regulate lung fibrosis in IPF. a potential treatment.

School at: UTS School of Life Sciences School at: UTS School of Life Sciences

Keywords: lung fibrosis, idiopathic pulmonary fibrosis, Keywords: Alpha-1 antitrypsin, COPD, PCR, CRISPR animal models, extracellular matrix proteins

Alphabetical by supervisor surname.

Student Research Projects for 2021 Student Research Projects for 2021

52 53 PhD PROJECTS

Supervisor: Dr Stefan Oehlers Supervisor: Dr Ulf Schmitz Supervisor: Dr Ulf Schmitz Supervisor: Clinical Associate Professor Mycobacterial Program: Head - Professor Warwick Britton Gene and Stem Cell Therapy Program: Head - Professor Gene and Stem Cell Therapy Program: Head - Professor Devanshi Seth AO, Immune-Vascular Interactions Laboratory: Head - Dr John Rasko AO, Computational BioMedicine Laboratory: John Rasko AO, Computational BioMedicine Laboratory: Liver Injury and Cancer Program: Head - Professor Geoff Stefan Oehlers Head - Dr Ulf Schmitz Head - Dr Ulf Schmitz McCaughan, Alcoholic Liver Disease Laboratory: Head - Clinical Associate Professor Devanshi Seth E: [email protected] E: [email protected] E: [email protected] E: [email protected] P: +61 2 9565 6114 P: +61 2 9565 6209 P: +61 2 9565 6209 T: +61 2 9565 6268

● Bidirectional interaction between the ● Deciphering the cross-talk between ● Core transcriptional networks in cell trans- ● Role of lipid metabolism in alcohol- cardiovascular system and infectious microRNAs and retained introns in cancer differentiation induced liver cirrhosis diseases gene regulation Core transcriptional networks are essential drivers Risky drinking continues to be a major concern in Our research group uses the zebrafish model system to Perturbations to the highly calibrated system of gene and determinants of cell-fate transitions. To date, our Australia. The major medical consequence of risky better understand and treat this disease. The zebrafish regulation can have severe consequences and cause mechanistic understanding of these essential regulatory drinking is alcohol-induced liver cirrhosis (AC). Our is an emerging model for the study of infectious diseases including cancer. MicroRNAs can regulate layers is very limited, especially in the context of trans- discovery of novel variant in FAF2 gene (lipid droplet/ diseases that complements existing mouse infection dozens of target genes and intron retention has been differentiation, despite being one of the most promising metabolism) associated with the risk of AC in drinkers, models in the Tuberculosis Research Program at the found to be another mechanism of post-transcriptional therapeutic cell replacement strategies in regenerative is significant because it fits well with the current Centenary Institute. gene regulation affecting hundreds of genes. medicine. knowledge of other single nucleotide polymorphisms (SNPs) in genes (PNPLA3, TM6SF2 and HSD17B13) Mycobacterial infection results in the formation of In this project we will identify gene-regulatory network In this project, we will reconstruct gene-regulatory also linked to lipid biology. Build-up of lipid droplets in complex aggregates of immune cells known as modules using a data integration approach to determine networks involving non-coding RNAs and mRNAs the liver due to heavy drinking can cause inflammation, granulomas, and these can be readily visualised in patterns of competitive post-transcriptional gene that drive trans-differentiation of human cells and leading to cirrhosis in some drinkers. zebrafish. These granulomas behave similarly to regulation. identify key alternative splicing events during cell-fate tumours in many ways including the way they recruit transitions. My group is interested to understand the mechanisms leaky blood vessels to the site of infection. We have Toward this, we will integrate expression profiles of of action of these genes in the development of shown that angiogenesis (http://dx.doi.org/10.1038/ microRNAs and genes, intron retention profiles and School at: School of Medical Sciences cirrhosis. We will use our established zebrafish model nature13967),vascular permeability (http://dx.doi. predicted gene-regulatory interactions between (i) of alcohol-induced liver injury. Function of risk genes org/10.1093/infdis/jiw355), and haemostasis (http:// microRNAs and target genes, (ii) transcription factors Keywords: bioinformatics, systems biology, next and their mechanisms driving disease development dx.doi.org/10.1093/infdis/jiz110) aid mycobacterial and target genes, and (iii) microRNA-intron retention generation sequencing data analysis will be studied using gene-editing (Crispr-Cas9), growth in zebrafish infection models. interactions. For a selected sub network relevant in transgenics and state-of-art imaging technology. It will cancer we will construct a mathematical model of advance knowledge on the role of lipid biology genes This project will expand these findings by determining competitive post-transcriptional gene regulation. in chronicity of AC development. Importantly, it will the effects of vascularisation on host and bacterial generate a list of new drug targets. physiology using a combination of in vitro cell culture School at: School of Medical Sciences assays, zebrafish infection experiments and mouse School: School of Medical Sciences models of pulmonary TB. Keywords: microRNA, alternative splicing, bioinformatics, systems biology Keywords: cirrhosis, SNPs, lipid, alcohol, genetics, School at: Infectious Diseases and Immunology zebrafish, crispr

Keywords: infection & immunity, cardiovascular & respiratory diseases, vascular biology, zebrafish

Alphabetical by supervisor surname.

Student Research Projects for 2021 Student Research Projects for 2021

54 55 PhD PROJECTS

Supervisor: Clinical Associate Professor Supervisor: Dr Sj Sijie Shen Supervisor: Dr Dannel Yeo Supervisor: Dr Dannel Yeo Devanshi Seth Centenary UTS Centre for Inflammation: Head - Professor Gene and Stem Cell Therapy Program: Head - Professor Gene and Stem Cell Therapy Program: Head - Professor Liver Injury and Cancer Program: Head - Professor Geoff Phil Hansbro John Rasko AO John Rasko AO McCaughan, Alcoholic Liver Disease Laboratory: Head - Clinical Associate Professor Devanshi Seth E: [email protected] E: [email protected] E: [email protected] E: [email protected] T: +61 2 9565 6268 P: 0466 574 995 P: +61 2 9565 6286 P: +61 2 9565 6286

● Why do only some drinkers develop liver ● Modulating the gut microbiome to ● Circulating tumour cells to monitor ● Investigating CAR-T therapy for pancreatic cirrhosis? Risk stratification of drinkers using influence the progression of lung diseases cancer patients cancer genomics+clinical risk factors Dr Shen is a postdoctoral researcher in Professor Circulating tumour cells (CTCs) are tumour cells that Chimeric antigen receptor-engineered T-cell (CAR-T) Risky drinking continues to be a major ongoing concern Phil Hansbro’s group at the recently established UTS/ have been released from the primary tumour tissue to therapy is an exciting new cellular immunotherapy for in Australia despite public health measures. As 90% Centenary Centre for Inflammation, based at the form metastases by travelling through the blood and the treatment of cancer. of alcohol is metabolised through the liver, vulnerable Centenary Institute. lymphatic system. Capturing and analysing these rare population, especially those with drinking problems, cells is now possible using our next generation liquid Isolated patient T-cells are modified to target a specific are at high risk of alcohol-induced liver cirrhosis (AC). His research aims to provide deeper insights into the biopsy platform. tumour surface antigen and then injected back into There is limited information to predict who amongst the “gut-lung axis”. The project will explore how our lifestyle the patient. CAR-T therapy is now approved for blood drinkers are at a greater risk of developing cirrhosis. and environment alters the bacteria in the gut (the We are able to identify, capture and characterise these cancers but the same success has not been observed gut microbiome) to influence lung inflammation during CTCs. Hence, this platform has the potential to provide in solid cancers. The project will utilize our multinational GenomALC severe asthma and chronic obstructive pulmonary ‘real-time’ cancer monitoring throughout all stages of a Consortium data from thousands of drinkers. We disease (COPD). The major aim of this project is to patient’s cancer journey and identify potentially effective Novel CAR-T therapies will be evaluated in pancreatic recently reported that algorithm combining a few delve deep into understanding the mechanisms by treatments in cancers such as pancreatic cancer, lung cancer using the latest cancer model systems genomic with clinical risk factors performed better than which bacteria interacts with and influences host cancer, and mesothelioma. Potential research topics including 2D cells, 3D organoids and mice models. either alone in stratifying drinkers ‘at risk’ of developing immune cells and responses in the gut, and how this include: To test the efficacy of CAR-T cells, cytotoxicity and AC. modulates inflammation in the lungs. This project will immune activation/persistence will be evaluated, and utilise well-established animal models combined with 1. Evaluate CTCs to predict patient response and guide mechanisms of resistance will be explored. We will generate predictive models and precision cutting-edge techniques for research. patient management. Skills/tools: mammalian cell culture, cell biology algorithm using machine learning (ML) tools as novel 2. Characterise CTCs using genetic, cellular and Dr Shen received his PhD in medicine/immunology assays (including cellular impedance assays, live cell means in this disease to allow reliable identification and imaging techniques. stratification of drinkers by disease risk. Understanding from Monash University in 2019. His research shows imaging), isolating T cells, lentivirus gene transfer, individual risks will revolutionise clinical management of that host immune and environmental factors change the 3. Establish and characterise patient-derived CTC immune phenotyping (by flow cytometry), RT-qPCR, patients with AC gut microbiome and alter colitis. organoid cultures. cytokine analysis (ELIZA), and mouse models. 4. Evaluate CTCs and other blood biomarkers as a School: School of Medical Sciences School at: UTS School of Life Sciences diagnostic marker to improve early detection. School at: Pathology

Keywords: cirrhosis, alcohol, genetics, coffee, Keywords: microbiome, gut, lung, respiratory, COPD, Skills/tools: Mammalian cell culture (3D), cell Keywords: cancer, immunotherapy, CAR-T diabetes, risk prediction, machine learning bacteria, asthma biology assays, western blot, RT-qPCR, microscopy, immunofluorescence, cell picking, mouse models

School at: Pathology

Keywords: cancer, translational medicine, liquid biopsy, circulating tumour cells

Alphabetical by supervisor surname.

Student Research Projects for 2021 Student Research Projects for 2021

56 57 PhD PROJECTS

Where to find Centenary Institute

Supervisor: ClinicalDr Hui Emma Associate Zhang Professor DevanshiLiver Enzymes Sethin Metabolism and Inflammation Program: LiverHead Injury - Professor and Cancer Mark Gorrell Program: Head - Professor Geoff McCaughan, Alcoholic Liver Disease Laboratory: Head - Clinical Associate Professor Devanshi Seth E: [email protected] E: [email protected] P: +61 2 9565 6115 T: +61 2 9565 6268

● WhyProteases do only in liversome cancer drinkers develop liver cirrhosis? Risk stratification of drinkers using Primary liver cancer is the 4th leading cause of cancer genomics+clinicalrelated deaths and there risk is an factors urgent need to develop improved medical therapy. Our team is the first to Riskyfind that drinking the protease continues DPP9 to be is a amajor druggable ongoing target concern in inhepatocellular Australia despite carcinoma public (HCC).health measures.DPP9 inhibition As 90% has ofshown alcohol anti-cancer is metabolised actions through in acute the myeloid liver, vulnerable leukaemia population, especially those with drinking problems, and lung cancer. This project aims to better understand Centenary are at high risk of alcohol-induced liver cirrhosis (AC). the roles of DPP9 in the pathogenesis of HCC. Institute There is limited information to predict who amongst the drinkersProjects arewill atbe a these, greater or risksimilar of developing based on student cirrhosis. interests: The project will utilize our multinational GenomALC Consortium1. To elucidate data molecular from thousands mechanisms of drinkers. of DPP9 We using recentlyliver cancer reported cell that lines. algorithm combining a few genomic with clinical risk factors performed better than either2. To generate alone in stratifyingcell-specific drinkers DPP9 ‘at depletion risk’ of developingin mice to AC.study the role of DPP9 in the immune system. 3. To measure growth of orthotopic tumours in DPP9 Weinhibitor will generate treated predictive mice. models and precision algorithm using machine learning (ML) tools as novel meansSkills that in this the disease student to can allow learn: reliable cell identification culture, and stratificationhistopathology, of immunohistochemistry,drinkers by disease risk. immunoblotting, Understanding individualqPCR, flow risks cytometry, will revolutionise confocal clinicalmicroscopy. management of Our official address is But the easiest way to find us is patients with AC School at: Pathology Building 93, RPA Hospital Follow Johns Hopkins Drive, off Missenden Road or, School: School of Medical Sciences Missenden Road walk through the University of Sydney and our building Keywords: protease, liver cancer, inflammation, DNA Camperdown 2050 is next to the Charles Perkins Centre. Keywords:repair cirrhosis, alcohol, genetics, coffee, diabetes, risk prediction, machine learning

Student Research Projects for 2021 Student Research Projects for 2021

58 59 www.centenary.org.au 1800 677 977