CPC Honours Projects 2020

Honours Projects on offer in the Charles Perkins Centre Hub 2020

Research Group Leader Department/School Research Area

Associate Professor Kim Bell-

Anderson

School of Life and

Environmental Sciences

Nutritional physiology and

metabolic disease

Dr Amanda Brandon School of Medical Sciences Energy Metabolism and Insulin

Action Laboratory

Professor Arthur Conigrave School of Life and

Environmental Sciences

Nutrient sensing mechanisms in

biology and medicine

Dr Leslie Caron School of Life and

Environmental Sciences

Human Pluripotent Stem Cells for

disease modelling and Cellular

Therapy

Dr Kristina Cook Northern Clinical School,

Sydney Medical School

Sleep and Cancer

Associate Professor Anthony Don Pathology, School of

Medical Sciences

Discovery and development of new

drugs to treat metabolic disease

and type II diabetes

Professor Barbara Fazekas De St

Groth

Pathology, School of

Medical Sciences

Cancer and Personalised Medicine

Professor Stuart Grieve Heart Research Institute Advanced brain and cardiovascular

imaging

Associate Professor Tina Hinton Pharmacology, School of

Medical Sciences

GABA, dietary flavonoids and

diabetes

Dr Markus J. Hofer School of Life and

Environmental Sciences

Neuroimmunology and Signalling

Dr Andrew Hoy Physiology, School of

Medical Sciences

Lipid Metabolism

Professor David James School of Life and

Environmental Sciences

Metabolism and Biological Sciences

Dr Melkem Kebede School of Life and

Environmental Sciences

Islet Biology and Metabolism

CPC Honours Projects 2020

Professor Nicholas King Pathology, School of

Medical Sciences

The immunopathology of central

nervous system inflammation

Dr Mark Larance School of Life and

Environmental Sciences

Nutrient Deprivation and the

Protective Proteome

Associate Professor Laurence Macia School of Life and

Environmental Sciences

Nutrition, gut microbiota and

immunity

Associate Professor Lenka Munoz Pathology, School of

Medical Sciences

Glioblastoma: Cell Signalling and

Drug Discovery

Associate Professor Matt Naylor School of Medical Sciences Developmental & Cancer Biology

Laboratory

Associate Professor Greg Neely School of Life and

Environmental Sciences

Functional annotation of the

genome

Dr Freda Passam Central Clinical School,

Sydney Medical School

Mechanisms of thrombosis and new

antithrombotics

Professor Peter Reeves School of Life and

Environmental Sciences

(SOLES)

Infection and Immunological

Conditions; Bacteriology

Professor Peter Thorn Physiology, School of

Medical Sciences

Utilising modern imaging to

understand insulin secretion

Dr Anna Waterhouse Central Clinical School,

Heart Research Institute

Cardiovascular Medical Devices:

Nano to Macro Technologies

Dr Steve Wise Sydney Medical School Applied materials group

Associate Professor Paul Witting Pathology, School of

Medical Sciences

Anti-inflammatory potential of

cyclic nitroxide derivatives

CPC Honours Projects 2020

ASSOCIATE PROFESSOR KIM BELL-ANDERSON Faculty of Science, Charles Perkins Centre, School of Life and Environmental Sciences Rm 3213, Charles Perkins Centre D17 | The University of Sydney | NSW | 2006 +61 2 9351 6267 | M +61 405 228 530 kim.bellanderson@sydney.edu.au Kim is a nutritional physiologist and one of the main goals in her lab is to gain insight into the mechanisms underpinning diet-mediated phenotype in order to better understand the developmental origins of obesity and related disorders. Established techniques in the lab include in vivo physiological measurements of energy balance and metabolism in mice, gene expression, and biochemical analysis of plasma and tissues from animal studies. Kim is also collaborating with A/Prof Tina Hinton on an Honours project to investigate the role of flavonoids in type 2 diabetes.

1. Project 1: Carbohydrate availability and developmental programming in mice 2. Project 2: Development of a Shiny App for analysis of Promethion metabolic data 3. Project 3: GABA, dietary flavonoids and diabetes (co-supervised with A/Prof Tina Hinton, School

of Medical Sciences)

DR AMANDA BRANDON | Senior Research Fellow Faculty of Medicine and Health School of Medical Sciences | Physiology University of Sydney, Charles Perkins Centre E amanda.brandon@sydney.edu.au The broad aim of our research is to understand how different aspects of genetic make-up, environment (temperature, nutrition) and behavior (exercise) contribute to altered energy balance and the development of obesity and metabolic disease. Project 1 - Role of environment and nutrition in the development of obesity-induced insulin resistance. The exact mechanisms responsible for obesity-related metabolic disease such as diabetes and cardiovascular disease are not completely understood but are associated with the development of insulin resistance in liver, muscle and adipose tissue. Over-nutrition (including the macronutrient content of the diet) and environmental conditions like ambient temperature and exercise can impact on body fat accumulation and alter normal metabolism. We have developed dietary models of obesity in mice housed at different temperatures that differ in the degree of impairment of insulin action. This project will comprehensively examine the differences in insulin action in tissues from these mouse models using metabolic flux measurements, assessment of insulin signalling pathways and lipidomic and proteomic analysis to tease out what aspects of obesity predispose animals to insulin resistance and whether dietary or environmental interventions can reduce obesity-related metabolic disease. This project will be co supervised by Professor Gregory Cooney Project 2 - Nutritional influences on health and lifespan in mice Understanding the processes and mechanisms that define the relationships between diet and physiology holds great promise for improving human health. Indeed, nutrition has the potential to be the most significant single primary prevention intervention in humans. Tailoring nutrition to the specific needs of the patient and their disease(s) has obvious potential in the management of obesity-associated diseases.

CPC Honours Projects 2020

However, progress towards this has been impeded by the complex relationships between diet, physiology and health. Traditional approaches have focused on responses linked to individual genes, proteins, pathways or microbial constituents, rather than considering the interactions in the entire system. Similar approaches have typified the science of nutrition, where approaches have usually been ‘one-nutrient-at-a-time’ rather than considering the entire mixture. Studies that focus on perturbing single nutrients or comparing two experimental diets have a high likelihood of providing oversimplified conclusions and increased risk of drawing erroneous conclusions about the relationships between nutrition and pathophysiology. Our approach will investigate the role of varying the ratio of macronutrients (fat, carbohydrate and protein) on the health of mice at various time points after starting the diets to track the age–related changes associated with different dietary regimes. This project will be co supervised by Professors Stephen Simpson and Gregory Cooney.

PROFESSOR ARTHUR CONIGRAVE Head of School and Dean | Sydney Medical School School of Life and Environmental Sciences | Faculty of Science Charles Perkins Centre D17 T +61 2 9351 3883 E arthur.conigrave@sydney.edu.au Nutrient sensing mechanisms in biology and medicine

• Calcium sensing: control of gene expression

• Calcium sensing: control of hormone secretion

• Calcium sensing: control of cell survival and differentiation

• Amino acid sensing: control of appetite

• Phosphate sensing: what goes wrong in Chronic Kidney Disease and why?

LESLIE CARON, PHD | Research Fellow The Charles Perkins Centre, School of Life & Environmental Sciences THE UNIVERSITY OF SYDNEY The Charles Perkins Centre D17 | The University of Sydney | NSW | 2006 T 02 8627 5619 | M 0449 956 379 E leslie.caron@sydney.edu.au | W http://sydney.edu.au/science/people/leslie.caron.php Human pluripotent stem cells (hPSC) are potential models of human development and disease and an unlimited source for cell replacement therapies. Our research focuses on using hPSC systems to identify cellular and molecular mechanisms that regulate differentiation into specific cell types and test drugs that affect human development and diseases. I have a particular interest in stem cell therapy and modeling neuro-muscular degenerative disorders. Project title 1: Developing a stem cell therapy for Neuropathic Pain. Project title 2: Using hPSC as a model for muscular Dystrophy and sarcopenia.

DR KRISTINA COOK

CPC Honours Projects 2020

Cancer Institute NSW ECR Research Fellow & Professor Tony Basten Fellow Charles Perkins Centre | The University of Sydney T +61 2 8627 4858 | E kristina.cook@sydney.edu.au 1. Starving for Oxygen: Targeting Hypoxia Inducible Factor (HIF) in Sleep and Cancer. Project Background: Oxygen sensing mechanisms have diverse and fundamental roles in health and disease and my lab studies how these natural systems are utilised by cancer. Low-oxygen (hypoxic) environments are a universal hallmark of all solid cancers due to rapid proliferation and few blood vessels. Cancer cells exploit this environment to activate the oxygen sensing pathway through hypoxia inducible factor (HIF). HIF controls the expression of >1000 genes including those involved in metastasis, chemotherapy-resistance, and cancer progression. 2. Role of Hypoxia in Regulating Circadian Rhythms in Cancer http://sydney.edu.au/medicine/study/honours/projectdetail.php?id=971 3. Cancer Drug Development: Targeting Hypoxia Inducible Factor (HIF) http://sydney.edu.au/medicine/study/honours/projectdetail.php?id=815 4. Sleep and Cancer: Understanding the role of obstructive sleep apnoea in cancer growth and spread http://sydney.edu.au/medicine/study/honours/projectdetail.php?id=771

ASSOCIATE PROFESSOR ANTHONY DON Discipline: Pathology Co-supervisors: Jacob Qi Keywords: Diabetes, Biochemistry, Mass spectrometry Contact: Anthony Don The enzyme ceramide synthase 6 (CERS6) produces the lipid ceramide that is widely implicated as a villain in the pathogenesis of diabetes fatty liver disease. Our research group was the first in the world to develop a specific pharmacological inhibitor of the related enzyme family member ceramide synthase 1, demonstrating that this compound enhances triglyceride metabolism (fat “burning”) in skeletal muscle (Turner et al, Nature Communications, 2018). However, the primary target of interest for the pharmaceutical industry is CERS6. We will use our expertise in this area to discover and develop potent and specific inhibitors of CERS6 for metabolic disease. Project Aims: 1. Screen chemical libraries for lead compounds that show inhibitory activity towards CERS6. 2. Test compounds in cell culture models to characterise their potency and selectivity on CERS6. 3. Determine the effects of CERS6 inhibition on insulin responsiveness and mitochondrial function in culture cells. Techniques: •Sophisticated Metabolomic Mass Spectrometry •Biochemistry and Western Blotting *Cell culture

CPC Honours Projects 2020

PROFESSOR BARBARA FAZEKAS DE ST GROTH, MBBS PHD Director, Ramaciotti Facility for Human Systems Biology Professor, Discipline of Pathology Sydney Medical School Room 5110, Charles Perkins Centre - D17 P +612 8627 5783 E barbara.fazekas@sydney.edu.au 1. Taking on cancer with personalised medicine

PROFESSOR STUART GRIEVE Parker Hughes Chair of Radiology, Sydney Medical School Group Leader in Cardiac Imaging at the Heart Research Institute (HRI) stuart.grieve@sydney.edu.au https://sydney.edu.au/medicine/people/academics/profiles/stuart.grieve.php Co supervisor: Dr Sarah Hellewell 1. Advanced imaging of cardiovascular function

Aortic stenosis is a significant cause of morbidity and mortality in cardiovascular disease, with

replacement of aortic valves the surgical treatment of choice. In recent years, there has been an increase

in transluminal aortic valve insertion (TAVI) procedures, which are less invasive than valve replacement

via open heart surgery. However, TAVI surgery is associated with adverse cardiac and neurological

outcomes which are poorly understood. This honours project will apply cutting-edge clinical data linkage

and MRI of the brain and heart to assess for structural and functional changes after aortic valve

replacement.

The Sydney Translational Imaging Laboratory (STIL) at the Heart Research Institute, Sydney, Australia has

an exciting opportunity for an honours position examining the cardiac consequences of TAVI surgery for

aortic valve replacement. Using cutting-edge 4D-flow and neuroimaging MRI, this project will examine the

post-surgical development and consequences of chronic diseases such as stroke, atrial fibrillation and

heart failure after TAVI. 4D-flow MRI is a sensitive and reliable tool to measure cardiac function, and allows

us to detect changes in blood flow after aortic valve replacement. We will also apply novel neuroimaging

protocols developed in the lab to measure network changes following the procedure. Our laboratory has

developed an in-house data processing pipeline to rapidly capture advanced data such as brain

connectivity and cardiac parameters such as velocity profiling, fluid shear strain, wall shear stress and

turbulent flow measurements. Imaging data will be linked to cognition, long-term clinical outcomes and

other clinical data via linkage analysis.

2. Advanced brain imaging of mild traumatic brain injury: mTBI passport

Mild traumatic brain injury (mTBI; also known as concussion) occurs frequently in contact sports due to

direct hits or rotational acceleration of the head. There is currently no reliable diagnostic measure of mTBI,

with diagnosis made on the basis of symptoms alone. Recent advances in brain MRI techniques may

enable accurate and rapid assessment of brain pathology in unprecedented detail, with potential use as

CPC Honours Projects 2020

a ‘biomarker’ of mTBI. This honours project will apply cutting-edge diffusion MRI techniques to varied

populations of human mTBI subjects to quantify pathological brain changes over time. The Sydney

Translational Imaging Laboratory (STIL) at the Heart Research Institute, Sydney, Australia has an exciting

opportunity for an honours studentship examining the pathological consequences of sport-related mild

traumatic brain injury (mTBI). Our research focuses on the assessment of mTBI both acutely in active

sportspeople to detect initial injury-induced pathological changes, and chronically in retired players to

detect long-term brain consequences. This project will examine subjects acutely and long-term after mTBI

using cutting-edge ultra-high angular diffusion imaging to detect white matter pathology, and

connectomics to understand structural and anatomical brain changes due to injury. We have recently

acquired the highest-ever resolution image of the brain, and are applying this methodology across a

number of concussion projects under our “Brain Passport” program – designed to both generate scientific

novel findings and provide practical diagnostic tools to improve clinical management of concussion.

ASSOCIATE PROFESSOR TINA HINTON School of Medical Sciences (Pharmacology) tina.hinton@sydney.edu.au, Rm 2W74 Charles Perkins Centre D17 co-supervisors A/Prof Kim Bell-Anderson and E/Prof Graham Johnston. The simple amino acid, GABA (gamma-aminobutyric acid) is well known as the major inhibitory

neurotransmitter in the brain. Less well known is the importance of GABA outside the brain. It is found

in relatively high concentration in the pancreas where it is associated with -cells.

GABA is known to be secreted from beta-cells and to be involved in -cell replication. There is evidence

that GABA can turn pancreatic -cells into -cells. In the brain the action of GABA is known to be modulated by flavonoids obtained from the diet. Flavonoids might be useful in preventing and treating

type 2 diabetes which develops as a result of -cell failure and reduced -cell mass. Dietary intake of flavonoids has been correlated with the incidence of type 2 diabetes in Europe. The major flavonoid in green tea, epigallocatechin gallate, has been shown to alleviate insulin resistance in animal studies. The aim of this project is to probe the interactions and role of flavonoids and GABA in type 2 diabetes with a view to developing therapies based on such interactions. This is an exciting opportunity to apply and extend the considerable expertise that we have developed studying GABA and flavonoids in the brain to investigating their role in diabetes.

Established -cell lines will be used to measure the influence of GABA and flavonoids on insulin content and secretion. Detection methods will include Western blotting, immunohistochemistry, and glucose-stimulated insulin secretion assays followed by ELISA. Research will be undertaken in the Charles Perkins Centre using well established protocols.

DR MARKUS J. HOFER Biochemistry, Cell and Molecular Biology Cluster Charles Perkins Centre and School of Life and Environmental Sciences Faculty of Science Rm 710, Molecular Bioscience Building G08 | The University of Sydney | NSW | 2006

CPC Honours Projects 2020

T +61 2 9351 2233 E markus.hofer@sydney.edu.au W www.hoferlab.com Our lab is dedicated to understanding the complexities of immune signalling in the brain. We combine a wide range of techniques from classical neuropathology to cutting-edge molecular approaches to address a number of important questions. For more information, please visit also www.hoferlab.com. Project area 1: Targeting the brain vasculature as a treatment for cerebral type I interferonopathies Abnormal blood vessels are feature of cerebral type I interferonopathies. Discover how the endothelial cells that line the brain’s blood vessels contribute to disease in patients with cereb ral type I interferonopathies. Project area 2: The pathogenic and protective effects of microglia in cerebral cytokinopathies Microglia are the primary immune cells of the brain and have the potential to both protect and contribute to neurological disease. Explore the molecular mechanisms that microglia use to mediate their biological effects in cerebral cytokinopathies. Project area 3: How different cell types of the brain contribute to cerebral cytokinopathies The brain consists of a large number of different cell types, including neurons, astrocytes, oligodendrocytes, microglia and endothelial cells. Discover how these different cell types mediate the pathogenesis of cerebral cytokinopathies using transgenic mouse models. Project area 4: Effects of type i interferons in chronic viral infections When type I interferon signalling is impaired, infection with lymphocytic choriomeningitis virus results in chronic infection and dysfunctional CD8+ T cell function. Investigate how CD8+ T cell function leads to chronic viral infection and if reactivation can promote virus clearance.

DR ANDREW HOY LIPID METABOLISM LABORATORY Lab 3 West, The Hub, Charles Perkins Centre Telephone: +61 2 9351 2514 andrew.hoy@sydney.edu.au @HoyLipidLab http://sydney.edu.au/medicine/people/academics/profiles/andrew.hoy.php The Lipid Metabolism Laboratory investigates the mechanisms linking perturbed lipid metabolism and a range of pathologies. Currently, our primary interests are in insulin resistance/type 2 diabetes/obesity and cancer including breast, pancreatic and prostate, particularly how these cancers behave differently in an obese patient vs a lean patient. The lab located in The Hub, Charles Perkins Centre where the following projects will be available.

CPC Honours Projects 2020

Project 1: Novel proteins involved in fatty liver and insulin resistance Insulin resistance is a unifying feature of the metabolic syndrome. The liver is an early site of perturbed insulin action and a critical regulator of whole body glucose and lipid homeostasis. The lipid droplet is the major site for storage of lipids and the movement of stored lipids out of this reservoir is highly regulated. We have recently identified proteins that locate to the lipid droplet whose abundance is altered in fatty liver and insulin resistance using innovative mass spectrometry and bioinformatic approaches. In this project these highly novel candidate targets will be characterised using techniques including cutting-edge microscopy, cell culture, biochemical and radiometric metabolic analysis, and genetic manipulation. Project 2: Lipid metabolism and breast and prostate cancer Lipid accumulation in both breast and prostate cancer is a common observation, especially in aggressive cancers. The vast majority of lipid is stored as triacylglycerols in lipid droplets within these cells. These lipid droplets are closely located to mitochondria, to serve a readily available supply of energy for tumour progression. This project will target the enzymes that regulate lipid flux at the lipid droplet, and elucidate their function and potential for therapeutic targeting in cancer. The project is part of a Movember-funded international program and will employ techniques including cell culture, genetic manipulation, radiolabel metabolic analysis, mass spectrometry, cutting-edge microscopy and cancer cell progression including proliferation, migration and invasion. Project 3: Nutritional geometric framework and liver biology Fatty liver is an initial starting point for a wide-range of pathologies. The seminal work of Prof Steve Simpson and Dr Samantha Solon-Biet has identified components of dietary intake, that for reasons yet to be determined, result in fatty liver. In collaboration with Prof Simpson and Dr Solon-Biet, this project will elucidate the influence of branch chain amino acids, non-branch chain amino acids and other factors on liver lipid homeostasis and its potential flow-on effect on hepatocellular carcinoma progression. The project will employ techniques including cell culture, biochemical analysis, gene expression, genetic manipulation, radiometric metabolic analysis and cancer cell proliferation. (Co-supervisors: Dr Andrew Hoy, Prof Steve Simpson (SoLES/CPC) and Dr Samantha Solon-Biet (SoLES/CPC)) Project 4: A Key Metabolic Switch in Cardiometabolic Disease Non-alcoholic fatty liver disease (NAFLD) is now the commonest form of liver disease in the Western world, affecting one in three people in the general population, 90% of obese patients with T2D, and 5.5 of 6 million Australians with liver disease – accounting for much of the $51 billion annual cost to our healthcare system. Liver fat is increasingly considered a primary driver of T2D, although exact mechanisms remain unclear, and is an independent risk factor for atherosclerosis. Further - and most clinically challenging - it is unknown which patients with liver fat will progress to metabolic complications. Our collaborator, Dr John O'Sullivan from the Heart Research Institute recently discovered a new plasma biomarker (dimethylguanidino valeric acid [DMGV]) of liver fat that independently predicted diabetes up to 12.8 years before diagnosis in three distinct human cohorts of different ethnicity (O’Sullivan et al., J Clin Invest, 2017). He has subsequently shown that DMGV is elevated in a human cohort of hepatic insulin resistance, and that the gene producing DMGV is upregulated in fatty liver disease. Intriguingly, in dietary models of NAFLD, we found sucrose (fructose + glucose) caused the most dramatic dysregulation of this pathway, consistent with recent reports showing fructose to have dramatic effects

CPC Honours Projects 2020

on hepatic insulin resistance in humans and mice. Together, these data suggest this pathway is most activated in lipogenesis leading to hepatic insulin resistance. In collaboration with Dr O’Sullivan, this project will test our proposed hypothesis using dietary models and genetically modified murine models in addition to liver biopsy and plasma samples from carefully characterized human cohorts. (Co-supervisors: Dr Andrew Hoy and Dr John O'Sullivan (RPAH/HRI)) Project 5: Examining the role of common genetic variants in short-chain acylcarnitine metabolism in NAFLD and Type 2 Diabetes. Dr John O'Sullivan from the Heart Research Institute recently demonstrated that short-chain acylcarnitines are associated with hepatic insulin resistance in a human hyperinsulinaemic-euglycaemic clamp study. He subsequently revealed that these metabolites were associated with liver fat and insulin levels in a large human cohort, and discovered common genetic variants in the ACADs gene that control their levels. In collaboration with Dr O’Sullivan, this project will utilize human iPSCs carrying these variants in the ACADs gene and will be performed in the. These iPSCs will differentiated to hepatocytes, and functional assays will be used to compare lipid and glucose biology in hepatocytes homozygous for the minor allele of these variants with hepatocytes homozygous for the major allele. (Co-supervisors: Dr Andrew Hoy and Dr John O'Sullivan (RPAH/HRI)) Direct enquiries can be made by email to: Dr Andrew Hoy – andrew.hoy@sydney.edu.au

THE JAMES LABORATORY Professor David James Charles Perkins Centre – Level 5 West david.james@sydney.edu.au Research Interest Summary: Metabolism plays a central role in all biological processes. It is coordinated by numerous homeostatic mechanisms across multiple organs and defining the rules that govern the control of this complex network is one of our major interests. To do so we work both at the systems level to measure processes as broad as protein phosphorylation on a global scale as well as at the molecular level to interrogate the role of specific pathways in whole body metabolism. Many of our studies are performed across different genetic backgrounds in mice and involve different environmental perturbations such as diet or exercise. Technologies span a range of areas including mass spectrometry, molecular biology, biochemistry, cell biology, live cell imaging and bioinformatics. Project title 1: Mapping new functions of insulin and exercise Insulin and exercise activate extensive signalling cascades to regulate an array of cellular processes. Identifying the composition of these signalling networks and the proteins responsible for eliciting specific functions of insulin and exercise is essential in understanding the defects that cause metabolic disease where insulin signalling is defective, and in harnessing the power of exercise to promote health. We have recently interrogated the insulin and exercise-regulated phosphoproteome, revealing the extent of these signalling networks and a number of new phosphorylation sites on proteins modified in response to these stimuli. This project aims to characterise the function of novel insulin or exercise-regulated phosphoproteins and to identify the upstream kinase. Project title 2: Mapping the gene x environment interaction in health and disease It is well known that many complex human diseases are due to a complex interaction between genes and environmental factors like diet. It is very difficult to study this interaction in humans due to the challenge of controlling environmental factors and so model systems like mouse have been invaluable.

CPC Honours Projects 2020

We have developed a highly genetically diverse outbred mouse panel that displays huge variation in disease phenotypes when exposed to different diets. By combining this resource with genetic mapping and the acquisition of other omics data it is feasible to discover key mechanistic drivers of key health outcomes that affect heart function, metabolism, bone and the brain to name but a few. Project title 3: The mechanism of insulin resistance Insulin resistance is a risk factor for the development of a number of diseases including type 2 diabetes, cardiovascular disease and some cancers. Our group has discovered several links between nutrient processing and insulin resistance. This project aims to investigate the molecular basis for how mitochondrial metabolism affects insulin responses. Project title 4: Insulin regulation of lipolysis One of the most important actions of insulin in mammals is to suppress lipolysis or fatty acid release in adipocytes. Indeed, an impairment in this process may play a major role in diseases including non-alcoholic fatty liver disease and steatohepatitis. We have recently discovered a novel regulator of lipolysis in fat cells. This project will explore how insulin regulates the function of this protein to coordinate the release of fatty acids from the lipid droplet. Students will learn a wide range of techniques including molecular biology, cell culture, metabolic/biochemical assays, mitochondrial bioenergetics, microscopy, western blotting, mass spectrometry and statistical analyses. Project title 5: Dissecting novel functions of the major nutrient sensor mTOR. The mechanistic target of rapamycin (mTOR) is a master regulator of cell growth, metabolism and survival that responds to a diverse set of environmental cues. Deregulation of mTOR has been linked with metabolic diseases, cancer and ageing. Despite the diverse processes controlled by mTOR, few substrates are known. Our group recently defined the mTOR-regulated phosphoproteome by quantitiative mass spectrometry and identified a new kind of mTOR substrates unlike any other mTOR downstream target reported before. This project will dissect this novel class of mTOR substrates, opening new areas of investigation in mTOR biology.

KEBEDE ISLET BIOLOGY AND METABOLISM LAB Dr Melkam Kebede melkam.kebede@sydney.edu.au Faculty of Science, School of Life and Environmental Science, D17, Charles Perkins Centre A major feature in the pathogenesis of type 2 diabetes (T2D) is the loss of pancreatic β-cell function. This manifests mainly as a reduction in glucose-stimulated insulin secretion. The molecular mechanisms that control β-cell failure during the progression to T2D remain poorly understood. Our research interest is to understand the mechanisms of β-cell failure in the pathogenesis of T2D. The current projects in the lab focus on understanding the mechanisms behind insulin biogenesis, maturation, stability and targeting for secretion. Project title 1: Role of Golgi proteins on insulin secretory granule biogenesis. Project title 2: Role of cytosolic adaptor proteins on insulin secretory granule biogenesis.

CPC Honours Projects 2020

Project title 3: Proteomics of insulin secretory granules.

PROFESSOR NICHOLAS KING Professor of Viral Immunopathology Pathology, School of Medical Sciences Bosch Institute nicholas.king@sydney.edu.au Thomas Ashhurst, High-dimensional cytometry specialist thomas.ashhurst@sydney.edu.au The immunopathology of central nervous system inflammation 1. Trafficking of pathogenic moocytes into the inflammed CNS using flow and mass cytometry 2. Preventing monocyte migration by intravenous infusions of Immune Modifying Particles (IMP) 3. Tracking inflammatory haematopoietic responses to viral encephalitis and other inflammatory

pathologies using high-dimensional flow and mass cytometry 4. Developing and optimising analytical approaches to analysing high-dimensional cytometry data

MARK LARANCE CINSW Future Research Leader Fellow Faculty of Science, School of Life and Environmental Sciences Charles Perkins Centre – D17 T +61 2 (8627 5571) E mark.larance@sydney.edu.au Research area: "Nutrient Deprivation and the Protective Proteome".

1. -Analysis of the response to intermittent fasting using systems proteomics

2. -Functional characterisation of a new mammalian hormone

ASSOCIATE PROFESSOR LAURENCE MACIA a’Beckett Fellow | Nutritional Immuno-metabolism Group Leader Discipline of Physiology School of Medical Sciences | Faculty of Medicine and Health D17-Charles Perkins Centre Research and Education Hub T +61 2 8627 6525 | E Laurence.macia@sydney.edu.au While we know that an unhealthy diet can trigger diseases, what constitute a healthy diet is still poorly known. The aim of my team is to understand how diet composition can affect immune cell development and function to fight diseases such as allergies, metabolic or autoimmune diseases. We are interested in how changes in the gut microbiota might trigger or prevent diseases. Project 1: Role of diet composition on allergic diseases Project 2: Role of diet and gut microbiota on immune function and disease development.

CPC Honours Projects 2020

ASSOCIATE PROFESSOR LENKA MUNOZ |PharmD, PhD Associate Professor Cancer Institute NSW Career Development Fellow School of Medical Sciences | Discipline of Pathology Charles Perkins Centre – D17 | Room 4210 T +61 2 9351 2315 E lenka.munoz@sydney.edu.au Glioblastoma: Cell Signalling and Drug Discovery 1. Delineating MK2 signalling in glioblastoma chemoresistance. 2. Targeting epigenetic signaling in drug-tolerant persistent cells. 3. Delineating DYRK1A signalling in dormant glioblastoma cells.

ASSOCIATE PROFESSOR MATT NAYLOR Matt Naylor | Associate Professor The University of Sydney School of Medical Sciences Faculty of Medicine and Health Room 4214, Charles Perkins Centre (D17) | The University of Sydney | NSW | 2006 +61 2 9351 4267 | +61 2 9351 2521 (fax) | +61 404 828 940 matthew.naylor@sydney.edu.au | sydney.edu.au Head, Developmental & Cancer Biology Laboratory Research Integrity Advisor – Medicine & Health sydney.edu.au/researchintegrityadvisers Unit of Study Coordinator PHSI3012 & PHSI3912 Research in the Developmental & Cancer Biology Lab focuses on understanding how normal development and cell function is controlled, and then, how this regulation is perturbed to result in human disease such as cancer. Specifically, research in the lab has focused on transcriptional and cell-matrix 'master' regulators of cell fate (eg. whether or not a cell undergoes proliferation or differentiation) in breast and prostate development and cancer. Using whole genome transcript profiling and subsequent mouse and human cell based models, we have identified several novel regulators of normal breast and prostate development and shown that altering the function of these genes can either speed up or slow down cancer progression. Project Descriptions: 1) Investigate the role of Paxillin in breast cancer & metastasis. Breast cancer is the most common invasive cancer of women, with Australian women having a lifetime risk of 1 in 9 for developing the disease. Although prognosis for early or locally contained disease is good, patients diagnosed with metastasis have a long term survival rate of only 5-10%. We have previously shown that Integrins, which regulate the interaction between a cell and its local environment, control normal breast development and cancer progression. The role of paxillin, an integrin adaptor protein in this process remains unknown, but its expression is correlated with aggressive disease and cancer cell migration. This project will explore the role of paxillin in

CPC Honours Projects 2020

breast cancer cell function, tumourigenesis and metastasis. Techniques employed will include a combination of in vitro based techniques such as cell culture, morphology, migration and proliferation assays, shRNA, and in vivo based approaches such as genetic mouse models and xenografts. 2) Exploring the role of Paxillin in prostate cancer. Prostate cancer is the most common cancer of men and kills as many men as breast cancer does women each year. Similar to the Paxillin Breast Cancer Project, we have also recently demonstrated a role for a number of integrin and integrin related molecules in the progression of prostate cancer. This project will continue to explore the role of integrin signaling in prostate development and prostate cancer progression by using newly generated Paxillin floxed genetic mouse models, transgenic prostate cancer mouse models and by determining the effects of paxillin in prostate cancer cell function using cell culture, morphology, migration and proliferation assays, shRNA viral approaches, and further in vivo based approaches such as xenografts. 3) Metabolism and breast cancer. There is a clear link between metabolic disorders and obesity within a variety of different cancer types, including breast cancer. In addition, a key component in the progression of cancer is said to be the ability of a cancer cell to rewire its metabolic pathways to cope with increased energetic and biosynthetic demands required during tumour progression. We have demonstrated a novel role for ACC1 in this process. Using novel inhibitors in cell culture studies along with proliferation assays and mouse based carcinogenesis models, this project will investigate the effects of inhibiting lipogenesis and determine the subsequent effects on breast cancer cell growth and tumourigenesis. 4) Transcriptional regulators of mammary gland development and breast cancer. Control of cell fate and normal cell function is critical during development and is often perturbed during carcinogenesis and tumour progression. We have identified and developed a number of new mouse and cell based models to investigate or continue to define a completely novel function for a number of transcription factors not previously implicated in both the regulation of normal breast development or breast cancer. This project will utilise similar approaches and techniques to the projects previously described to determine the role of these transcription factors in the breast.

ASSOCIATE PROFESSOR GREG NEELY Head, Dr. John and Anne Chong Lab for Functional Genomics The Charles Perkins Centre School of Life & Environmental Sciences D17 - Charles Perkins Centre, Johns Hopkins Drive T +61 2 8627 0519 E greg.neely@sydney.edu.au W https://www.neelylab.com/ Honours stream: Biochemistry Research interest Our lab is focused on functional annotation of the genome. Our objective is to identify genes and coding mutations that participate in major age-related and neurological diseases. We combine human

CPC Honours Projects 2020

genomics data with functional validation in vivo to identify new genes that contribute to human neurological disease. Projects 1. Lifespan extension while preserving brain function 2. How does diet alter taste perception? 3. Environmental factors that suppress synaptic function. 4. Whole Genome CRISPR screening

DR FREDA PASSAM Clinical Academic Haematologist, Group Leader, Heart Research Institute-Charles Perkins Centre Sydney Medical School, Faculty of Medicine and Health Charles Perkins Centre hub D17, Level 3E, Room 3116 |T +61 2 8627 7492 | E freda.passam@sydney.edu.au The Haematology Research Lab aims to discover novel pathways in blood clotting which can lead to the development of effective and safe drugs to treat thrombosis. Thrombosis is the cause of heart attacks, strokes and venous thromboembolism which are the leading causes of death in Australia. Current projects focus on understanding the role of platelet receptors and clotting proteins in thrombosis. 1. Thiol isomerases as novel antithrombotic targets http://sydney.edu.au/medicine/study/honours/projectdetail.php?id=942 Aim: To discover alternative pathways in the clotting system that can be targeted to develop efficient and safer antithrombotic drugs. Background: It has recently been discovered that thiol isomerases constitute a new clotting pathway. Thiol isomerases are a group of enzymes that regulate the function of blood cell receptors and clotting proteins by reacting with their disulphide bonds. We have identified a thiol isomerase, named ERp5, which is released into the circulation from activated platelets and promotes clot formation in vivo Project overview: In this project we will dissect the role of ERp5 in platelet function and clot formation by using mice with genetic deletion of ERp5 in their platelets. We will investigate how this thiol isomerase regulates the interaction of platelets with clotting proteins (fibrinogen, von Willebrand factor) and vascular cells (endothelial cells and neutrophils). We will explore the potential of ERp5 inhibitors to prevent thrombus formation and become candidate antithrombotic drugs. Techniques: These studies will employ platelet function tests, cell perfusion assays, flow cytometry and confocal microscopy. This project will provide the opportunity to learn the method of intravital microscopy for the study of clot formation in mice. 2. Developing biochips for the evaluation of haemostasis and thrombosis http://sydney.edu.au/medicine/study/honours/projectdetail.php?id=951 Aim: To develop microfluidic devices which can detect the thrombotic or bleeding tendency in patients with clotting problems. Background: Many patients with bleeding and clotting disorders go undetected by routine laboratory tests in part because the available assays do not reflect the conditions in the circulation. The Haematology Research Group uses biochips in a microfluidic system that allows blood to flow through passages under controlled conditions. The passages are designed to mimic blood vessels and include features e.g. stenosis, that simulate the circulation in stenosed vessels. The flow of blood through these biochips generates thrombi that can be visualized by real-time microscopy and quantified.

CPC Honours Projects 2020

Project overview: This project will study blood cell adhesion and thrombus formation in the microfluidic devices to assess for persisting thrombotic tendency in patients with a history of venous clots, who have completed treatment. Samples from patients with bleeding disorders on treatment will be assessed for haemostatic potential. A range of parameters, which participate in clot formation, will be measured in the microfluidics system including platelets, fibrin, neutrophil extracellular traps, von Willebrand factor. Techniques: This project involves the preparation of the microfluidics chips, microscopy and image analysis 3. Redox biomarkers in thrombotic disease. http://sydney.edu.au/medicine/study/honours/projectdetail.php?id=943 Aim: To identify new biological markers that can be used in the monitoring and treatment of patients with thrombotic disease. Background: The redox balance (balance of reduction and oxidation reactions in our blood) is essential for a healthy circulation. Redox imbalance causes alterations of protein function contributing to the development of thrombosis. The Haematology Research group is focused on redox modification of disulphide bonds in two proteins critical for thrombus formation: the platelet receptor integrin a2bb3 and the plasma protein von Willebrand factor. We have found that reduced forms of a2bb3 and vWF have decreased thrombotic activity and may therefore protect from thrombotic disease, such as venous clots. Project overview: We have developed assays which measure the redox balance in blood including tests which measure the disulphide reducing activity of plasma and the production of reactive oxygen species by platelets. We will study the redox modifications of platelet a2bb3 and plasma vWF which occur in patients at high risk for thrombosis to identify those most likely to benefit from drugs which restore the normal redox balance. Techniques: This project employs mass spectrometry to study the posttranslational modifications of clotting proteins using disulphide labels specifically developed for this purpose. It also involves plasma and platelet functional assays

PROFESSOR PETER REEVES School of Life and Environmental Sciences Member of the Charles Perkins Centre G08 - Biochemistry and Microbiology Building The University of Sydney +61 2 9351 2536 | preeves@usyd.edu.au Project 1. Biology of O antigen gene clusters Surface-associated polysaccharides, which are often the major surface components of bacteria, play a critical role in cell protection and survival. The polysaccharide structures are enormously diverse: E. coli alone has about 180 different forms of O antigen. This structural diversity plays a major role in evasion of host immune responses. Each O antigen has its own set of genes predominately located within a gene cluster. These gene clusters consist of genes for sugar synthesis, sugar transfer genes to assemble a small oligosaccharide for attachment to the outer membrane, a wzx gene encoding a flippase to transport the oligosaccharide across the membrane, and a wzy gene for oligosaccharide polymerisation. Much like the O antigens themselves, Wzx and Wzy are highly variable. However we are only now learning about their reactions and specificity. We are using gene knockouts and cloning to study selected wzx and wzy genes that can provide us with new information on substrate specificity, protein-

CPC Honours Projects 2020

protein interactions and protein function. The diversity in Wzx is thought to be responsible for much of the O-antigen diversity, with each Wzx form flipping a different set of O antigens. The project will have a specific Wzx to study and add to our knowledge of the patterns in Wzx specificity. We collaborate scientists working on Wzx structures, which is also needed to understand wzx function. Project 2. Strain-level analysis of the dynamics of bacteria in the human gut We have a new protocol for using a different approach to metagenomic analysis to target a selected species in a microbiome in great detail. This is in contrast to most current metagenomic analysis which can covers all bacteria but only at about genus level, so usually not even species are identified. The current strategies have had great success in relating species groups to various health risks, for example intestinal bacteria and obesity, and also in understanding the role of the different bacteria in environmental niches. However most bacterial species consist of a variety of strains, many with major differences, and strain variation will be very important, but until now barely touched in metagenomic analysis. We have used the new protocol on DNA from human stool samples, and targeted E. coli. The protocol uses the accuracy of PacBio sequencing for strain determination on hundreds of thousands of bacteria per run. A single run can include many samples, each having a thousand bacteria allocated to specific strains. We have applied the protocol to E. coli, and could follow dominant strains over time, and can also see strains present in very low numbers. Until now most strain determination was done by isolating bacteria from colonies on a plate, as traditional metagenomic analysis can give indications on dominant strains but no individual sequence data.

PROFESSOR PETER THORN Chair in Molecular and Cellular Physiology Physiology: School Medical Sciences Charles Perkins Centre p.thorn@sydney.edu.au 1. UNDERSTANDING THE STRUCTURE AND FUNCTIONS THAT CONTROL INSULIN SECRETION WITHIN ISLETS. Our data the suggest that insulin secretion is targeted towards the vasculature. Ongoing projects in the lab are designed to prove this targeting. The work involves advanced imaging techniques, molecular biology and electron microscopy. We use islets from mice and humans to identify key proteins and then test for their role in controlling insulin secretion. 2. UNDERSTANDING THE DEFECTS IN INSULIN SECRETION THAT OCCUR IN DISEASE. Changes in insulin secretion from beta cells are known to cause disease but despite a lot of work the basis of these changes is unclear. We have new data that shows that in a condition called prediabetes insulin secretion is dramatically upregulated. Using islets from diabetic mice and humans we are aiming to understand the principal mechanisms of control. 3. REFINING CELL-BASED THERAPIES TO CURE DIABETES. We have established a type 1 diabetes node at the Charles Perkins Centre and are now part of a multidisciplinary team working towards a cure for type 1 diabetes. Our experiments are testing some of

CPC Honours Projects 2020

the factors we are finding to be important in the control of beta cells in the islet with an aim to enhance the control of insulin secretion. For diabetic patients, cell replacement therapies have the promise, one day, to provide a cure for disease.

DR ANNA WATERHOUSE Group Leader | DECRA Fellow | CPC EMCR Co-chair The University of Sydney and Heart Research Institute Central Clinical School | Charles Perkins Centre Faculty of Medicine and Health Member of the University of Sydney Nano Institute 3 East, Charles Perkins Centre hub D17 | The University of Sydney | NSW | 2006 | Australia 7 Eliza Street | Newtown | NSW | 2042 | Australia +61 2 8627 5648 | +61 498 202 064 anna.waterhouse@sydney.edu.au | sydney.edu.au anna.waterhouse@hri.org.au | hri.org.au 1. Biomolecular Nanorobotics: Molecular-level changes in early heart disease occur on the nanoscale. In this project we will focus on designing and developing biomimetic models to study and develop haematological and immunological compatible biomolecular devices by integrating molecular, protein, and materials engineering to find and identify early stage diseased blood vessels. 2. Slippery surface coatings to prevent thrombosis and pathogenic biofouling of medical devices Newly developed, super slippery, liquid-repellent surface coatings have great potential to revolutionise medical devices, imparting anti-adhesive properties to materials and reducing bio-fouling and subsequent thrombosis or pathogen adhesion in biofilm formation. In this project, we aim to clarify the mechanism by which the liquid-surface, Tethered-Liquid Perfluorocarbon (TLP), is anti-adhesive to proteins, mammalian cells and bacteria, with the goal of translating this to medical devices in the clinic to prevent their failure. 3. Development of micro-systems to study medical devices and their failure mechanisms To better understand thrombosis and biofouling and develop improved materials for medical devices, we are creating innovative microsystems to study medical device materials in the laboratory. This multidisciplinary project aims to create microsystems that mimic aspects of medical device materials and geometries to study how variations in material properties and blood flow dynamics govern the initiation of biomaterial-induced thrombosis.

DR STEVEN WISE Email: steven.wise@sydney.edu.au @docswise Phone: 8627 9458 Location: Lab 3 West, The Hub, Charles Perkins Centre http://sydney.edu.au/medicine/people/academics/profiles/steven.wise.php

CPC Honours Projects 2020

The Applied Materials Group is developing new materials and devices for tissue repair, particularly for cardiovascular applications. Working in multi-disciplinary research teams the group specialises in device and materials engineering, blood compatibility and interactions with endothelial and smooth muscle cells. A strength of his group is their comprehensive range of pre-clinical models for evaluation of new materials. The lab located in The Hub, Charles Perkins Centre where the following projects will be available. 1. Engineering a physiologically relevant blood vessel in vitro The development of biocompatible materials for treatment of cardiovascular disease, will be improved by better in vitro models of the vascular system. However, the field is lacking sophisticated bioreactor technology that sufficiently recapitulates key physiological parameters. The primary outcome of this project will be the development of a high value product; an advanced perfusion bioreactor technology with an unparalleled ability to mimic biological environments in vitro. This project is a partnership with Codex Research who have designed a prototype bioreactor for use in vascular applications, bearing synthetic vascular grafts engineered in our lab. The bioreactor aims to generate physiological arterial pressure, flow and shear conditions and allow real-time monitoring of these parameters. The project will determine: 1) optimal synthetic graft parameters to support vascular cells, 2) validation of vascular cell functionality and 3) response to balloon injury, using synthetic conduits seeded with human vascular cells. (Co-supervisors: Dr Steven Wise, Dr Joy Michael) 2. Next Generation Immunomodulatory Cardiovascular Devices Although it is well established that chronic inflammation is central to the progression of cardiovascular disease (CVD), immunotherapies are not routinely used for clinical management. Large clinical trials have shown that systemically delivered broad-spectrum immunotherapies can compromise patient immune function. Immunotherapy localisation to sites of disease may increase effectiveness and safety, revolutionising the treatment of CVD. This project will design and develop new bioactive vascular materials that modulate local inflammation, representing a promising new way to treat underlying pathology, thereby establishing safe, effective, and lasting immunotherapies. The project will include design and engineering of bioactive material surface coatings, evaluation in cell culture models, with the potential for evaluation of devices in established pre-clinical models. The focus will be to increase our understanding of how materials can be designed to reduce pathological inflammation. (Co-supervisors: Dr Steven Wise, Dr Richard Tan) 3. Carbon-based nanocarriers for emerging therapeutics Nanomedicine is a rapidly emerging research field aimed at enhancing specific targeting, accumulation and controlled release of therapeutics, whilst minimising effects on healthy tissue. However, translation into clinical practice has been limited by the complexity and costs associated with development of safe and efficient nanomaterials. This project aims to further develop a new class of patented nanoparticles. Different project streams are available including: (a) optimised delivery of genetic materials (e.g. siRNA, miRNA, plasmids) co-delivered using the nanoparticle platform and (b) evaluation of the potential of combination therapies, comprising chemotherapeutic drugs (e.g. paclitaxel, docetaxel) to advance treatment options for metastatic breast cancer in partnership with collaborators at the Garvan Institute of Medical Research. (Co-supervisors: Dr Steven Wise, Dr Miguel Santos, Dr Monica Lam)

CPC Honours Projects 2020

ASSOCIATE PROFESSOR PAUL WITTING Discipline of Pathology The University of Sydney Charles Perkins Centre Rm 4212, D17 +61 2 91140524 paul.witting@sydney.edu.au