2013 Garvan PhD_brochure

CELEBRATING50YEARS

POSTGRADUATE STUDIES AT THE GARVAN

2014 PhD PROJECTS

Postgraduate Studies at the Garvan 01Why Choose the Garvan 01Garvan PhD Open Day 23 August 2013 01

Cancer 02Tumour Progression Group 02Cancer Cell Invasion & Metastasis Group 04Pancreatic Carcinogenesis Group 05

Immunological Diseases 06B Cell Biology Group 06Immunology & Immunodeficiency Group 07Autoimmunity & Gene Therapy Group 08Diabetes & Transcription Factors Group 09Antibody Engineering Group 09

Metabolic Diseases 10James Lab 10Islet Biology Group 11Cooney Group-Obesity & Insulin Resistance 12Parkinson's Disease-Neurodegeneration,

Cell & Molecular Biology, Genetics 13Hesselson Group-Beta Cell Regeneration 14Clinical Prader-Willi Research Group 14Clinical Diabetes Group 15

Neurological Diseases 16Eating Disorders Group 16Bone Regulation Group 19Neurodegenerative Disorders Research Group 21

Osteoporosis & Bone Biology 22Bone & Cancer Pharmacology Group 23

Garvan Bioinformatics 24

How to Apply 25

Contents

In partnership with the University of New South Wales, Garvan Institute provides a learning andteaching environment of excellence for PhD students who are looking forward to being part of thenext generation of great medical researchers.

As one of the world's leading medical research institutes with programs in cancer, diabetes and obesity,immunology, neuroscience and osteoporosis, Garvan is playing a leadership role in translating theamazing developments in modern biomedical research into real improvements in health care andquality of life. The joint initiative with St Vincent's Hospital in establishing The Kinghorn Cancer Centrewill enable Garvan's research discoveries to make a real difference in the prevention and treatment ofthis devastating disorder. This however is only the beginning - the future for Garvan will be to ensurethat this paradigm is expanded to all of our research areas.

A focus on the promise of genomic medicine and new technologies such as next generationsequencing, and a complementary depth of expertise in cell biology, proteomics, systems biology,bioinformatics, epigenetics and translational research together make Garvan one of the most excitingplaces to be doing medical research right now and in the future.

As well as ensuring the development of scientific knowledge and skills for the future, postgraduatescholars undertaking their PhD at Garvan are valued as important contributors to the life of theInstitute as a whole.

We look forward to you joining us.

Why Choose the Garvan_ We offer a competitive salary top-up on

eligible scholarships

_ The Garvan boasts state-of-the-art researchfacilities which incorporate a range of cutting-edge equipment and expertise

_ Students at Garvan (SAG), the studentrepresentative group within the GarvanInstitute provides both academic support andsocial activities in our off-campusenvironment

If you would like to find out more about thefantastic opportunities that doing your PhD atGarvan Institute can provide, please [email protected] or visitwww.garvan.org.au/education

Garvan PhD Open Day 23rd ofAugust 2013The PhD Open Day will take place on Friday23rd of August from 2.00 pm to 6.00 pm.

It will provide the opportunity to meetprospective supervisors, current PhD studentsand view our state-of-the art facilities. Pleaseregister your attendance at www.garvan.org.au

Outside of this period, you may contact specificresearchers directly or visitwww.garvan.org.au/education for furtherinformation.

Postgraduate STUDIES AT THE GARVAN

John Mattick AO FAA FRCPA

Executive DirectorGarvan Institute of Medical Research

01POSTGRADUATE STUDIES AT THE GARVAN

Prof Sue ClarkActing Division HeadCancer

CANCER DIVISION

The Cancer Division at the Garvan Institute is the largest division at the Garvan and one of the most highlyregarded cancer research teams in Australia and internationally. With complementary skills in cancergenomics, cancer epigenomics, cancer molecular and cellular biology, cancer biomarker and therapeutictarget identification & validation and translational research, the division is focussed on understanding thecauses of and developing new diagnostic, prognostic treatment and prevention strategies for the mostcommonly diagnosed and most lethal cancers including breast, prostate, pancreatic, colorectal, lung, andovarian. Among the many succesful PhD graduates are Directors of major research institutes and academicdepartments, professorial heads of independent research groups and clinical units, and recipients ofprestigious NHMRC and ARC Fellowships.

Cancer

Tumour Progression Group

Project 1: Mapping the cellular origin ofaggressive breast cancersBreast tumours display marked clinical heterogeneitymanifest in their histology, aetiology and geneexpression profiles. Breast cancers can be groupedby gene expression into several 'subtypes' with verydifferent biology and clinical outcome. Recentevidence suggests that the different subtypes ofbreast cancer may derive from different 'cells oforigin' in the breast. This model suggests that muchof what 'makes a breast cancer tick' derives from itshistory as a normal cell. Therefore by understandingthe origins of breast cancers, we may discoverynew ways to detect and treat disease.

The identity of the breast stem cell is elusive and amajor question in the area of breast biology. Wehave recently discovered a new marker for thebreast stem cell, known as Id4. We showed that Id4is required for breast development during puberty.Furthermore, we showed that a proportion of veryaggressive breast cancers (basal breast cancers)express high levels of Id4 and have featuresresembling the mammary stem cell, suggesting thatthey derive from the breast stem cell.

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This project aims to use sophisticated mousemodels to provide the definitive proof that basalbreast cancers derive from the Id4-positive breaststem cell. Furthermore, we will use these models toprovide new insights into the identity of the elusivebreast stem cell.

Our group is a diverse mix including cell biologists,bioinformaticians and clinicians. This exciting projectwill place the investigator at the cutting edge ofstem cell and cancer biology and will introduce themto translational research, genomics, transcriptomicsand bioinformatics.

CANCER DIVISION

Project 2: A genome-wide analysis of microRNAfunction in breast cancerOnly through a deep understanding of the'molecular circuitry' of cancer can we understandcancer's origins, predict its clinical trajectory andfind its sensitivities to treatment. MicroRNA arepowerful controllers of gene expression and haveemerging potential as biomarkers and therapeutictargets in cancer. However, our understanding ofthe importance and mechanism of microRNAsfunction in cancer is fragmented, restricting ourability to capitalise on their potential as biomarkersof disease and therapeutic targets.

Recent technological development now places thetools of genome-wide functional studies withinreach, providing the capacity to systematically andcomprehensively examine the role for classes ofgenes, such as microRNAs, in biological processesand disease. The result is high quality datagenerated far more efficiently and cost-effectivelythan through small-scale candidate studies.

We have recently performed the first systematicbiological evaluation of the impact of microRNAs oncancer cell proliferation, survival, migration andchemosensitivity. From this screen we haveidentified ~ 100 novel microRNAs controlling breastcancer biology. This project will study candidatemicroRNAs from this list.

First we will refine the list of candidates based ontheir expression, regulation and correlation withclinical outcome in breast cancer. We will thenfocus on the mechanism by which thesemicroRNAs act by identifying the networksregulated individually and in common by leadmicroRNA candidates. Finally will we use preclinicalmodels of breast cancer to determine the efficacyof targeting microRNAs for breast cancer therapy.

Our group is a diverse mix of cell biologists,bioinformaticians and clinicians. This excitingproject will place the investigator at the cuttingedge of microRNA and cancer biology and willintroduce them to translational research,genomics, transcriptomics and bioinformatics. This position will suit students with an interest inmolecular & cellular biology or informatics.

Supervisor: Dr Alex SwarbrickEmail: [email protected]

Recent publicationsNair, R., D. Roden, S. Lakhani, S. O'toole, W. Kaplan, M. Naylor, C.Ormandy, and A. Swarbrick, c-Myc and Her2 cooperate to drive a

stem-like phenotype with poor prognosis in breast cancer.

Oncogene, 2013.

Plummer et al MicroRNAs Regulate Tumor Angiogenesis Modulated

by Endothelial Progenitor Cells. Cancer Res, 2013. 73(1): p. 341-352.

Swarbrick, A.,et al miR-380-5p represses p53 to control cellular

survival and is associated with poor outcome in MYCN-amplified

neuroblastoma. Nature Medicine, 2010. 16(10): p. 1134-40.

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CANCER DIVISION

Cancer Cell Invasion & Metastasis Group

BackgroundCancer invasion and metastasis occur in a complex3D- environment, with reciprocal feedback fromthe surrounding host tissue and stroma governingcancer cell behaviour. Understanding this behaviourin an intact host setting allows us to examine, in aphysiological context, the aberrant regulation ofcritical events that lead to dissemination and spread of the primary tumour. Intravital (in vivo)

imaging is providing new insights on how cellsbehave in their native microenvironment in real-time, thereby improving our understanding ofdisease progression (1).

Our group specialises in applying state-of-the-artimaging technology and 3D modelling to assess thespread of cancer in living tissue (2-4). Two PhDprojects are available in our laboratory using novelfluorescent biosensors to monitor cancer cell responseto anti-invasive drug targeting in live tumours. Bothprojects involve cutting-edge training in 3D cultureof cancer cells with associated stromal tissueengineering and involve molecular intervention withregards to controlling extracellular matrix strengthand stiffness (a key feature known to drive theaggressive nature of cancer and its response tocurrent therapeutics (5)). Response of tumour cellsto drug targeting in relation to their proximity toblood vasculature (imaged using quantum dots) willalso feature heavily in each project.

Each project will involve the use of novel cre-inducible mouse models engineered to uncouple themetastatic process into key stages, to identify criticalsteps in the metastatic cascade that are aberrantlyregulated by candidate genes previously identified inour screen for drivers of invasion. Currently unavailableelsewhere, these models permit real-time, intravitalimaging, ranging from whole body tumour progressionto single-cell invasion events, and will help us tounderstand how (i) tumour cell dissociation (E-cadherin-GFP; FRAP model), (ii) invasion(Rac/RhoGTPase FRET reporter models) or (iii) cellgrowth/survival (GFP model) are controlled andhow this is linked to the development of metastasisin the native tumour tissue microenvironment.

New approaches to a complex problemTwo sub-cellular applications currently in use incollaboration with pharmaceutical industry will formthe basis of each project:

Project 1: In vivo FRAPE-cadherin-based cell-cell contacts are prominentsites of remodeling during early stages of epithelialto mesenchymal transition (EMT). The deregulationof E-cadherin-based adhesions leads to the collapseof normal epithelial architecture that precedes theinitial spread of tumours from their primary site andcan therefore serve as an early molecular marker ofinvasion. We recently established the first applicationof Fluorescence Recovery After Photobleaching(FRAP) in live tumours to examine and predict E-cadherin cell-cell junction turnover during earlystages of cancer dissemination. Importantly, we havenow generated the world's first E-cadherin-GFPFRAP mouse and will use this pre-clinical model toassess the effects of therapeutic intervention on E-cadherin dynamics using clinically approved anti-invasive drug therapy, and investigate whethercandidate molecules from our screen alter E-cadherin dynamics to drive early tumour invasion (3).

Project 2: In vivo FRETCo-ordinated regulation of RhoGTPases is known tocontrol actin-mediated cell movement that is centralto tumour cell invasion. Recently, we usedFluorescence Resonance Energy Transfer (FRET), forthe first time, at the sub-cellular level in vivo, toexamine RhoA activity during invasion in live tumours(4). Here, we identified at high resolution a small yetimportant pool of active RhoA at the poles ofinvading cells, not observed in vitro, that correlateswith invasion in live tumours. Expansion of this workled to the first use of FRET to monitor the activity ofRhoA at a sub-cellular, rather than global level, upontherapeutic intervention. As above, we have nowgenerated a fluorescent RhoA-FRET mouse and willuse this pre-clinical model to examine whethercandidate molecules from our screen/drug targetingalter actin-mediated cell movement and invasion inlive tissue.

Supervisor: Dr Paul TimpsonEmail: [email protected]

References1. Timpson et al Journal of cell Science 2011 Sep 1;124(Pt 17):2877-90.2. Morton et al Proc Natl Acad Sci USA. 2010 Jan 5;107(1):246-51.3. Serrels et al Cancer Research 2009 Apr 1;69(7):2714-9.4. Timpson et al Cancer Res 2011 Feb 1;71(3):747-57.5. Samuel et al Cancer Cell 2011 Jun 14;19(6):776-91.

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CANCER DIVISION

Pancreatic Carcinogenesis GroupPancreatic Cancer is the fourth leading cause ofcancer death in our society. Almost 90% of thepatients succumb within a year of diagnosis, unlessdetection is done at very early stage. Evidence alsosupports a long period in which preneoplasticlesions are present.

The Pancreatic Carcinogenesis team is focused onidentifying key drivers and biomarkers of pancreaticcancer through studying the earliest changes inexocrine cell differentiation and proliferation usingpancreas specific models (in vitro and in vivo).

The Pancreatic Carcinogenesis group sits within thePancreas Cancer Group (Prof. A. Biankin) which co-leads the Australian Pancreatic Cancer GenomeInitiative (APGI), a member of the International CancerGenome Consortium (www.icgc.org). The APGI aimsto fully characterize the genomic, epigenomic andtranscriptomic aberrations in tumor samples ofpancreatic cancer patients using the latest nextgeneration sequencing technologies. As such, theAPGI provides a unique resource to investigatemolecular mechanisms involved in pancreaticcarcinogenesis, to eventually reveal new targets forthe development of novel detection methods,chemoprevention and chemotherapeutic strategies.

Specific projects available include:

Project 1Investigating the expression and the role ofcandidate gene aberrations identified by APGI inmodels of early pancreatic cancer; geneticallymodified mouse models have been introduced andneed to be further investigated. In addition,genetic manipulation is used in vivo and in vitro todefine the functional consequences and molecularmechanisms of these novel gene aberrations inmodel systems of early pancreatic cancer.

Project 2Investigating ENU-induced mutagenesis mousemodels, including forward screens to identify newgenes that can impact on exocrine pancreas celldifferentiation and proliferation and reversescreens where the effects of a known mutation ina gene of our interest (as identified by APGI) arefurther investigated for a contribution topancreatic carcinogenesis.

Supervisor: Dr Ilse Rooman Email: [email protected]

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IMMUNOLOGICAL DISEASES

B Cell Biology Group

Project 1: Tracking the origin and fate of immunecells critical for vaccine-induced immunityImmune responses to pathogens are characterisedby a complex interplay of dynamic interactionsbetween many different immune cells that arelocated in different anatomical compartments in thebody. These interactions are tightly co-ordinatedand depending on the nature of the interactions, itis possible for the same precursor cell population togive rise to multiple diverse cell types that servedifferent functions. For example, naive CD4+ T cellsmay acquire the capacity to 'help' B cells makeantibodies or activate CD8+ T cells to kill infectedcells, secrete different cytokines and migrate todifferent lymphoid organs and microanatomicallocations. Similarly, germinal centre B cells may giverise to long-lived plasma cells or memory B cells.

To understand the origin of this heterogeneity, wehave taken the novel approach of fluorescently'tagging' antigen-specific immune cells and directlyvisualising the behaviour of these cells in real-timeusing intravital two-photon microscopy.Fluorescently tagged cells can be tracked for longperiods of time over large distances within liveanimals. Two-photon microscopy will then becombined with multiparameter flow cytometry andphenotypic, functional and gene expression analysesat the single cell level to characterise the fates ofthese cells.

The project therefore involves the use of severalcutting-edge technologies to answer questions thatare fundamental to our understanding of theimmune response and may reveal novel pathwaysthat may be perturbed to promote vaccine-inducedimmunity.

Supervisors: Dr Tri Giang Phan and A/Prof Robert BrinkEmail: [email protected]

Project 2: Using real-time intravital two-photonmicroscopy of intestinal barrier function todetermine the pathogenesis inflammatory bowel diseaseIdiopathic inflammatory bowel diseases (IBD)comprise two types of chronic intestinal disorders:Crohn's disease and ulcerative colitis. This is a chronicrelapsing disease with early onset in young adultswith lifelong impact and considerable mortality andmorbidity. Emerging evidence indicates thatinflammatory bowel disease (IBD) results from anunrestrained immune response to intestinalmicrobial antigens in genetically susceptibleindividuals. Based on clinical data, we believe thatbaseline epithelial barrier defects (“leaky gut”) inpredisposed individuals exposes the intestinalimmune system to gut microbiota and initiates theinflammatory cascade that results in disease.

To test this hypothesis we have developed a novelpre-clinical mouse model of leaky gut through acuteexogenous administration of recombinant murineTNF. The aims of the project are to:

ImmunologicalDISEASES

A/Prof Robert Brink Division HeadImmunological Diseases

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The work of the research team at the Garvan Immunological Diseases Division is divided between studyinghow a immune system functions in a balanced way during health and how this can goes wrong in diseasessuch as type I diabetes, asthma and immunodeficiency. Program Head Assoc. Prof Robert Brink and theGroup Leaders in the Immunology team regularly published in many high profile journals including Nature,

Cell, Nature Immunology, Immunity and J. Exp. Med.

Many successful PhD students trained in the Immunological Diseases Division have published at least onehighly cited first author paper in either Immunity or J. Exp. Med.; a number have also been awarded New

Investigator of the Year honours at the annual conference of the Australasian Society of Immunology aswell as the Garvan thesis prize. Since completing their PhDs, many Garvan Immunological Diseases Divisionalumni have successfully obtained NHMRC Fellowhips for further postdoc study both in Australia andoverseas at such prestigious institutes as Harvard Medical School, Genentech, Max-Planck Institute in Berlin,Stanford University, Rockefeller University (New York) and Yale University.

_ Establish the kinetics and cellular dynamics ofepithelial cell shedding, immune cell activation andinflammatory cell recruitment in this model.

_ Determine how the intestinal immune system,particularly IntraEpithelial Lymphocytes (IELs),innate lymphoid cells (ILCs), dendritic cells andmacrophages senses and responds to leak ofluminal microbial antigens.

_ Determine the molecular interactions required forthe initiation and amplification of intestinalinflammation as a pathway for drug discovery.

These studies will involve two-photon microscopy,multiparameter flow cytometry and gene functionanalyses as well as pharmacological studies usingmonoclonal antibodies and small molecular inhibitorsto target steps in the pathogenesis of intestinalinflammation.

Supervisors: Dr Tri Giang Phan and Dr Mark DantaEmail: [email protected]

Immunology & Immunodeficiency Group

STAT3-mediated regulation of human antibodyresponses

BackgroundThe ability of B cells to differentiate into antibody(Ab)-secreting plasma cells (PC) is critical for hostprotection against infectious pathogens. This uniquefeature of B cells also underlies the success of mostavailable vaccines. B-cell differentiation into PCs isregulated by the integration of signals provided byantigen, T-cell help and specific cytokines. Signaltransduction pathways activated by thesemolecules converge to activate key transcriptionfactors (TFs) that mediate the commitment ofactivated B cells to a PC fate.

The requirements for B-cell differentiation havebeen gleaned from studies of humans and mice withmutations in key genes. Our studies of a series ofmonogenic primary human immunodeficiencies haveidentified the critical role of the IL-21-IL-21R/γc-STAT3 signalling axis in mediating the differentiation

of naïve B cells into memory cells and PCs, andtherefore the generation of robust humoralimmune responses and establishing long-livedserological memory. The next step is to advanceour understanding of how STAT3 controls humanB-cell function, and translate this knowledge intoimproved vaccine development and drug discoveryfor various immunopathologies. To this end, it isimperative to determine the molecular mechanismby which IL-21/STAT3 signalling operates in thecontext of human B cells to induce their activationand differentiation.

ObjectivesThe objectives of this PhD project will be to:

_ Identify how targeting of genes by STAT3 isdifferentially regulated by cytokines in naïve andmemory B cells

_ Determine how this contributes to enhancedresponses by memory B cells; and

_ Elucidate the mechanisms by which diseasecausing mutations affect STAT3 function.

Outcomes and significanceElucidating the mechanism by which STAT3functions to regulate human B-cell differentiationis highly significant to human health and disease.First, it will shed substantial light on the molecularrequirements for human B-cell function. Second,and more importantly, it will reveal molecules andpathways that could be targeted therapeuticallyto, on one hand improve humoral immunity incases of immunodeficiency, immune suppressionand vaccination, or, on the other, attenuatepathological Ab responses in the setting of B-cellmediated autoimmmunity. As this project focuseson human immunology, translation of findings toclinical settings will be immediately feasible,representing a substantial advance over studies ofnon-human species.

Supervisors: A/Prof Stuart Tangye and Dr Elissa DeenickEmail: [email protected]

IMMUNOLOGICAL DISEASES07

Autoimmunity & Gene Therapy GroupThe Autoimmunity and Gene Therapy Group studiesthe immunology of inflammatory diseases includingautoimmune diabetes and rejection of transplants.Our research involves basic science research as wellas clinical studies and trials in the field of humanislet transplantation. A number of projects areavailable that would suit highly motivated andambitious students. Our research includes analysisof gene expression and regulation, molecular signallingpathways that regulate inflammation, cellularimmunology, and animal models of type I diabetesand organ graft rejection. Cutting edge technologiesused in our research include use of animal knock andtransgenic models; cell signalling and molecularbiology, cellular immunology, as well as moleculargenomic approaches including RNAseq, micro-array,methylation studies and histone modifications, andbioinformatics. This work covers the fields ofimmunology, diabetes, genetics and transplantation.

Project 1: Immunology of transplantationTransplantation of organs is a life saving procedure,that can only happen with the use ofimmunosuppression. However, even withimmunosuppression most transplanted organs willnot survive forever. Also immunosuppression can betoxic, causes cancer, and may prevent the ability ofthe body to accept (tolerance) the transplant. Forthese reasons we are looking at different ways toreduce the need for immunosuppression. We areinterested in how signalling pathways in T cells, butalso the transplant itself, cross talk to drive thedestruction of the transplanted organ. By changingand re-wiring this 'rejection-circuitry' we can showthat transplants survive longer with lessimmunosuppression. This idea may be beneficial inthe case of pancreatic islet transplantation, onepotential therapeutic option to restore normal bloodsugar regulation in people with type 1 diabetes.

ReferencesGrey ST, et al., J. Immunol. 2003Walters S, et al., J Immunol. 2009Webster K, et al., J Exp Med. 2009Zammit N, et al., Cell Transplant. 2012Cantley J, Cell Transplant. 2012;

Project 2: The role of NF-kappaB in pancreaticislet biologyNF-kappaB is a transcription factor that controlscellular pro-inflammatory response genes but alsogenes like TNFAIP3 (otherwise known as A20). Wehave found that the TNFAIP3 gene is regulated byNFkappaB signalling axis in pancreatic islet cells.TNFAIP3 functions as a negative feedback todampen NF-kappaB activation and prevent celldeath. These data suggest that NF-kappaB controlsanti-inflammatory and protective responses, whilstsimultaneously elaborating pro-inflammatoryresponses. Thus, it can be seen that a tissueinvolved in inflammation undergoes a complexseries of signalling responses dependent upon thesemultiple actions of NFkappaB, which couldcontribute to the final outcomes of tissuedestruction or tissue survival and repair.Understanding this signalling axis may be importantin the case of autoimmune disease and transplantrejection - situations where tissue inflammationdrives a destructive immune response. Indeed,TNFAIP3 has been identified in a number of humanGWAS studies for autoimmune disease. Using cellspecific deletions of NF-kappaB genes and state ofthe art genomics to map the islet transcriptome andmethylome, we are unravelling these complexsignalling pathways in the context of transplantationand diabetes. Understanding the molecularnetworks that control tissue inflammatoryresponses may lead to novel ways to preventtransplant rejection and autoimmunity.

Supervisor: A/Prof Shane GreyEmail: [email protected]

ReferencesGrey ST, et al., J. Exp. Med. 1999, 190 (8): 1135-1145Liuwantara D, et al., Diabetes. 2006. Sep;55(9):2491-501Cowley MJ, Cell Transplant. 2012 Zammit N, et al., Cell Transplant. 2012Tan BM, Diabetologia. 2013


Diabetes & Transcription Factors Group

Project 1: Brown fat and obesityOver half of the Australian population is nowoverweight or obese. Current treatments forobesity are minimally effective, work onlytemporarily or have serious side effects.

Brown fat is an important type of fat whichconsumes calories to produce heat, and isassociated with decreased weight in both peopleand in animals. We have identified a drug whichincreases brown fat, and prevents obesity in mice.This project will examine the mechanisms behindthis exciting effect.

Techniques will include histology, tissue collection,real-time PCR, genotyping. We have developednovel mouse knockout models for this project.

Project 2: A novel therapy for liver disease?Liver disease is the 5th most common cause ofdeath in Australia and the UK.

Acute liver failure (ALF) is a devastating conditionwith high mortality rates. It often occurs in young,previously healthy individuals, including children. ALFhas a mortality rate of ~33-50% with intensivesupport including liver transplantation.

With the exception of N-acetyl cysteine, there areno proven therapies. Many treatments includingcorticosteroids, heparin, insulin, glucagon, blood orplasma exchange and prostaglandins have beentrialled without success. A therapy that diminisheshepatocyte death or enhances replacement throughregeneration is highly desirable. This project willwork on a novel therapeutic target which ourpreliminary data demonstrates is important forhepatocyte survival, and liver outcomes.

The project will include work with novel mouseknockout models, histology, tissue collection, real-time PCR, and next-generation sequencing, some ofwhich are demonstrated in our recent paper below.

Supervisor: A/Prof Jenny GuntonEmail: [email protected]

Recent publicationDing N, Yu RT, Subramaniam N, et al. (2013). A Master CistromicCircuit Governing Hepatic Fibrogenesis. CELL in press.

Antibody Engineering GroupOur laboratory is working on the development ofnew antibody therapeutics.

The following PhD projects are available:

Project 1: Molecular engineering of antibodytherapeuticsTherapeutic monoclonal antibodies are among thefastest growing class of drugs in the pharmaceuticalsector with more than $30 billion sales in 2012.Examples include the breast cancer drug Herceptinand the anti-inflammatory drug Humira.Unfortunately, many human antibodies displaypoor stability and a tendency to aggregate. Thisgreatly hinders the development of therapeuticsand results in high failure rates in pre-clinical drugdevelopment. Our group has pioneeredapproaches to increase the stability of humanantibody therapeutics using high-throughputphage display and X-ray crystallography methods.

Project 2: Targeted cancer therapyMonoclonal antibodies hold great promise for the treatment of cancer. Unfortunately, themajority of current antibody drugs are directedagainst a limited number of well characterized cell surface receptors (such as HER2, EGFR). New targets and therapeutics are urgentlyrequired. Our group is developing new antibodytherapeutics against targets emerging from theGarvan research programs.

Supervisor: Dr Daniel ChristEmail: [email protected]

Recent publicationsDudgeon K, Rouet R, Kokmeijer I, Schofield P, Stolp J, Langley D,Stock D and Christ D. (2012) General strategy for the generation ofhuman antibody variable domains with increased aggregationresistance.Proc Natl Acad Sci USA. 109: 10879-10884. [Editorial:http://www.pnas.org/content/109/27/10741.full.pdf]

Rouet R, Dudgeon K, Schofield P, Lowe D, Jermutus L and Christ D.(2012) Expression of high affinity antibody fragments in bacteria.Nature Protoc. 7: 364-373.

Lowe D, Dudgeon K, Rouet R, Schofield P, Jermutus L and Christ D.(2012) Aggregation, stability, and formulation of human antibody

therapeutics. Adv Protein Chem Struct Biol 2011;84:1-206

O'Toole SA, Machalek DA, Shearer RF, Millar EK, Nair R, Schofield P,McLeod D, Cooper CL, McNeil CM, McFarland A, Nguyen A,Ormandy CJ, Qiu MR, Rabinovich B, Martelotto LG, Vu D, HanniganGE, Musgrove EA, Christ D, Sutherland RL, Watkins DN, Swarbrick A.(2011) Hedgehog overexpression is associated with stromalinteractions and predicts for poor outcome in breast cancer. Cancer

Res 71(11):4002-4014


Prof David James Division HeadMetabolic Diseases

MetabolicDISEASES

Obesity is a major risk factor for many other diseases including diabetes, cardiovascular disease, Parkinson'sdisease and cancer. This indicates that these diseases are mechanistically linked. Our division takes a verybroad approach involving basic and clinical research to tackle the complexity of metabolic disease. This bydefinition requires interdisciplinary research so that we can integrate various layers of information thatdepict the behaviour of mammals as they respond to changes in their environment. We have expertise inislet, fat cell, liver and muscle biology. We use a combination of molecular, cellular, biochemical andphysiological approaches to dissect the metabolic wiring in these different organs with the ultimate goal ofpinpointing major regulatory features that both cause disease and/or may be manipulated therapeutically.

Most of our students publish first author papers in top level journals and end up doing postdoctoralfellowships in some of the best labs throughout the world. Many have gone on to successfully establish theirown labs around the world.

METABOLIC DISEASES10

James Lab http://www.jameslab.com.au/We are interested in understanding the relationshipbetween changes in the environment and disease.Most complex diseases including diabetes,cardiovascular disease and cancer involve aninextricable link between environmental change (foodintake, physical activity, smoking) and genetics. Wehave a number of projects involving systemsbiology, cell biology or animal physiology dissectingwhich molecular systems change in response toenvironmental change and how this varies in animalsof different genetic backgrounds. We are particularlyinterested in changes in the insulin signallingpathway since defects in this pathway have beenlinked to many diseases and to lifespan in a range ofanimals (flies, worms, mice and humans).

Project 1Systems biology analysis of metabolic disease. Thisinvolves acquisition of large data sets from animals/humans as they transition from the normal to thediseased state. Suitable for students with an interestin bioinformatics and integrated data analysis.

Project 2Mapping insulin signal transduction pathway in wildtype and insulin resistant cells. We have completedthe phosphoproteome of adipocytes identifying37,000 phosphorylation sites by massspectrometry of which 15% are highly insulinresponsive. Similar studies need to be done inanimal and human tissues with diabetes. Suited forstudents with a desire to learn mass spectrometry.

Project 3Dissecting heterogeneity in insulin action betweenindividual cells. Recent research in our lab using totalinternal reflection microscopy has revealed anunexpected heterogeneity in insulin action between

individual cells and this needs to be explored further.Suited for students with interest in morphology oruse of sophisticated live cell microscopy approaches.

Project 4Gene-environment interaction and lifespan.Different recombinant mouse strains will be feddifferent diets comprised of different combinationsof macronutrients. They will be studied for theduration of their life during which a number ofanalytic approaches will be taken to pinpointmechanistic determinants that depict discretedifferences in lifespan. Suited for students with aninterest in animal based experiments.

Supervisor: Prof David JamesEmail: [email protected]

Recent Publications by graduated PhD students from the James LabHumphrey, SJ, Yang, G, Yang, P, Fazakerley, DJ, Stöckli, J, Yang, JY,James, DE. Dynamic adipocyte phosphoproteome reveals Akt directlycontrols mTORC2. Cell Metab In press, 2013.

Davey, JR, Humphrey, SJ, Junutula, JR, Mishra, AK, Lambright, DG, James,DE, Stöckli, J. TBC1D13 is a RAB35 specific GAP that plays an importantrole in GLUT4 trafficking in adipocytes Traffic 13: 1429-41, 2012

Rowland, AF, Larance, M, Hughes, WE, James, DE. Identification ofRhoGAP22 as an Akt-Dependent Regulator of Cell Motility inResponse to Insulin. Mol Cell Biol 31: 4789-4800, 2011

Hocking, SL, Wu, LE, Guilhaus, M, Chisholm, DJ, James, DE Intrinsicdepot-specific differences in the secretome of adipose tissue,preadipocytes and adipose tissue derived microvascular endothelial

cells. Diabetes 59: 3008-16, 2010

Larance, M, Rowland, AF, Hoehn, K, Humphreys, DT, Preiss, T, Guilhaus,M, James, DE Global phosphoproteomics identifies a major role for aktand 14-3-3 in regulating Edc3. Mol Cell Proteomics 9: 682-94, 2010

Yip, MF, Ramm, G, Larance, M, Hoehn, KL, Wagner, MC, Guilhaus, M,James, DE. CaMKII-Mediated Phosphorylation of the Myosin MotorMyo1c Is Required for Insulin-Stimulated GLUT4 Translocation inAdipocytes Cell Metab. 8: 384-98, 2008

Ng, Y, Ramm, G, Lopez, JA, James, DE. Rapid Activation of Akt2 IsSufficient to Stimulate GLUT4 Translocation in 3T3-L1 Adipocytes CellMetab. 7: 348-56, 2008

Islet Biology GroupThe current epidemic of type 2 diabetes representsa major global health problem, with over 7% of theAustralians suffering the disease. While there is awell-established relationship between obesity andinsulin resistance, the majority of overweightindividuals do not develop type 2 diabetes becausetheir pancreatic ß-cells compensate with enhancedinsulin secretion. It is the failure of ß-cellcompensation that is fundamental to thedevelopment of diabetes. The ß-cell is a highlyspecialised cell with a unique metabolic profile anddifferentiation specifically geared towards makingthese cells able to sense fluctuations in circulatingglucose levels and secrete insulin accordingly. Wepropose that in susceptible individuals, a gradual risein blood glucose (hyperglycaemia) and lipid levelsresulting from increasing obesity and insulinresistance leads to a loss of the unique expressionpattern of genes necessary for appropriate insulinsecretion. This exacerbates hyperglycaemia, whichcauses further ß-cell dedifferentiation andeventually the death of ß-cells by apoptosis. Ourgroup has recently found evidence in several modelsof diabetes that supports this hypothesis. We haveidentified and are investigating novel candidategenes that link hyperglycaemia to the developmentof impaired ß-cell function. Furthermore, we areinvestigating endoplasmic reticulum (ER) stress as apotential mechanism for ß-cell destruction in type 1and type 2 diabetes. We are using in vivo and invitro systems to investigate the followinghypotheses important for our understanding of ß-cell failure and progression to diabetes:

_ The loss of ß-cell phenotype (dedifferentiation)underlies the loss of insulin secretory function intype 2 diabetes.


_ Hyperglycaemia plays a critical role regulatingthe progression to ß-cell dedifferentiation.

_ The overexpression of key candidate geneproducts play an integral role linkinghyperglycaemia to the loss of ß-celldifferentiation and secretion.

_ ER stress is necessary and contributes to ß-celldeath in type 1 and type 2 diabetes.

Identifying the mechanisms of ß-cell failure indiabetes is of critical importance considering thatthe incidence of newly diagnosed diabetes isgrowing to epidemic proportions. Our studies willmake a major contribution to our understanding ofwhy ß-cells fail in diabetes and aim to provide noveltherapeutic targets in the treatment of diabetes.

Supervisor: Dr Ross LaybuttE-mail: [email protected]

Recent publicationsChan JY, Luzuriaga J, Bensellam M, Biden TJ, Laybutt DR. Failure ofthe adaptive unfolded protein response in islets of obese mice islinked with abnormalities in _-cell gene expression and progression todiabetes. Diabetes 62(5):1557-68, 2013.

Chan JY, Biden TJ, Laybutt DR. Cross-talk between the unfoldedprotein response and nuclear factor-∫B signalling pathways regulatescytokine-mediated beta cell death in MIN6 cells and isolated mouseislets. Diabetologia 2012; 55:2999-3009

Achard CS, Laybutt DR. Lipid-induced endoplasmic reticulum stress inliver cells results in two distinct outcomes: adaptation with enhancedinsulin signaling or insulin resistance. Endocrinology 153(5): 2164-77, 2012

Åkerfeldt MC, Laybutt DR. Inhibition of Id1 augments insulinsecretion and protects against high-fat diet-induced glucoseintolerance. Diabetes 2011; 60:2506-2514

Cooney Group-Obesity & InsulinResistanceIncreased body fat (obesity) is one of the mostimportant current health problems because obesityis associated with the development of a number ofserious and common diseases such as heart disease,stroke, type 2 diabetes, liver disease, arthritis andcancer. The broad aim of our projects is tounderstand how different tissues and differentgenes contribute to the way the body balances foodintake and energy expenditure to maintain healthybody weight and what goes wrong when thisbalance breaks down and obesity develops.

Project: Circadian rhythms and energymetabolismMany important genes of metabolism are expressedin a circadian rhythm synchronized with thelight/dark cycle and feeding/sleeping patterns. Themodern lifestyle is associated with disrupted eatingand sleeping patterns and an increase in obesity butwhether this is accompanied or caused by adisruption in the circadian rhythms of geneexpression is not known. This project investigateswhether circadian gene expression is altered insituations of obesity and insulin resistance and whatmetabolic processes these genes regulate indifferent tissues. Our recent studies haveestablished that altering feeding patterns can havesignificant and different effects on energy

metabolism in liver and muscle (1). Future studieswill involve altering the expression of specific genesthat control circadian rhythms in liver and muscleand examining how this alters the way liver andmuscle deal with glucose and lipid metabolism.

Supervisor: A/Prof Greg Cooney Email: [email protected]

Recent publicationsAltered feeding differentially regulates circadian rhythms and energymetabolism in liver and muscle of rats. Reznick J, Preston E, Wilks DL,Beale SM, Turner N, Cooney GJ. Biochim Biophys Acta. 20131832:228-38

Wright LE, Brandon AE, Hoy AJ, Forsberg G-B, Lelliott CJ, Reznick J,Löfgren L, Oscarsson J, Strömstedt M, Cooney GJ & Turner N. (2011).Amelioration of lipid-induced insulin resistance in rat skeletal muscle byoverexpression of PGC-1_ involves reductions in long-chain acyl-CoAlevels and oxidative stress. Diabetologia 54:1417-1426.

Hoehn KL, Turner N (co-first author), Swarbrick MM, Wilks D, Preston E,Phua Y, Joshi H, Furler SM, Larance M, Hegarty BD, Leslie SJ, Pickford R,Hoy AJ, Kraegen EW, James DE & Cooney GJ. (2010). Acute orchronic upregulation of mitochondrial fatty acid oxidation has no neteffect on whole body energy expenditure or adiposity. Cell Metab 11:70-76.

Turner N, Bruce CR, Beale SM, Hoehn KL, So T, Rolph MS, Cooney GJ.Excess lipid availability increases mitochondrial fatty acid oxidativecapacity in muscle: evidence against a role for reduced fatty acidoxidation in lipid-induced insulin resistance in rodents. Diabetes. 200756(8):2085-92.

Kraegen EW, Cooney GJ. Free fatty acids and skeletal muscle insulinresistance. Curr Opin Lipidol. 2008 19:235-41.


Parkinson's Disease-Neurodegeneration,Cell & Molecular Biology, GeneticsParkinson's disease (PD) is a debilitatingneurodegenerative disorder that affects ~80,000Australians and >6 million people worldwide. Theprevalence of PD is expected to increasesignificantly in our aging population and currentlythere is no test for early diagnosis, no cure and nolong-term effective therapy. The lack of knowledgeof the underlying mechanisms responsible forcausing PD and its progression is the majorimpediment to therapeutic advances. To achieveearlier diagnoses and development of treatmentsand drugs, our research, currently funded by boththe Australian NHMRC and Michael J FoxFoundation, centers on discovering the cascade ofmolecular and cellular events that cause the loss ofneurons in PD. Attaining these goals will:

_ provide critically needed biomarkers for PD thatwill allow significantly earlier diagnosis, screen forpeople at risk for PD, and to monitor both diseaseprogression and therapeutic effectiveness.

_ provide mechanistic insights that will result in thedevelopment of treatments and drugs, andpotentially a cure.

Project 1: The role of long non-coding RNAs inParkinson's DiseaseLong non-coding RNAs (lncRNAs) are RNAtranscripts of >200 bases (distinct frommicroRNAs) that typically do not encode proteinsand instead function by binding RNA, DNA orproteins to perform a wide range of activities thatinclude modulating transcription, alternative splicing,mRNA stability, mRNA translation, and epigeneticevents, such as chromatin remodeling. Currently>15,000 human lncRNAs have been preliminarilyidentified and the number is predicted to exceedthe number of protein coding genes. The rapidincrease in the number of lncRNAs within theprimate lineage suggests that lncRNAs have playeda part in the evolution of human brain form andfunction. lncRNAs represent a burgeoning field ofregulatory elements that play diverse regulatoryroles in gene expression while their dysregulation isassociated with human diseases includingAlzheimer's and Huntington's disease. lncRNAsrepresent a new frontier in molecular genetics andmolecular biology that have tremendous potentialfor a transformative advance in our understandingof PD by integration of the genetics, cellularpathways and potential environmental impacts ofthis disease. Integrating human PD patient geneticdata with bioinformatics analysis has led us toidentify a number of human lncRNAs that are clearlycontributing to the disease. This project offers awide range of interesting aspects to investigateincluding modulating their expression as therapy,identifying their targets and functional mechanisms,and their use as informative biomarkers.

Project 2: The Inter-Relationship of αSynuclein and Dysfunctional Mitochondria in Parkinson's diseaseThe molecular mechanisms responsible for PDdevelopment remain unclear but diverseapproaches have shown that abnormalities in thesynaptic protein αSynuclein play a central role inPD. Our whole genome functional screeningapproaches have identified αSynuclein to causedefects in several major cellular pathways. Thisproject will dissect the inter-relationship(s)between αSynuclein, dysfunctional mitochondria(a common feature in PD), endoplasmic reticulumand reactive oxygen species to identify theinitiating events in PD as they provide excellentpoints for therapeutic intervention.

Project 3: Exosomes-mediators of cell-cellcommunication and their role in Parkinson'sdisease progressionCurrent treatments do not prevent the inevitableand insidious progression of PD as new regions ofthe brain degenerate and expand the symptoms toinclude depression, anxiety and severely reducedcognitive function. Recently, toxic forms ofαSynuclein has been found to be capable oftransferring from within a degenerating neuroninto neighbouring healthy neurons and trigger theirdegeneration. Such inter-neuronal transmission ofαSynuclein is proposed to be responsible for theprogression or “spread” of PD. Exosomes are smallvesicles released extracellularly by cells includingneurons, that can be taken up by recipient cellsand evoke biological responses and as suchprovide a form of cell-cell communication.Exosomes have also been found to containαSynuclein and are proposed to mediate thisinter-neuronal transmission of αSynuclein.Therefore preventing either the release and/oruptake of αSynuclein containing exosomes offers areal opportunity to stop disease progression. Thisproject involves a whole genome screeningapproach to identify the molecular mechanismresponsible for the biogenesis of αSynucleincontaining exosomes and testing the findings inrodent PD models for their effectiveness as adisease treatment.

Our research projects utilise a wide range ofapproaches including genome-wide screening,Next Generation sequencing, bioinformatics, celland molecular biology techniques, fluorescencemicroscopy, qRT-PCR, lipodomics, proteomics,metabolomics, siRNA knockdown, gene knockouts,FACS analysis, cell culture, virus mediated geneexpression, primary neurons, transgenic micemodels and human PD patient brain samples.Further information regarding these projects canbe obtained by contacting Antony Cooper.

Supervisor: A/Prof Antony Cooper Email: [email protected]


Hesselson Group-Beta CellRegenerationThe common forms of diabetes are characterized bythe destruction (type 1) or an insufficiency (type2) of insulin secreting pancreatic beta cells. We aretaking an interdisciplinary approach to devise novelstrategies for beta cell replacement therapy. Ourprimary experimental system is the zebrafishembryo, a model that is at the intersection ofgenetic and pharmacological research.

Project 1: Directed reprogramming of acinar cellsWe are applying insights from developmentalbiology to use the abundant pancreatic acinar celltype as a source of progenitors for beta cellregeneration. We have established an in vivo modelto induce acinar cell reprogramming and track thefate of the cells as they transition to insulinproducing beta cells. This project will focus onincreasing the efficiency and specificity of cellularreprogramming. We are particularly interested indeveloping a protocol that is responsive to themetabolic dysfunction associated with diabetes.

Project 2: in vivo drug screeningTraditional drug screens have targeted singlemolecules or cell types. While the targets are oftenwell justified, it is difficult to predict how the hitswill behave in vivo, which has contributed to thepoor success rate for new drugs in recent years. Wehave developed a number of transgenic models thatallow us to monitor metabolic parameters in intactembryos (glycemia, beta cell mass, etc.) to helpidentify the next generation of antidiabetic drugs.Projects in this area would include assaydevelopment and screening as well as mechanisticanalysis of previously discovered lead compounds.

Selected publicationsGut P, Baeza-Raja B, Andersson O, Hasenkamp L, Hsiao J, Hesselson D,Akassoglou K, Verdin E, Hirschey MD, Stainier DY. (2012) Whole-organism screening for gluconeogenesis identifies activators of fastingmetabolism. Nature Chemical Biology 9, 97-104.

Hesselson D, Anderson RM, *Stainier DYR. (2011) Suppression ofPtf1a induces acinar-to-endocrine conversion. Current Biology 21,712-717.

Hesselson D, Anderson RM, Beinat M, Stainier DYR. (2009) Distinctpopulations of quiescent and proliferative pancreatic ß-cells identifiedby HOTcre mediated labeling. PNAS 106(35), 14896-14901.

Clinical Prader-Willi Research Group

Advancing therapeutical management of obesityin Prader-Willi syndromePrader-Willi syndrome is one of the most commonknown genetic causes of obesity, occurring in1:15,000 live births. Besides some behavioural andendocrine abnormalities, this syndrome is known forthe insatiable appetite and hyperphagia which leadsto severe obesity if access to food is not restricted.There are no tested pharmacological treatmentsavailable so far, and strong behavioural restraintswith locking the fridge are usually the only optionsto prevent these patients from gaining weight.

Our PWS Research Group at the Garvan has aconsiderable track record of doing research in PWS,usually recruiting patients from the PWS Clinic atRPAH and through the PWS Society. PWS is anexcellent human model to understand and learnmore about appetite dysregulation and obesity ingeneral. Our published research includes assessment of systemic inflammation, bodycomposition, hunger and satiety ratings during ameal, and assessment of autonomic nervoussystem. Furthermore, we have conducted the firstclinical trial testing a GLP-1 analogue for its use tocontrol appetite and body weight.

Based on the successful pilot study where wetested a short acting GLP-1 analogue, a project isnow being built up aiming to test different clinicallyavailable GLP-1 analogues for their efficacy andsafety in PWS. A theoretical risk with these agentsremains the still open question whether gastricemptying is delayed in PWS, which is stillcontroversial, and whether it could be furtherdelayed by GLP-1, increasing the risk of thepotentially lethal complicating of gastric necrosis.

This project aims at recruiting 8-10 PWS subjectfor a randomised cross-over trial testing once dailyand once weekly GLP-1 agonists. Gold standardmethods of gastric emptying will be used to ruleout significant alteration in gastric emptying. If thisstudy can prove the safety and efficacy of thesepharmacological agents in PWS, then these wouldbe the first effective treatments available forhyperphagia in PWS, and represent a hugemilestone for the patients, families and carers.

The project would involve conducting clinicalresearch using state-of-the-art techniques formetabolic phenotyping, with much opportunity forlearning standard laboratory techniques.

Supervisors: Prof. Lesley Campbell and Dr Alex ViardotEmail: [email protected]


Clinical Diabetes Group

Personalised medicine for diabetes The increasing prevalence of obesity and type 2diabetes (T2D) has reached epidemic proportions,and new ways of prevention and effectivetreatment are urgently needed. T2D is a chronicdisease accounting for 95% of diabetes worldwide,and is characterized by an insufficientcompensatory insulin secretion to insulin resistance.In contrast to other diseases, it consists of anumber of subgroups differing in phenotype,manifestation and disease mechanisms. Personalisedmedicine represents a novel approach for definingboth disease subtypes and biomarkers that couldidentify those patients who are most likely tobenefit from a specific treatment. It can be used inprevention, detection, individualised treatment andmonitoring of diseases. In today's treatmentalgorithms, little attention is given to the hugevariation in phenotype in these patients, who mighthave significant differences in insulin resistance,beta-cell function, gut hormone levels, systemicinflammation and central control of metabolismincluding the autonomic nervous system. Notreatment decision is currently made on this basis,but rather on the available evidence as to whichtreatment the biggest numbers of patients respond.However, phenotypic assessments complementedwith genomic data may well enable identification ofa subtype with specific treatment options whichcould avoid ineffective and time wastingtreatments, and ultimately lead to a more targetedand rational treatment strategy in T2D.

In addition to the above, many patients are thoughtto be misdiagnosed for type of diabetes, whichresults in suboptimal treatment and worse clinicaloutcome. This includes many cases of monogeneticforms of diabetes, most commonly Maturity OnsetDiabetes of the Young (MODY) who never hadgenetic testing and are presumed either T1D orT2D. Many of these patients present clinically in-between T1D and T2D, and treatment allocation ismost commonly based on clinical judgment and alsoon their response to the chosen treatment regimen.Monogenetic diabetes may make up 1-5% ofpatients in a large diabetes clinic. There are clearadvantages of diagnosing these monogenetic formsof diabetes: In many patients, insulin may not berequired and could be substituted with oral agents.In addition, families should be screened andadditional affected patients could be identified and

appropriately treated at an early stage. However,genetic testing is still not widely available, isexpensive, and routine tests may not detect all theknown genetic mutations if they are notspecifically looked for.

The aims of this project include novel approachesto carefully phenotype individual patients withT1D or T2D to:

_ Identify the most commonly affectedmechanisms of disease in T2D, leading to thedefinition of specific disease-subtypes

_ Screen for gene variants associated with thesephenotypic features. Identification of specific riskgenes could eventually assist or even replacefuture clinical assessment for stratifying thesepatients into their specific subgroups.

_ Test the effect of allocating these T2D patientsto suitably targeted treatment optionsconsidering the specific pathophysiology.

_ Prospectively collect data to track treatmentresponders and non-responders in order toidentify gene polymorphisms which could serveas predictors and be used to build new treatmentalgorithms, using a pharmacogenomic approach.

_ Set up a genetic testing facility in our clinicalgenomics centre to be able to screen patientsfor monogenetic diabetes

_ Analyse genome data and try to find newcandidate genes for T1D

In summary, these new strategies could test anew methodology of personalized medicine whichcould prove to be more health protective and costeffective in the long term, and provide a newtreatment algorithm for T2D for the future.Screening for the most common forms ofmonogenetic diabetes would allow identifying sofar undiagnosed patients and allow tailoring theirtreatment specifically for their gene defect. Theproject would involve conducting clinical researchwith a strong link to the genome sequencing andbioinformatics facilities.

Supervisor: Dr Alex ViardotEmail: [email protected]


Prof Herbert Herzog Division HeadNeurological Diseases

The Garvan Neurological Diseases Division is an active, collaborative research community that investigateshow the brain functions. Research undertaken by the Division looks at the brain at many different levels,from genes and molecules to synapses, neurons, brain regions and behaviour. A wide range of models fromflies, mouse to humans and state-of-the-art molecular and biochemical techniques are employed to addressboth basic and medically relevant problems in neuroscience. The Division's goal is to understand how thebrain works and to improve understanding, diagnosis, and ultimately develop novel therapies for neurologicaldisorders. We are particularly interested in conditions like Parkinson's Disease, Alzheimer's Disease andgeneral conditions of dementia in which the natural ability of the brain to regenerate itself (via neuro-stemcells) is compromised. Furthermore, we investigate the role of the nervous system in pain perception as wellas how the brain communicates with other organs and tissues in the body, for example to control boneformation; and in the regulation of energy balance (intake and expenditure), which affects fertility, mood,weight gain, physical fitness and how this can lead to obesity.

The majority of the PhD students trained in the Neurological Diseases Division are supported by AustralianPostgraduate Awards or NHMRC scholarships, and have received numerous presentation awards and travelfellowships to national and international meetings. Research produced by our students is published in high-ranking journals such as PNAS, J.Biol.Chem, J.Clin.Invest., JBMR, Nat. Med, PlosONE, Cell Metabolism, J.

Neurosci, Cell and Nature. We are currently looking for candidates in areas such as: Neuropeptide signalling,Neurodegenerative diseases, Neuronal control of bone density, Regulation of appetite, Neural endocrinology,Pain perception, Sleep disorders and Behavioural genetics.

Eating Disorders Group

Project 1: Novel neuropeptide regulators ofenergy homeostasisThe worldwide prevalence of obesity is increasing atalarming rate, and is a major risk factor for type 2diabetes and other diseases. Although the benefits oflosing excess weight are undisputed, there currentlyexists no effective non-surgical treatment for obesity.Body weight and body composition such as fat tissuemass are regulated by an interactive complex ofenergy homeostatic system. Thus to meet the urgentand desperate need for the development of novelpharmacological tools for treating obesity, researchersneed not only to know the identity and functions ofindividual molecules and pathways involved in theregulation of energy homeostasis, but also tounderstand how these molecules and pathwaysinteract. Among these, neuropeptide Y (NPY), - oneof the most widely expressed molecule in the brain, isa known player critically involved in the regulation ofbody weight ad adiposity via its control on everyaspects of energy homeostasis, such as appetite,energy expenditure, physical activity and fuelpartitioning 1. Recently, our unpublished studies showthat neuropeptide FF and NPFF receptor 2 (NPFF2R)are the novel players in the energy homeostaticcomplex. Interestingly, our preliminary results suggestthat NPFF system may exert its control on energyhomeostasis via interacting with NPY pathway.Therefore, this project is to further investigate themechanism by which NPFF system regulates energyhomeostasis; and to investigate how the NPFF and

NPY systems interact in these regulations. To achievethis, we will examine aspects of energy homeostasisand factors in controlling them in multiple mousemodels where either or both NPFF and NPY systemhave been genetically altered. Such mouse modelsinclude mice with NPFF overexpression by deliveringthe NPFF-containing adeno-associated viral vector tothe adult mouse brain, germline NPFF2R knockoutmice, and mice with adult-onset specific deletion ofNPFF2R from NPY neurons. By utilizing cutting edgeinternationally competitive technology and uniquegermline and conditional knockout and transgenicmouse models, this project will make highly originaland high-impact contributions to the understanding ofthe role of NPFF system in energy homeostasis and itsinteractions with the NPY pathway, and willdemonstrate whether targeting NPFF2R could providethe basis of novel anti-obesity treatment.

Major techniques involved in this projectIndirect calorimetry, infrared imaging, stereotacticbrain injection, oral glucose tolerance test,intraperitoneal insulin test, dual-energy X-rayabsorptiometry, tissue dissection, in situ hybridyzation,Western blotting, immunohistochemistry, variousserum assays.

Supervisor: Prof Herbert HerzogEmail: [email protected]

Selected recent publicationZhang L et al. The neuropeptide Y system: Pathological andimplications in obesity and cancer. Pharmacol Ther. 2011Jul:131(1):91-113.

NeurologicalDiseases

NEUROLOGICAL DISEASES16

Project 2: Insulin action in the brainThe prevalence of obesity has reached epidemiclevels and is further increasing at an alarming rate.Currently there are no effective therapeutictreatments for obesity, however it is generallyrecognized that any treatment must be associatedwith a reduction in energy intake, an increase inenergy expenditure or ideally both. Therefore,defining how the central nervous systemcoordinates information to regulate energy balanceis important for understanding the pathology ofobesity as well as for designing treatments tocombat this disease. Insulin is a potent anabolichormone, secreted by the pancreas in response tothe increase in blood glucose levels. Recently, insulinhas been reported to have effects not only in theperipheral tissues, but also in the brain to regulatesatiety and glucose and energy balance. Previousstudies from our lab and others have establishedthe importance of the central neuropeptides Y(NPY) system in the regulation of food intake andenergy expenditure, with hypothalamic NPY mRNAlevels elevated in several rodent models of obesity.Increased NPY levels contribute to the developmentof obesity in a two-fold way by increasing foodintake and also reducing energy expenditure.Although insulin is known to influence energybalance, the precise neuronal action andpopulation(s) of neurons that mediate insulin actionremains unknown. Thus, the major aim of thisproject is to understand and define the role ofinsulin in NPY neurons in the regulation of energyhomeostasis. This research will not only help to getmore mechanistic insights in the etiology of obesity,but also contribute to the precise understanding ofcentral insulin action in the NPY-ergic pathway inthe regulation of energy homeostasis.

Specific aims_ To generate and characterize NPY-neuron specific

IR-deficient mice.

_ To investigate the molecular mechanisms by whichcentral insulin action regulates energy homeostasis.

Summary of techniques to be usedConditional knockout mouse models, indirectcalorimetry, metabolic measurements, real-timePCR, in situ hybridization, western blotting, patchclamp electrophysiology, immuno-histochemistry.


Project 3: SNORD RNA's and their role in obesityObesity is a major global public health concern,with Australia being one of the most affectedcountries. Although great effort has been placedon identifying treatments for obesity and criticalplayers and pathways that control appetite havebeen characterised, hardly any effective drugs areon the market. Therefore there is a desperateneed to identify new alternative targets to treatobesity. One way to learn more about the criticalpathways that control food intake and energyhomeostasis is by investigating naturally occurringmutations that lead to obesity. The identificationof the gene mutation in the leptin gene thatcauses the massive obesity in the ob/ob mousewas a landmark discovery, which has and stillprovides us with important information about thecontrol of this complex system. While mutations inthe leptin gene in humans are actually very rarethere are other genetic variations that also lead tomassive increase in appetite and the developmentof obesity that have much higher frequencies likethe one causing Prader-Willi-Syndrome (PWS),which is the most common known genetic causeof obesity, with a prevalence of 1 in 25,000 to 1in 10,000 live births.

PWS is characterized by severe infantile hypotoniawith poor suck and failure to thrive in the first 1 to2 years of life. This initial lack of feeding drivechanges then dramatically and subjects with PSWdevelop an obsession with food leading to an un-saturable appetite, which if not controlled, will leadto early-childhood onset obesity. PWS is due tothe absence of paternally expressed imprintedgenes at 15q11.2-q13. Interestingly, singledeletion of known genes in this region in micealthough showing some effects related to thePWS phenotype, do not result in a phenotype thatwould resemble the classical features ofovereating and development of obesity seen inhuman PWS subjects. Importantly, several recentstudies have identified subjects with PWS thathave only micro-deletion in this locus onchromosome 15, but still show many of the majorfeatures such as increased appetite and earlyonset of obesity characteristic for this syndrome.The different deletions vary in size but all containthe entire 27 copies of the SNORD116 locus.


Astonishingly hardly anything is known on how thegenetic variations in Snord genes cause theincredible high-level of appetite and massiveobesity in affected individuals. Therefore the majoraim of this study is to identify the underlyingmechanism that leads to increased appetite andbody weight of a particular mutation in this PWSlocus, called Snord116 using various geneticallymodified mouse models.

Specific aims_ Determine the effect of adult onset SNORD116

deficiency on food intake and energy homeostasis

_ Investigate whether re-introduction ofSNORD116 can rescue the hyperphagia ofSNORD116 KO mice

_ Identification of SNORD116 downstream affecterpathways


Project 4: Anorexia Nervosa-the starving brainAnorexia nervosa is a debilitating disorder affectingas many as 1 in 100 young women. Approximately10% of people suffering with anorexia are male.

Without treatment, up to 25% of people withanorexia nervosa die. With treatment, about 20% ofpatients make only partial recoveries, remaining toofocused on food and weight to be able toparticipate fully in life. An additional 20% ofsufferers do not improve, even with treatment.They are seen repeatedly in emergency rooms,eating disorders programs and mental health clinics.Clearly, new treatments for anorexia nervosa aredesperately required.

The precise causes of anorexia nervosa areunknown, but environmental and psychologicalfactors often cited as playing a role. However,

emerging evidence strongly suggests genetic causesfor anorexia nervosa. For instance, most peoplesimply cannot diet down to an unhealthily low bodyweight. That is because weight loss activates strongphysiological mechanisms that protect againstfurther weight loss. This 'famine reaction' istriggered by natural brain chemicals in a part of thebrain called the hypothalamus, with effects includeirrepressible hunger, lethargy and sharp reductionsin metabolic rate.

Paradoxically, people with anorexia nervosa do notdemonstrate these expected responses to weightloss, suggesting perturbations in the natural brainchemicals responsible for the famine reaction. If weunderstood exactly which chemicals in the brainwere responsible for mediating the famine reaction,how they worked, as well as how these moleculesare perturbed in anorexia nervosa, then we coulddevelop novel treatment strategies to target thephysical causes of this debilitating disorder, andpossibly therefore help people who do not respondto conventional treatments.

Using sophisticated genetic engineering techniques,we have developed mice with perturbations ingenes encoding substances that act on the brain tomediate the famine reaction, such as neuropeptideY, peptide YY, and dynorphins. Intriguingly, thesetransgenic mice demonstrate metabolic featurescharacteristic of people with anorexia nervosa,notably an enhanced ability to lose weight and burnbody fat. However, in order to fully investigate therole of these substances in the development andtreatment of anorexia nervosa, we need toinvestigate their effects on food intake and bodycomposition other eating related behaviours.



Project 5: Altering thermogenesis as weight-loss strategyObesity-associated cardiovascular diseases anddiabetes are leading causes of death and areexpected to increase as the obesity epidemicworsens. Current weight-loss therapies mainlytarget reduction of energy intake, providing only atransient or partial solution with limitedeffectiveness. Alternatives are needed to combatthis problem and one potential promising approachis to target the other side of the energy balanceequation, energy expenditure.

The therapeutic potential of brown adipose tissue(BAT) in weight reduction via the regulation ofenergy expenditure has emerged as a conceivablypromising yet underexplored area. Whilst previouslybelieved to be small animal-specific and exclusivelyneonatal in mammals including humans, theabundance of functional BAT in adult humans hasbeen recently confirmed to be widespread bypositron emission tomography (PET) marking it apromising target for anti-obesity therapy. However,little is known about the control of BAT activity andfunction. BAT is the main tissue that harboursuncoupling protein 1 (UCP1), the major componentthat is responsible for mediating metabolicthermogenesis. Our preliminary data demonstratesthat elevated neuropeptide Y (NPY) levelsspecifically in the arcuate nucleus (ARC) of thehypothalamus, which is known to be a major driverfor marked reductions in energy expenditure, alsoinfluences UCP1 expression in the BAT. We thus aimto investigate the specific role of the NPY system inintegrating hypothalamic functions with energyexpenditure specifically focusing on BAT activity. Toachieve this, we will utilize a set of novel and uniquemouse models that allow for the neuron-typespecific conditional deletion or over-expression ofNPY in an inducible adult-onset fashion. A widerange of laboratory techniques will be employed,including but not limiting to in-situ hybridization,immunohistochemistry, high-sensitivity infraredthermal imaging, histological examination, cellcultures, quantitative real time-PCR and Westernblotting, to determine the key regulators ofthermogenesis and mitochondrial function andmechanistic central pathways possibly involved. Allof the mouse models, methods and experimentalparadigms are well established in our laboratory asdemonstrated by our extensive publication recordon these topics in highly ranked journals like Nature

Medicine and Cell Metabolism (1,2,3,4,5).

Results from this study will provide critical newinsights on NPY's role in the control of BAT-mediated energy expenditure. These results will alsoprovide valuable contributions to the developmentof potential therapeutics to increase energyexpenditure, likely being a more effective way forthe treatment of obesity.

Supervisors: Dr Yan Shi and Dr Shu LinEmail: [email protected]

Selected recent publicationsJohnen H, Lin S, et al. Tumor-induced anorexia and weight loss aremediated by the TGF-beta superfamily cytokine MIC-1. Nat Med.

2007 Nov;13(11):1333-40.

Lin S, Shi YC, et al. Critical role of arcuate Y4 receptors and themelanocortin system in pancreatic polypeptide-induced reduction infood intake in mice. PLoS ONE. 2009;4(12):e8488.

Cox HM, Tough IR, et al. Peptide YY Is Critical for AcylethanolamineReceptor Gpr119-Induced Activation of Gastrointestinal MucosalResponses. Cell Metab. 2010 Jun 9;11(6):532-42.

Shi YC, Lin S, et al. NPY-neuron-specific Y2 receptors regulateadipose tissue and tranbecular bone but not cortical bonehomeostasis in mice. PloS ONE. 2010;5(6):e11361

Shi YC, Lin S, et al. Peripheral-specific Y2 receptor knockdownprotects mice from high-fat-induced obesity. Obesity. 2011 Nov;19(11): 2137-48

Bone Regulation Group

Project 1: Inter-organ signalling: A new level ofregulatory controlOur laboratory has a long-standing interest indefining the brain's role in controlling and co-ordinating peripheral tissue homeostasis. Usingsophisticated genetic studies in mice, we havedemonstrated that the hypothalamus regulates thebehaviour of numerous organ systems, throughmodulation of specific neuropeptide pathways.

Our primary focus has been upon the powerful,multi-system responses that surround starvationand obesity, with a particular emphasis upon theneuropeptide Y (NPY ) system. NPY is one of themost powerful regulators of energy homoeostasisthroughout the body, and our group, incollaboration with the Eating Disorders Group, isamongst only a few in the world able to dissectthe activity of this crucial pathway, through uniqueanimal models made at the Garvan.

Using specific tissue responses, such as adipose,skeletal and pancreatic tissue, we have defined the mechanism whereby specific NPY pathwaysfrom the brain act within the periphery. Thesepathways are extremely potent, altering fat massby over 4-fold and the production of bone by 7-fold, as well as altering endocrine function throughaltered production or end-organ responses.Moreover, these signals are co-ordinated acrossmany organ systems, demonstrating a level ofintegration between organ systems, not fullyappreciated previously.


Excitingly, during the course of these studies, wehave uncovered unique signalling pathways, thatindicate an additional layer of communication notpreviously appreciated, acting between the organsthemselves. Endocrine regulation has typically beenviewed as a top-down process, from thehypothalamus via the pituitary to the circulation.Our research will focus upon emerging inter-tissuecommunications, defining entirely new signallingmolecules and axes of communication.

Our initial studies have identified actions entirelynovel to science. For example, using tissue-specificneuropeptide models, we have demonstrated bone'ssignalling to the brain to control its own production,as well as bone's regulation of both adipose andglucose homeostasis.

Post graduate projects within the lab will involveinvestigations of inter-organ communication,concerning, but not restricted to:_ Coordination of energy, skeletal and glucose

homeostasis _ Feedback signals from bone to brain_ Regulation of tumour cell growth by marrow and

skeletal tissue_ Consequences of chronic obesity/leptin resistance_ Neuropeptide regulation of central endocrine

function

These studies represent the forefront of ourunderstanding of how tissues communicate and co-ordinate their activities, and offer the potential forentirely new modalities for disease control. Everystudent within our lab has won at least oneinternational young investigator award for oralpresentation of their studies, and gone on tointernational positions. Our lab is integrated withmany others within the Institute, including ongoingclinical studies, and offers a rewarding, productiveand enjoyable experience for those eager to explorethis emerging field.

Project 2: Sclerostin and Dickkopf-1 in regulationof bone massThe WNT pathway is a powerful regulator of bonecell differentiation and formation. Two WNTmodulators, sclerostin ad Dickkopf 1, are underdevelopment as the next generation of therapeuticagents for metabolic bone disease and representthe most exciting development in bone active drugsin decades. Decreases in the activity of Dickkopf 1

(Dkk1) and Sclerostin (Scl) are associated withmarked increases in bone formation. Inactivatingmutations of the sclerostin gene in humans resultsin extreme bone mass gains (+9 SD). In light of thisenormous bone anabolic potential, antibody therapiesare in Phase II trials for osteoporosis and areproducing powerful and unprecedented increases inbone mass. Such agents based on Dkk1 and Scl arealso potential therapies in osteogenesis imperfect,multiple myeloma and orthopaedic applications.

However, critical questions remain unanswered: _ Are these agents safe during growth?_ Is long term therapy effective? _ Do circulating levels predict and /or regulate

bone mass? _ Are Scl and DKK1 responses equivalent?

The answers to these questions representimportant outcomes in terms of: _ Their use in children, particularly as therapy for

osteogenesis imperfects, a crippling bone disease. _ The treatment strategy, cyclical dosing vs long

term therapy. _ The monitoring/interpretation of patient levels

and the basic mode of action of these agents. _ The tuning of particular agents to specific patients.

To answer these questions specific animal models arerequired, enabling conditional deletion of Dkk1 andScl expression. These have been developed at theGarvan and will be ready for experimentation in 2014.This study will employ these unique mouse modelsto clarify these outstanding questions regarding themode of action and application of these pivotalemerging therapies, with a view to maximising theirapplication, while ensuring patient safety.

The project will involve cutting edge in vivo imagingtechnology for tracking the skeletal response totemporal, spatial and lineage-specific Scl and DKK1deletion. This will be combined with next generationtranscriptomics and detailed histological assessmentto detail the structural, cellular and molecularchanges evoked by the loss of Scl/DKK1 expression.This project represents the most detailed andsystematic analysis of these WNT modulatorsconducted in bone to date.

Supervisor: Dr Paul BaldockEmail: [email protected]


Neurodegenerative Disorders Research GroupPhD Studies in Dr Bryce Vissel's group allow you theopportunity to learn and develop cutting edgetechnologies and approaches that will contribute toa deeper understanding and treatment ofParkinson's disease, Alzheimer's disease or spinalcord disorders. The group uses sophisticatedapproaches to understand how synaptic dysfunctionleads to neurodegeneration and to identify potentialapproaches to reverse the disease process. Inaddition to studying mechanisms ofneurodegeneration, the group studies stem cells andthe mechanisms underlying regeneration in thenervous system. The goal of this work is to identifyapproaches that could drive recovery in the brain indiseases such as Parkinson's and Alzheimer'sdisease. All our projects will train you in a widerange of cutting edge approaches, includinganatomy, molecular biology, gene therapy,physiology, animal behaviour, cell culture, high endmicroscopy, surgery and so on. Our group is helpful,friendly and highly motivated. These are kinds ofstudies you could undertake:

Project 1: Neural regeneration research andstudies of stem cells in Parkinson's andAlzheimer's diseaseStudents will have the opportunity to study neuralregeneration in our group. Adult neurogenesis is theprocess by which the brain generates new nervecells in the adult central nervous system (CNS) fromstem cells that naturally exist in the brain.Stimulating neurogenesis may potentially offer atherapeutic approach for neurodegenerativediseases such as Parkinson's disease, Alzheimer'sdisease, and spinal disorders. In our group, we areworking to identify mechanisms that regulate adultneurogenesis (neural repair mechanisms) in thenormal and diseased brain, to determine ifmanipulating these mechanisms may offertherapeutic potential. The students who areinterested in research projects in this area will learnadvanced techniques in the study of neurogenesisand neural stem cells. Techniques learned willinclude: (1)Stereotaxic survival surgery and genetherapy approaches, (2) Immunohistochemistrycombined with advanced confocal microscopy andstereology for analysis of regeneration. (3) Use of invitro cell systems, including neural stem cells, forstudying neurogenesis. (4) Behavioural testing todetermine the capacity for functional recovery inanimal models (5) molecular biology. Research intomechanisms and role of neural regeneration is a

cutting edge area of research worldwide and theresearch has significant potential to lead toimportant discoveries.

Project 2: The role of immune processes inlearning and memory, and in Parkinson's andAlzheimer's diseaseOur lab's studies are identifying a criticallyimportant role for inflammatory processes in brainplasticity and disease. In our group, we areworking to identify mechanisms that regulate theinteraction between inflammatory cells andneurones in specific brain regions, with a view tounderstand how these mechanisms ultimately leadto normal bran function, or abnormal brainfunction in diseases such as Parkinson's andAlzheimer's disease. The students who areinterested in research projects in this area will learnadvanced techniques in the study ofneurodegeneration and neuroinflamation.

Techniques learned will similarly include: _ Stereotaxic survival surgery and gene therapy

approaches,

_ Immunohistochemistry combined with advancedconfocal microscopy and stereology for analysisof regeneration.

_ Use of in vitro cell systems.

_ Sophisticated learning and memory andmovement studies in mice

_ Molecular biology. Research into mechanisms androle of neurodegeneration and neuro-inflamationis another cutting edge area of researchworldwide and the research has significantpotential to lead to important discoveries.

Project 3: Post-transcriptional events thatregulate neural plasticity, memory and diseases We have recently identified RNA editing of specificneuronal RNAs as a novel mechanism that canaffect Parkinson's disease, Alzheimer's disease andbehaviour in mice. This is an exciting and novelproject that offers interesting possibilities forsignificant new insights into brain function. Theexperiments will use similar methods to thosedescribed for the projects above.

Supervisor: Dr Bryce VisselEmail: [email protected]


The Croucher lab's research interests are in themajor diseases of the skeletal system, particularly indiseases such as osteoporosis and tumours thatgrow in bone, including multiple myeloma, or thosethat metastasise to bone, such as breast andprostate cancer. Our research interests are inunderstanding the cellular and molecularmechanisms that lead to these conditions with theaim of developing new approaches for clinicalintervention. In recent years we have developednew screening tools that have allowed us to identifynew genes that control bone strength anddeveloped new approaches to increasing bonemass. We have also developed novel high-resolutionimaging technologies that allow us to visualizeindividual metastasis-initiating cells as they colonisethe skeleton. Building upon these discoveries we arenow utilizing the latest next generation genomictechnology, bioinformatic and systems biologyapproaches, and the latest high-resolution imagingto take these projects forward.

We have a number of projects available in thefollowing areas:

Project 1: New gene targets for anabolic therapyin osteoporosisTreatments for osteoporosis prevents further boneloss but have a limited ability to restore bone massso patients continue to fracture. In collaborationwith Professor Graham William and Dr DuncanBassett at Imperial College London, we havescreened knockout mice from the Wellcome TrustSanger Institute Mouse Genetics Programme andidentified strains with increased bone strengthresulting from deletion of genes not previouslyknown to have a role in the skeleton. This project

will establish the role of these pathways incontrolling bone strength and identify newtherapeutic targets for treating osteoporosis.

Project 2: Targeting 'metastasis initiating cells' inbreast and prostate cancerBone metastases are a devastating clinicalconsequence for patients with breast and prostatecancer. The mechanisms leading to theirdevelopment are poorly defined, and approaches toprevention and treatment limited. We havedeveloped new high-resolution imaging technologythat allows us to visualize the tumour initiating cells,at a single cell resolution, in the skeleton. Projects inthis area will use the latest imaging technology andnext generation genetic and bioinformatic tools toestablish a genetic and molecular fingerprint ofthese tumour-initiating cells and utilise thisknowledge to develop new therapeutic approachesto preventing the development of bone metastasis.

Project 3: Defining the tumour initiating cells inmultiple myeloma Multiple myeloma is a B-cell neoplasm characterisedby the growth of tumour cells in the skeleton andthe development of a devastating bone disease. Wehave developed novel in vivo imaging technology tostudy single myeloma cells and their interactionswith bone in vivo and discovered new moleculesimplicated in myeloma bone disease. We will usethis new technology and next generation geneticand bioinformatic approaches to define a geneticand molecular fingerprint of these cells, establishthe role of osteoblasts in regulating their behaviourand utilise this knowledge to develop newtherapeutic approaches.

Supervisor: Prof Peter Croucher Email: [email protected]

Prof Peter Croucher Division HeadOsteoporosis & Bone Biology

Osteoporosis & BONE BIOLOGY

Research at the Osteoporosis and Bone Biology Division is focused on understanding the causes anddevelopment of new treatments for major diseases of the skeleton, particularly osteoporosis and cancers,such multiple myeloma, and breast and prostate cancers that metastasise to bone. The latest cutting edgetechnology in genomics, proteomics and contemporary imaging approaches are being applied to addresscritical clinical questions in skeletal medicine. Students in the Division have made fundamental discoveriesthat are having a real impact in skeletal medicine. Garvan researchers were the first to show the importanceof genes in regulating the skeleton; have identified critical molecular pathways that regulate bone; andrecently discovered the importance of neurological control of bone. Work undertaken at the Garvan has alsoled to the development of new approaches to predicting who will fracture their bones, an example oflaboratory discoveries being translated directly into the clinic for patient benefit. Research from theOsteoporosis and Bone Biology Division has been published in high ranking journals such as Nature, Nature

Genetics, Blood, JAMA, and N.Engl J. Med. PhD students participate and present their work at majorinternational scientific meetings and attracted numerous awards. Our postgraduate students are highlyregarded, gaining their own fellowships and have established their own independent scientific careers oftenat prestigious Institutes and Universities in the US, UK and Europe.

OSTEOPOROSIS & BONE BIOLOGY 22

Bone & Cancer Pharmacology Group

BackgroundBisphosphonates are a “blockbuster” class of drugsused worldwide for the treatment of common bonediseases such as post-menopausal osteoporosis,cancer-induced bone loss and Paget's disease. Mylab is a world-leader in characterising how thesedrugs work at the cellular and molecular level. Wemade the breakthrough discovery a few years agothat most of these drugs act by inhibiting FPPsynthase, a critical enzyme involved in thebiosynthesis of cholesterol and a variety of lipidintermediates necessary for the lipid modification(prenylation) and hence normal function of essentialsignalling proteins. Several PhD projects will beavailable in my group and in collaboration with otherresearch groups at Garvan. All of the projects willaddress clinically important questions about thepharmacology and biological actions of these drugs,particularly their anti-tumour actions and effects onmyeloid immune cells.

Project 1: Using biosensors to visualise the effectsof bisphosphonate drugs on small GTPase signalling In collaboration with Dr Paul Timpson (CancerDivision) we will use state-of-the-art imagingtechniques to visualise novel biosensors that reflectthe activity of small GTPase signalling proteins. Thisapproach will provide new insights howbisphosphonate drugs, which inhibit the prenylationof small GTPases, affect the subcellular localisationand activity of small GTPases and how this influencesthe function of a variety of cell types, includingbone-resorbing osteoclasts, macrophages and otherimmune cells. The project will provide training invarious techniques including cell culture, transfection,microscopy and transgenic animal models.

Project 2: New insights into the regulation of themevalonate pathway and its inhibition bybisphosphonate drugsIn this project we will use a variety of next-generation sequencing, bioinformatic and proteomicapproaches to examine the importance of isoformsand newly-discovered post-translationalmodifications of FPP synthase, the enzyme targetof bisphosphonate drugs. Differences in theexpression or activity of this enzyme may accountfor differences in drug responsiveness betweenpatients and resistance to bisphosphonate therapy.We will also seek to test, in well-established cell andorgan culture models, a mathematical model of themevalonate pathway that we have developed. Thiscould be used to predict the effect of

bisphosphonates and other drugs on lipidmetabolites and enzyme expression using a rangeof molecular biology techniques including massspectrometry and quantitative PCR.

Project 3: Anti-tumour effects ofbisphosphonates in multiple myelomaBisphosphonate therapy has been shown toprolong the survival of patients with multiplemyeloma and has anti-tumour activity in variousanimal models of cancer, including myeloma, butthe exact mechanism remains unknown. Incollaboration with Prof Peter Croucher, this projectwill seek to identify the mechanism underlying theanti-cancer activity of these drugs in the contextof myeloma, focusing on effects ofbisphosphonates on immune myeloid cells. In vivoand ex vivo 2-photon microscopy and flowcytometry will be used to determine thedistribution and cellular uptake of fluorescently-tagged bisphosphonates in a mouse model ofmyeloma. We will also use a wide variety of cellculture and molecular biology techniques toexamine whether bisphosphonate treatmentaffects the immune-suppressive function ofmyeloid cells in mice and in myeloma patients, andwhether such effects are mediated via inhibition ofprotein prenylation.

Project 4: Physiological regulation of myeloid-derived suppressor cells during cancerdevelopmentMyeloid-derived suppressor cells (MDSCs) are atype of immature cell of the monocyte/granulocytelineage that increase dramatically in number duringthe development of tumours in mice and humansand could be targets of bisphosphonate drugs.These cells promote tumour growth andmetastasis, by producing factors that promoteangiogenesis and by suppressing T cells thatnormally remove tumour cells by immunesurveillance. Little is known about the mechanismsinvolved in the expansion of MDSCs in the bonemarrow, but disabling MDSCs has been shown todecrease tumour growth by enabling normal T cellfunction. In collaboration with Dr Paul Baldock, wewill use a wide variety of animal models toexamine the influence of hormones and otherphysiological factors on MDSCs and theirexpansion and activation in the bonemicroenvironment during tumour developmentand metastasis.

Supervisor: Prof Mike RogersEmail: [email protected]

OSTEOPOROSIS & BONE BIOLOGY 23

Required BackgroundThese positions could be filled by students from arange of backgrounds, including bioinformatics,biochemistry, chemistry, physics, or computerscientists and an interest in using data visualization,human computer interaction, usability, or design toaddress key challenges in basic biomedical research.Of particular interest would be students with strongJavaScript or Java3D skills, as well as a stronginterest in using HTML 5 to build the next-generation of visualization tools for analysing omicsdatasets for systems biology. There is also scope forstudents wishing to focus not on tool development,but on applying visualization techniques to datafrom various disease areas, possibly in collaborationwith other groups at Garvan.

Supervisor: Dr Seán O'DonoghueEmail: [email protected]

In the last decade new technologies like massively parallel sequencing have transformed biology and medicalresearch from the study of individual genes or proteins to system-wide approaches. These technologiesprovide us with unprecedented insights into the biology of disease. However, they also generate enormousamounts of data and the role of Garvan's Informatics group is to make sense of these data. We do this onour locally housed data using high-performance computing methods, but as datasets have grown so largethat we cannot bring them in-house,we also mine them on remote locations. Much of what we do is thewriting of software to analyse the data, but because of its complexity we also use and develop innovativevisualisation methods to gain deeper insights into disease. We work very closely with bench scientists atGarvan who use our analyses to test hypotheses that we develop. Our students are an integral part ofachieving this vision. As bioinformatics is a new field with very few practitioners having been trained asbioinformaticians we look for talented individuals from the worlds of mathematics, physics, chemistry,computer-science and biology to achieve these aims.

PhD Opportunity: Visual Analyticsapplied to Biological Data

General Research Project AreaThe Garvan has recently started a new groupfocused on developing methods and tools forvisualizing biological data. Jointly associated withCSIRO, the group focuses primarily on usingprinciples of usability, data visualization, human-computer interfaces, and graphic design to developstate-of-the-art methods and tools that addresscutting edge challenges in biological and biomedicalresearch. A second focus of the team is on usingthese methods to analyse experimental datasets incollaboration with groups at the Garvan. Projectswill include the VIZBI initiative (http://vizbi.org), theReflect system for enhancing scientific literature(http://reflect.ws), and developing methods forintegrating macromolecular 3D structures withgenomics, proteomics, and other systems biologydata. For further details see http://odonoghuelab.org/

Techniques UsedBioinformatics software development, graphicsdesign, 3D graphics, 3D animation, Human-computer interface development. Applications todata from genomics, proteomics, systems biologyand scientific literature databases.

Bioinformatics

BIOINFORMATICS24

Applications are submitted online at:www.garvan.org.au/education.

All applications are considered by the GarvanHigher Degrees Committee (HDC).

Closing dates for applications are:

_ 31 October for admission in Semester 1 (March commencement)

_ 30 April for admission in Semester 2 (July commencement)

Applications outside these times will only beconsidered in exceptional circumstances.

As Garvan is a not-for-profit organisation, it isunlikely that a research program would have thefunds to take on a postgraduate student withoutscholarship funding of some kind. However,there are many different sources of fundingavailable for postgraduate research students,such as UNSW APA, UIPA, IPRS and NHMRC.

Prospective students must also lodge anapplication for admission to UNSW online at:http://www.grs.unsw.edu.au/futurestudents/apply.html.

As part of this process, you will need to haveagreed a potential research project with yoursupervisor.

How to Apply

HOW TO APPLY25

2013 Garvan PhD_brochure

Health & Medicine

Transcript of 2013 Garvan PhD_brochure