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    Garvan PhD_projects2013 Garvan PhD_projects2013 Document Transcript

    • Postgraduate Studies at the Garvan 01Why Choose the Garvan 01Garvan PhD Open Day 21st of August 2012 01Cancer Research Program 02Colon Cancer Genetics & Biology Group 02Ovarian Cancer Group 03Tyrosine Kinase Signalling Networks in Human Cancers 04Mitotic Control Group 05Pancreatic Carcinogenesis Group 05Epigenetic Laboratory Cancer Program 06Cancer Bioinformatics Group 10Immunology Research Program 11B Cell Biology Laboratory 11Diabetes & Transcription Factors Group 12Diabetes & Obesity Research Program 13Bioenergetics in Disease 13Regulation of Body Composition & Glucose Homeostasis by the Adaptor Protein Grb10 14Beta Cell Replacement Therapy 14Cooper Group - Neurodegeneration, Cell & Molecular Biology, Genetics 15Neuroscience Research Program 16Eating Disorders Group 16Inter-organ Signalling: A new level of regulatory control 19Bird and Swine Flu, Parkinsons Disease, Chronic Pain 21Neurodegenerative Disorders Research 23Hearing Research Unit 24Osteoporosis & Bone Biology Research Program 25Genetics and Epidemiology Group 26Molecular Pharmacology Group 28Garvan Bioinformatics 29How to Apply 30
    • Prof John Mattick In partnership with the University of New South Wales, Garvan Institute provides a learning andExecutive Director teaching environment of excellence for PhD students who are looking forward to being part of the next generation of great medical researchers. As one of the worlds leading medical research institutes with programs in cancer, diabetes and obesity, immunology, neuroscience and osteoporosis, Garvan is playing a leadership role in translating the amazing developments in modern biomedical research into real improvements in health care and quality of life. The joint initiative with St Vincents Hospital in establishing The Kinghorn Cancer Centre will enable Garvans research discoveries to make a real difference in the prevention and treatment of this devastating disorder. This however is only the beginning - the future for Garvan will be to ensure that this paradigm is expanded to all of our research areas. A focus on the promise of genomic medicine and new technologies such as next generation sequencing, and a complementary depth of expertise in cell biology, proteomics, systems biology, bioinformatics, epigenetics and translational research together make Garvan one of the most exciting places 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, postgraduate scholars undertaking their PhD at Garvan are valued as important contributors to the life of the Institute as a whole. We look forward to you joining us. Why Choose the Garvan Garvan PhD Open Day 21st of _ We offer a competitive salary top-up on August 2012 eligible scholarships The PhD Open Day will take place on Tuesday _ The Garvan boasts state-of-the-art research 21st of August from 2.00 pm to 6.00 pm. facilities which incorporate a range of cutting- edge equipment and expertise It will provide the opportunity to meet _ Students at Garvan (SAG), the student prospective supervisors, current PhD students representative group within the Garvan and view our state-of-the art facilities. Please Institute provides both academic support and register your attendance at social activities in our off-campus http://bit.ly/PhDopenday. environment Outside of this period, you may contact specific If you would like to find out more about the researchers directly or visit fantastic opportunities that doing your PhD at www.garvan.org.au/education for further Garvan Institute can provide, please email information. study@garvan.org.au or visit www.garvan.org.au/education POSTGRADUATE STUDIES AT THE GARVAN 01
    • The Cancer Research Program at the Garvan Institute is the largest program at the Garvan and one of the Prof Rob Sutherland Cancer Research Program Leadermost highly regarded cancer research teams in Australia and internationally. With complementary skills incancer genomics, cancer epigenomics, cancer molecular and cellular biology, cancer biomarker andtherapeutic target identification & validation and translational research, the program is focussed onunderstanding the causes of and developing new diagnostic, prognostic treatment and prevention strategiesfor the most commonly diagnosed and most lethal cancers including breast, prostate, pancreatic, colorectal,lung, and ovarian. Program Head Prof Sutherland, AO, FAA is a leader in molecular oncology and thepathophysiology of breast and prostate cancers, with over 350 primary publications in top rankingmultidisciplinary and specialist journals. Among the many successful PhD graduates are Directors of majorresearch institutes and academic departments, professorial heads of independent research groups andclinical units, and recipients of prestigious NHMRC and ARC Fellowships.Colon Cancer Genetics and Biology Group These two major findings have provided manyHow can an arthritis drug cause colon cancer in the different avenues for further research. The projectsmouse? Dissecting the origins of carcinogenesis. can be tailored to suit the expertise and interests of the PhD candidate - ranging from cell cultureProject 1 models to sulindac and the knockout mouse.We have made the unexpected discovery that anarthritis drug sulindac that is also used to prevent Supervisor: A/Prof Maija Kohonen-Corishcolon cancer in people with high-risk genes, can Colon Cancer Genetics and Biology Groupactually cause cancer in the mouse. Sulindac has E: m.corish@garvan.org.auopposite effects in different parts of the mouse T: 02 9295 8336colon - either preventing or causing cancer. We Referenceshave shown that sulindac triggers a molecular 1. Kohonen-Corish MR, Sigglekow ND, et al 2007. Promoterpathway in the mouse that may be informative for methylation of the mutated in colorectal cancer gene is a frequentunderstanding how colon cancer develops in humans. early event in colorectal cancer. Oncogene 26:4435-41. 2. Mladenova D, Daniel J, Dahlstrom J, Bean E, Gupta R, Pickford, R, Currey N, Musgrove EA, Kohonen-Corish M. 2011. The NSAIDProject 2 Sulindac is chemopreventive in the mouse distal colon butWe have discovered the importance of the MCC carcinogenic in the proximal colon. Gut 60:350-360 4. Pangon L, Sigglekow ND, Larance M, Al-Sohaily S, Mladenova D,(Mutated in Colorectal Cancer) gene silencing in Selinger C, Musgrove EA, Kohonen-Corish MRJ. 2010. Mutated inthe development - and potentially treatment - of colorectal cancer (MCC) is a novel target of the UV-induced DNA damage response. Genes & Cancer 1:917-926colon cancer. We have identified new biologicalfunctions for this gene, including a role in the DNAdamage response. We now want to pursue thesefunctions further in a model that is relevant for thedisease in humans, our newly engineered MCCknockout mouse, which allows us to determine thefactors that are important in initiating andpromoting cancer.02 CANCER RESEARCH PROGRAM
    • Ovarian Cancer Group Project 2Ovarian cancer is the most lethal gynaecological Effect of cMET pathway and its inhibitor INC280cancer. Every year in Australia, approximately 1200 in ovarian cancer.women are diagnosed with ovarian cancer and 800women die from the disease. The poor prognosis for cMet, a receptor tyrosine Kinase, and its ligandwomen with ovarian cancer is mainly due to an HGF are both mis-regulated in ovarian cancer, withinability to detect the disease at an early stage, higher expression being linked to poorer prognosis.before the cancer has spread. Indeed, over 75% of Both HGF and cMET have been shown to enhanceovarian cancers are diagnosed at an advanced cell migration, adhesion and proliferation in cancerstage, when the 5-year survival rate is 20%. In cells. Inhibitors of receptor tyrosine kinasesaddition, this poor prognosis is due in part to the (including cMET) have been shown to be effectivedevelopment of chemotherapy resistance in women against ovarian cancer, thereby making itfollowing surgery and several rounds of treatment. imperative to examine new therapeutic agentsThe Ovarian Cancer Research Group at the Garvan such as INC280. We hypothesize that targetingInstitute focuses on 3 main projects: cMET activation is likely a useful therapeutic tool in ovarian cancer. We propose to examine the_ Characterisation of novel therapeutic targets in effect of HGF, cMET and the cMET inhibitor the ovarian tumour microenvironment; INC280 on ovarian cancer growth and metastasis_ Development of a blood-based test for DNA in ovarian cancer cell lines and in vivo models. methylation as an indication of high-grade serous ovarian cancer in high-risk women Supervisor: Dr Goli Samimi_ Evaluation of biomarkers of response to Ovarian Cancer Group chemotherapy in treated women diagnosed with E: g.samimi@garvan.org.au ovarian cancer P: 02 9295 8362 ReferencesAvailable projects include: 1. Samimi, G., B. Z. Ring, et al. (2012). "TLE3 Expression Is Associated with Sensitivity to Taxane Treatment in OvarianProject 1 Carcinoma." Cancer Epidemiol Biomarkers Prev 21(2): 273-279. 2. Montavon, C., B. S. Gloss, et al. (2012). "Prognostic andEvaluation of TLE as a biomarker for response to diagnostic significance of DNA methylation patterns in high gradetaxane-based chemotherapy in ovarian cancer. serous ovarian cancer." Gynecol Oncol 124(3): 582-588. 3. Gloss, B. S. and G. Samimi (2012). "Epigenetic biomarkers in epithelial ovarian cancer." Cancer Lett.The standard ovarian cancer treatment includes 4. Ghosh, S., L. Albitar, et al. (2010). "Up-regulation of stromalsurgery followed by platinum/taxane combination versican expression in advanced stage serous ovarian cancer." Gynecol Oncol 119(1): 114-120.chemotherapy. While a majority of patients initially 5. Mok, S. C., T. Bonome, et al. (2009). "A gene signature predictiverespond to this regimen, 75% of treated women for outcome in advanced ovarian cancer identifies a survivaleventually relapse. Thus it is imperative that we factor: microfibril-associated glycoprotein 2." Cancer Cell 16(6): 521-532.identify biomarkers that can predict women whoare likely to respond to treatment, therebysignificantly improving patient management. Wehave demonstrated that transducin-like enhancer ofsplit 3 (TLE3) expression is associated withprogression-free survival in taxane-treated ovariancancer patients. In our study, TLE3 expression wasassociated with a favourable outcome only inpatients who had received a taxane as part of theirtreatment regimen. These findings warrant anindependent evaluation of TLE3 as a potentialtherapeutic response marker for taxane-basedchemotherapy in ovarian cancer. Studies are alsonecessary to determine whether and by whatmechanisms TLE3 may serve as a functionally-based biomarker in determining response. CANCER RESEARCH PROGRAM 03
    • Tyrosine Kinase Signalling Networks in Examples of PhD projects available within the Signal Transduction Group are:Human CancersTyrosine kinases function in key signalling pathways Project 1regulating fundamental cellular processes such as characterisation of how the cellular kinome isproliferation, survival, metabolism and motility. regulated by the proto-oncogene Src in basalImportantly, aberrant signalling by these proteins breast cancer cells.underpins many human cancers, and tyrosinekinases represent major targets for drug We have recently identified that a particularlydevelopment. Research in my group is aimed at aggressive form of breast cancer, termed basalcharacterising tyrosine Kinase signalling mechanisms breast cancer, exhibits a prominent Src-regulatedand networks in cancer cells, in order to develop signalling network. This project will utilise cutting-new or improved therapies. edge chemical proteomics to characterise the impact of Src activation on the entire kinome inRecent developments in mass spectrometry-based basal breast cancer cells.proteomics, coupled with affinity-based enrichmentstrategies, now allow global characterisation of Project 2particular types of intracellular signalling event, such Identification of sensitizers to Src inhibitors inas tyrosine phosphorylation. In other words, we can basal breast cancer.identify and quantitate all of the signalling eventshappening in a cell at any given point in time. In Despite the presence of a prominent Src signallingaddition, they enable the majority of kinases network in basal breast cancer cells, Src Kinaseexpressed by the cell (the kinome) to be co- inhibitors exert only modest effects on these cells inordinately characterised, in terms of both expression terms of attenuation of proliferation and survival.and activation. Consequently, such approaches This project will undertake a siRNA-based functionalallow us to obtain global snapshots of signalling in screen of the human druggable genome in order toparticular types of cancer cell, and importantly, identify genes whose knockdown sensitizes basalcompare cell types, such as normal and cancer cells, breast cancer cells to Src Kinase inhibitors, therebyor drug-sensitive and -resistant cells. My group has identifying candidate combination therapies for thisestablished these technology platforms and is disease subtype.currently using them to address key questions incancer cell signalling research, such as: Project 3characterisation of the signalling networks that Identification of kinases and signalling proteins thatdistinguish different breast cancer subgroups; mediate prostate cancer metastasis.whether pancreatic cancer can be subclassifiedbased on tyrosine phosphorylation patterns; and It is possible to grow primary human prostatewhether changes in cellular signalling networks can cancers as tumours in mice (xenografts). We haveidentify markers and mediators of therapeutic access to xenografts that differ in their ability toresponsiveness, such as to docetaxel in prostate spread (metastasize). Quantitative MS-basedcancer. In order to functionally interrogate the large proteomics will be used to screen these xenograftsnumbers of kinases and signalling proteins identified in order to identify signalling proteins that mediateby these approaches, we are also implementing cancer metastasis.siRNA screens that characterise the roles ofidentified candidates in regulation of cell Supervisor: Professor Roger Dalyproliferation and migration. Signal Transduction Group E: r.daly@garvan.org.au T: 02 9295 833304 CANCER RESEARCH PROGRAM
    • Mitotic Control Group Pancreatic Carcinogenesis GroupThe Mitotic Control Group sits within the Cell Cycle Pancreatic Cancer is the fourth leading cause ofgroup (Prof. Liz Musgrove) of the Garvans Cancer cancer death in our society. Almost 90% of theResearch Program. It is a new exciting team that is patients succumb within a year of diagnosis,focused on targeting novel mitotic checkpoint unless detection is done at very early stage.pathways to selectively target cancer cells. Recently, Evidence also supports a long period in whichwe demonstrated that correct mitotic progression preneoplastic lesions are present.was dependent on maintaining a tightly regulatedbalance between the activities of the phosphatase The Pancreatic Carcinogenesis team is focused onPP2A, and Kinase CDK1 [1,2]. Further, we identified identifying key drivers and biomarkers ofthe novel mitotic Kinase Greatwall as the master pancreatic cancer through studying the earliestregulator of this balance [3,4]. These results changes in exocrine cell differentiation anddramatically altered our understanding of mitosis proliferation using pancreas specific models (inand opened up several new and exciting research vitro and in vivo).pathways. The primary aim of the lab is to furtherexplore and characterise these pathways, to identify The Pancreatic Carcinogenesis group sits withinnew chemotherapeutic targets and improve the the Pancreas Cancer Group (Prof. A. Biankin)sensitivity and selectivity of existing cancer drugs. which co-leads the Australian Pancreatic Cancer Genome Initiative (APGI), a member of theProject 1 International Cancer Genome ConsortiumMapping the Human Mitotic Exit Pathway. (www.icgc.org). The APGI aims to fullyDuring mitotic exit certain CDK1 substrates need to characterise the genomic, epigenomic andremain phosphorylated while others must be transcriptomic aberrations in tumor samples ofdephosphorylated to ensure the highly ordered pancreatic cancer patients using the latest nextevents of mitotic exit occur in the correct sequence. generation sequencing technologies. As such, theHowever, currently very little is known about how APGI provides a unique resource to investigatethis order of dephosphorylation is achieved in molecular mechanisms involved in pancreaticmammalian cells. This project aims to identify the carcinogenesis, to eventually reveal new targetsorder of substrate dephosphorylation and the for the development of novel detection methods,phosphatase responsible. The project will utilise chemoprevention and chemotherapeutic strategies.quantitative live and fixed microscopy, advancedbiochemistry and Mass Spectrometry techniques. Specific projects available include:The outcomes will dramatically advance our under-standing of this fundamental stage of cell division, and Project 1may identify novel targets for future chemotherapies. Investigating the expression and the role of candidate gene aberrations identified by APGI inProject 2 models of early pancreatic cancer; geneticallyPreventing Mitotic Exit to Kill Cancer. modified mouse models have been introduced and need to be further investigated. In addition,Many classical and new-line chemotherapeutics genetic manipulation is used in vivo and in vitro totarget mitosis as a means of selectively killing define the functional consequences and molecularcancer cells. Unfortunately, many cancer cells are mechanisms of these novel gene aberrations inresistant to these drugs. Furthermore, it is very model systems of early pancreatic cancer.difficult to currently predict which cancers will besensitive or resistant. This project aims to identify a Project 2common signature of proteins that promote and Investigating ENU-induced mutagenesis mouseinhibit mitosis and determine if these can be used to models, including forward screens to identify newpredict response, and if subsequent targeting of genes that can impact on exocrine pancreas cellthese proteins improves current chemotherapies. differentiation and proliferation and reverseThis project will utilise multiple cancer cell line screens where the effects of a known mutation inmodels, immunohistochemistry, and advanced live- a gene of our interest (as identified by APGI) arecell imaging. The outcomes will hopefully provide a further investigated for a contribution tocritical predictive tool and help further our pancreatic carcinogenesis.understanding of why cancer cells are sensitive orresistant to mitotic poisons. Supervisor: Dr. Ilse RoomanReferences Pancreatic Carcinogenesis Group1. Burgess A et al. (2010), Proc Natl Acad Sci USA 107: 12564-12569. E: i.rooman@garvan.org.au2. Lorca T, et al. (2010) J Cell Sci 123: 2281-2291.3. Gharbi-Ayachi A,et al. (2010) Science 330: 1673-1677. T: 02 9295 83724. Vigneron S, et al. (2009) EMBO J 28: 2786-2793.Supervisor: Dr Andrew BurgessMitotic Control GroupE: a.burgess@garvan.org.auT: 02 9295 8327 CANCER RESEARCH PROGRAM 05
    • Epigenetic Laboratory Cancer Program Overall Aim To integrate chromatin modification marks, DNAProject 1 methylation and RNA expression across the genomeModelling epigenomic change during early breast in order to investigate the relationship betweencarcinogenesis using in vitro and in vivo model changes in the epigenomic landscape and thesystems. biology of early breast cancer.Epigenetic deregulation is an early and crucial event Aim 1: Epigenome Profilingin carcinogenesis so at diagnosis, tumours already To utilise our in vitro and in vivo HMEC modelcontain many genetic and epigenetic aberrations. systems of early breast cancer to further developTherefore, identifying the early epigenetic changes and generate epigenome maps of early breast cancer.in cancer is challenging, as it is difficult to separatethe drivers of carcinogenesis from epigenetic lesions Aim 2: Integrationthat are secondary passengers of carcinogenesis. To To integrate epigenomic and transcriptional maps ofidentify early epigenetic lesions in malignancy, our pre- and post-selection cells in the in vitro and inlaboratory is exploiting a Human Mammary vivo HMEC systems to identify epigeneticEpithelial Cell (HMEC) culture system as an in vitro modifications and biological (regulatory) pathwaysmodel of early breast carcinogenesis. In culture, which underpin the sequential transition from pre-HMECs undergo an initial phase of normal growth and post-selection state in vitro to DCIS-like in vivo.before entering a growth plateau. However, unlikeother normal cells, HMECs are able to overcome Aim 3: Predictionthis replicative barrier and enter into a second To utilise our newly acquired understanding ofexponential growth phase. Cells from this second epigenetic remodelling in the HMEC system and itsphase exhibit a much more aggressive phenotype role in driving early tumourigenesis from Aims 1 andand these post-selection cells are considered to 2 for prediction of early methylation changes asshare features with pre-malignant basal breast biomarkers of breast cancer.cancer cells. Recently, we have extend this in vitromodel to an in vivo mouse model system that can PhD Projectgenerate abnormal breast lesions that mimic human We seek a motivated PhD candidate to be activelyductal carcinoma in situ (DCIS). In this PhD project, involved in generation and analysis of epigeneticwe intend to utilise the in vitro and in vivo HMEC maps. The project can be tailored to the interestssystems to deliver a detailed and integrated and/or strengths of the candidate. For moreepigenomic map of very early breast cancer. We Bioinformatically oriented candidates there is anwill use these maps to identify potential early excellent opportunity to be involved in developingbiomarkers for breast cancer detection, and to of new techniques for processing and integration ofderive new understanding of the biology and next generation sequencing data.sequential epigenetic events that occur in early Referencesbreast carcinogenesis. 1. Hinshelwood, R.et al Clark, S. J., Cancer Res 2007, 67, (24), 11517-27.Hypothesis 2. Hinshelwood, R. et al Clark, S. J., Hum Mol Genet 2009, 18, (16), 3098-109.Epigenetic dysregulation is an early and crucialevent in breast carcinogenesis and epigenetic Supervisor: Prof Susan Clarkaberrations occurring early during pre-malignancy Co Supervisor: Dr Elena Zotenkoshape the fate of the cancer epigenome and E: s.clark@garvan.org.ausubsequent cancer phenotype. T: 02 9295 831506 CANCER RESEARCH PROGRAM
    • Project 2Epigenetic mechanism: how does aberrantacetylation of the histone variant H2A.Z drivegene activation in cancer?Epigenetic gene regulation is important in normalcell growth and differentiation and is commonlyderegulated in many diseases, including cancer.Epigenetic processes include DNA methylation,post-translational histone modification, exchange ofhistone variants and alterations in nucleosomepositioning. Our laboratory is interested in the roleof histone variants in deregulation of gene Aim 2: Identify the molecular machinery involvedtranscription in cancer cells, as the mechanisms in acetylation of H2A.Z.associated with exchange and post-translationalmodification of histone variants are still unclear. We will perform mass spectrometry assays toH2A.Z is an evolutionarily conserved H2A histone identify the complexes bound to acH2A.Z beforevariant. We recently reported for the first time that and after androgen treatment. This approach willthe acetylation of H2A.Z (acH2A.Z) is associated allow us to identify the factors involved in H2A.Zwith gene deregulation in prostate cancer; activated acetylation. We will then perform knock downoncogenes gain acH2A.Z and down-regulated experiments to down-regulate these factors andtumour suppressor genes lose acH2A.Z at the assay the changes in gene expression and H2A.Ztranscription start site (TSS). This exciting discovery acetylation. These studies will identify theprovides an entirely new dimension to the “histone complexes responsible for promoting acetylationcode”. We hypothesize that acetylation of H2A.Z is of H2A.Z.an important chromatin modification that drivesactive transcription in normal cells but aberrant Aim 3: Determine if acetylation of H2A.Z altersH2A.Z acetylation leads to transcriptional nucleosome occupancy.deregulation in cancer. There are however manyunresolved and key questions concerning the Changes in genome-wide nucleosome occupancymechanism of how H2A.Z acetylation promotes by acH2A.Z will be analysed by an innovativegene activation. The PhD project will address the approach where we will combine two state of thefollowing questions, (1) Is H2A.Z acetylation a art techniques: gNOMe-seq assay2 [AI: Profcause or consequence of gene activation? 2) What Jones] and ChIP-seq. This technique will allow usis the mammalian enzyme(s) responsible for H2A.Z to directly interrogate the nucleosomes containingacetylation? 3) Does H2A.Z acetylation alter acH2A.Z to detect changes in nucleosomenucleosome positioning? localisation upon androgen treatment. This approach will address how acH2A.Z affects the chromatinOverall Aim structure by altering promoter nucleosomeTo understand how acetylation of H2A.Z regulates positioning to activate gene transcription.gene activation in cancer. Significance and outcome: The project will addressAim 1: Determine how acetylation of H2A.Z for the first time the mechanism that promoteschanges gene transcription. acetylation of H2A.Z and its role in gene activation. The outcome will directly determine ifTo identify if acetylation of H2A.Z directly promotes H2A.Z acetylation is a key epigenetic regulator ofor is a consequence of gene activation using LNCaP gene transcription in cancer, and will identify theprostate cancer cells treated with androgens as a molecular targets that control acH2A.Z activity.model system of cancer gene activation. UsingChIP-seq we will study the genome-wide Supervisor: Prof Susan Clarkalterations in H2A.Z/acH2A.Z occupancy and gene Co Supervisor: Dr Fatima Valdes-Moraexpression upon androgen treatment. We will E: s.clark@garvan.org.auaddress whether transcriptional changes occur after T: 02 9295 8315over- or under-expressing H2A.Z and/or acH2A.Zto determine the temporal and sequential molecular Referencesevents that drive gene transcriptional activation. Valdes-Mora, F., et al Clark, S.J. Genome Res. 22, 307-321 (2012).This aim will address the still unresolvedmechanistic role of acH2A.Z in promotingregulation of gene expression. CANCER RESEARCH PROGRAM 07
    • Project 3 Aim 2: To map epigenetic modifier-mediatedEstablishing the importance of enhancer epigenetic enhancer/promoter interactions.reprogramming and atypical long-rangeinteractions in cancer cells. The structure of the genome is three-dimensional and complex interactions ensure that the correctCancer is extraordinarily complex and the result of gene expression patterns are established andwidespread genetic and epigenetic reprogramming. maintained. Using an innovative technologyThe phenomenon of epigenetic reprogramming (Chromatin Interactions by Paired End Tag(atypical silencing and activation achieved through Sequencing; ChIA-PET) we will delineate howaltered patterns of DNA methylation, histone enhancers and promoters interact throughcomposition, histone modifications and nucleosome epigenetic modifiers, RAD21 (cohesin, facilitatespositions) at gene promoters is a hallmark of cancer looping) and CTCF (blocks interactions), in normalcells, as we previously described. However, our and cancer cells. We will produce long-rangeexisting knowledge is compartmentalised and does interaction maps for normal and prostate cancernot yet adequately extend beyond promoters cells and address how DNA looping networks maydespite increasing evidence that suggests that the be disrupted.transcriptional profile of a cell is equally determinedby the activity of distal regulatory elements (eg. Aim 3: To define functional roles of epigeneticenhancers and insulators). Exciting data from our modifiers in enhancer/promoter interactions.most recent work has challenged the views of thefield; that is, enhancers with an unexpectedly We propose that in cancer cells, atypical“active” epigenetic signature can regulate enhancer/promoter interactions are directed bytranscriptionally repressed promoters. We found aberrant DNA methylation or binding of key DNAthat the purpose of such enhancers was to ensure modifying proteins. RAD21, CTCF and DNAthe correct tissue-specific gene expression methyltransferases are all disrupted in cancer.patterns, whilst retaining epigenetic flexibility that Therefore, we will manipulate their expression inallows normal cells to be amenable to cancer cells to investigate mechanisms of long-reprogramming. Moreover, we show that cells are range interactions (ChIA-PET) and the structuralrendered resistant to reprogramming when organisation of chromatin (gNOMe-seq). Atenhancers are epigenetically silenced. completion, we will understand how RAD21, CTCF and DNMTs contribute to atypical long-rangeIn this new PhD study, we emphasise the necessary interactions characteristic of cancer cells.and dynamic functions of enhancers; raising thepossibility that epigenetic reprogramming of distal Supervisor: Prof Susan Clarkregulatory elements could contribute to cancer Co Supervisor: Dr Phillippa Taberlayestablishment and progression. We hypothesize that E: s.clark@garvan.org.auepigenetic reprogramming alters the three- T: 02 9295 8315dimensional structure of the chromatin:DNAcomplex. Imminent interest in distal regulatory References 1. Coolen, M.W. et al Clark SJ. Nature cell biology 12, 235-46elements and their interactions ensures that the (2010).timing of this project is highly significant. 2. Taberlay, P.C. et al. Cell 147, 1283-94 (2011).Aim 1: To evaluate the scope of enhancerepigenetic reprogramming in cancer cells.We will investigate the extent to which enhancerepigenetic reprogramming occurs genome-wide inprostate cancer compared to normal prostateepithelial cells. At completion, we will understandhow epigenetic reprogramming pertains to distalregulatory elements in cancer.08 CANCER RESEARCH PROGRAM
    • Project 4 Overall AimRole of epigenetic modifiers MBD2 and TET proteins To understand the role of MBD2 and TET2&3in DNA methylation & demethylation in cancer. CpG binding proteins in promoting 1) DNA methylation and transcriptional repression, or 2)Cancer development is characterised by frequent DNA demethylation and gene activation in cancer.hypermethylation of CpG island gene promoters(including tumour suppressor genes), in parallel with Aim 1: To investigate the role and scope of MBD2hypomethylation of gene promoters (including in promoting DNA methylation and/or its loss inoncogenes) and repeat DNA sequences. While the promoting demethylation and transcriptionalvast majority of CpG islands remain unmethylated in deregulation in cancer.normal cells, some CpG islands and other promoters(especially tissue-specific ones) are maintained in a Aim 2: To investigate the role and scope ofmethylated state. Critical, yet unanswered questions TET2&3 in promoting 5hmC and potential DNAin cancer biology remain regarding the balance of demethylation and its aberrant function inhyper- and hypo-methylation in normal and cancer transcriptional deregulation in cancer.cells and the potential role that CpG bindingproteins play in controlling the DNA methylation Aim 3: To identify potential binding partners oflandscape. We previously developed an in vitro MBD2 and TET2&3 and the associated complexesprostate cancer cell model system, where we which determine differential specificity.showed that the methyl binding domain proteinMBD2 plays a critical role in aberrant de novo DNA Outcome and significancemethylation and that gene silencing precedes The findings from this project will have a majorepigenetic remodelling. We now have significant impact on understanding the key steps involved innew data showing that loss of MBD2 promotes both de novo DNA methylation and demethylationDNA demethylation. The mechanisms leading to in cancer and will demonstrate sets of genes thatDNA demethylation are still hotly debated, but are coordinately deregulated in cancer. These newrecently a new family of TET proteins that understandings may provide routes to use MBD2enzymatically convert 5-methylcytosines (5mC) to and/or TET proteins as pharmalogical targets in5-hydroxymethylcytosines (5hmC) has been cancer treatment.characterised. Hydroxy-methylation of cytosineresidues may be a critical facilitator of DNA Supervisor: Prof Susan Clarkdemethylation, and regulation of DNA methylation Co Supervisor: Dr Clare Stirzakerfidelity. Of particular interest, is that both MBD2 E: s.clark@garvan.org.auand TET proteins share similar DNA binding domains T: 02 9295 8315and preferentially bind CpG sites in CpG islands. References 1. Song, J. Z.; Stirzaker, C.; et al Clark, S. J., Oncogene 2002, 21, (7),Hypothesis 1048-61In a normal cell there is a dynamic balance between 2. Stirzaker, C et al Clark, S. J., Cancer Res 2004, 64, (11), 3871-7MBD2-mediated de novo methylation and TET-mediated demethylation at CpG islands to ensurethat the methylation state of CpG islands arefaithfully maintained. We propose that in cancer, thisbalance is disrupted, due to the potential differentialbinding of these factors or factor-associatedcomplexes, promoting alterations in DNAmethylation, epigenetic instability and changes ingene expression. CANCER RESEARCH PROGRAM 09
    • Cancer Bioinformatics Group Project 1 Integrate multiple dimensional -omics data generated by cancer genome sequencing projects. The advances in sequencing technology have now made it feasible to perform massive scale exhaustive, high throughput sequencing of nucleic acid. Several coordinated national and international efforts including The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC), have been initiated to generateProject 5 comprehensive catalogues of genomic,Integrated methods for the analysis of genomic transcriptomic and epigenomic changes in multipleand epigenomic data. different tumour types. In collaboration with Pancreatic Cancer group (Prof. Andrew Biankin) andEpigenetics Signal Transduction group (Prof. Roger Daly) withinGenetics is the study of the DNA sequence and how Garvan, and Prof. Sean Grimmonds group atit effects gene expression and function. Epigenetics University of Queenslands Institute for Molecularis the study of how gene expression is controlled Bioscience, we have the chance to integrate theindependently of the DNA sequence through pre-processed data at multiple molecular level forchemical modifications such as DNA methylation, ~400 individual pancreatic cancers (ongoing)chromatin modifications and expression of ncRNAs. including somatic mutations, copy numberThis area of biological research is rapidly growing. abberations, methylation sites, mRNA expression,Extremely large quantities of data are being protein expression and phosphorylation. Although agenerated daily, presenting new computing and preliminary version of an in-house integratinganalysis challenges that require strong analytical platform (InterOmics) has been developed toskills. Additionally, over the course of the last few automate the analysis and facilitate hypothesesyears it has become increasingly apparent that no generation, we need to improve the platform bysingle (epi)genomic experiment will provide answers including multiple significant important newto all biological and clinical questions. One of the functions on data annotation, data query, datamajor challenges facing biologists and computational mining and user interface. This platform will be alsoscientists is to integrate the knowledge from useful to quickly integrate and analyze the publiclyvarious genomic and epigenomic experimental available data from other ICGC and TCGA projects.approaches in order to gain insight into the biologicalmechanisms that underlie complex diseases. Project 2 Protein-protein interaction network analysis.(Epi)Genomic Data IntegrationOur research concerns the development and use of We have previously developed a Protein Interactionnovel statistical and bioinformatics methods in order Network Analysis (PINA) platform, which is ato gain a better understanding of the factors comprehensive web resource, including a databaseinvolved in disease. Projects would involve of unified protein-protein interaction data integrateddeveloping new methods for the initial processing from six manually curated public databases, and aand analysis of epigenomic data: (i) miR and other set of built-in tools for network construction,ncRNA levels, (ii) ChIP-seq data for histone marks, filtering, analysis and visualisation. Recently we(iii) RNA-seq and (iv) methylation levels. Further, we improved the PINA with its utility for studies ofare interested in investigating new statistical and protein interactions at a network level, by includingbioinformatics approaches to analyse the data multiple collections of interaction modules identifiedgenerated at each stage of a genomic or epigenomic by different clustering approaches from the wholeexperiment and the integration of several layers of network of protein interactions (interactome) forregulatory data with clinical information. six model organisms. There are still many interesting problems left including: 1) Utilising protein-proteinSupervisor: Dr Nicola Armstrong interaction network and pathway model to help theE: n.armstrong@garvan.org.au integration analysis mentioned in the project 1; 2)T: 02 9295 8319 Assessing the confidence of protein-protein interactions saved in the PINA database; 3) Include built-in network alignment tools. Selected recent publications 1. Cowley, M.J., Pinese, M., Kassahn, K.S., Waddell, N., Pearson, J.V., Grimmond, S.M., Biankin, A.V., Hautaniemi, S. and Wu, J. (2012) PINA v2.0: mining interactome modules. Nucleic Acids Res, 40, D862-865. 2. Wu, J.*, Vallenius, T., Ovaska, K., Westermarck, J., Makela, T.P. and Hautaniemi, S. (2009) Integrated network analysis platform for protein-protein interactions, Nature Methods, 6, 75-77. Supervisor: Dr Jianmin Wu Cancer Bioinformatics Group E: j.wu@garvan.org.au T: 02 9295 832610 CANCER RESEARCH PROGRAM
    • A/Prof Robert Brink The work of the research team at the Garvan Immunology Program is divided between studying how aImmunology Research ProgramLeader immune system functions in a balanced way during health and how this can goes wrong in diseases such as type I diabetes, asthma and immunodeficiency. Program Head Assoc. Prof Robert Brink and the Group 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 Immunology Program have published at least one highly 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 as well as the Garvan thesis prize. Since completing their PhDs, many Garvan Immunology Program alumni have successfully obtained NHMRC Fellowhips for further postdoc study both in Australia and overseas at such prestigious institutes as Harvard Medical School, Genentech, Max-Planck Institute in Berlin, Stanford University, Rockefeller University (New York) and Yale University. B Cell Biology Laboratory Project 2 Of all the cells in the body, B lymphocytes (B cells) The generation of long-term immunity from the undergo the most dramatic alterations to their germinal centre reaction. genetic material as they develop and participate in immune responses. The combined effects of two Project 3 independent sets of DNA rearrangements and Controlling the onset of autoimmune disease in somatic hypermutation of B cell immunoglobulin the germinal centre reaction. genes creates the diversity and specificity of antibodies required to eliminate infectious Project 4 pathogens such as viruses and bacteria from the The generation, localisation and survival of body. At the same time, B cells must be prevented normal and malignant plasma cells. from producing antibodies against the body itself (self-tolerance). Supervisor: A/Prof Robert Brink B Cell Biology laboratory In the B Cell Biology laboratory, we employ E: r.brink@garvan.org.au sophisticated in vivo experimental models in T: 02 9295 8454 combination with state-of-the-art molecular and cellular analytical approaches to investigate how B Dynamic in vivo two-photon imaging of cells produce antibodies against foreign threats but mucosal immune responses to commensal and normally avoid producing pathogenic autoantibodies. pathogenic bacteria. As well as defining the mechanisms by which B cells protect us from infectious diseases, we place a The gastrointestinal mucosa is constantly exposed particular focus on the role of B cells in initiating to commensal and pathogenic bacteria. The diseases such allergy (eg asthma), auto-immune immune response to these bacteria are critical to diseases (eg lupus, arthritis) and lymphoma. Our their containment in the gut and the prevention of laboratory publishes regularly in leading international systemic disease. One aspect of this protection is journals (Immunity, J. Exp. Med., Nature provided by IgA antibodies which are made by Immunology) and collaborates with a number of plasma cells and translocated across the epithelial high profile Australian and international laboratories. cell layer into the lumen of the gut. This project will examine the dynamics of the mucosal IgA A number of projects are available for high quality antibody response by transgenic B cells expressing PhD candidates in 2013: a knock-in BCR directed against a model antigen. It will involve the use of intravital two-photon Project 1 microscopy and optical highlighting supported by Dynamic in vivo two-photon imaging of multiparameter fluorescence activated cell sorting mucosal immune responses to commensal and (FACS) and genetic analysis to probe the pathogenic bacteria. spatiotemporal regulation of this response. Supervisor: Dr Tri Phan and A/Prof Robert Brink E: t.phan@garvan.org.au T: 02 9295 8414 IMMUNOLOGY RESEARCH PROGRAM 11
    • Diabetes & Transcription Factors Group Project 1 A novel therapy for liver disease? Liver disease is the 5th most common cause of death in Australia and the UK. In the UK, death from cirrhosis has increased by >65% for men and >35% for women over the last 50 years, highlighting the lack of effective therapies. Acute liver failure (ALF) is a devastating condition with high mortality rates. It often occurs in young, previously healthy individuals, including children. ALF has a mortalityThe role of subcapsular sinus (SCS) macrophages rate of ~33-50% with intensive support includingin LN melanoma metastases. liver transplantation. The commonest cause in Australia is paracetamol overdose. Other causesThe primary function of the lymph node (LN) is to include alcohol, drug reactions, surgery and sepsis.filter the lymph to trap and degrade any pathogensand cancer cells that may have infiltrated the host With the exception of N-acetyl cysteine, there areorganism. Afferent lymph enters the SCS which no proven therapies. Many treatments includingforms an anatomical and functional barrier to the corticosteroids, heparin, insulin, glucagon, blood orfree diffusion of lymph borne particles. This barrier plasma exchange and prostaglandins have beenis formed by lymphatic endothelial cells and tissue- trialled without success. A therapy that diminishesresident macrophages that express the sialic acid- hepatocyte death or enhances replacement throughbinding C-type lectin CD169 (sialoadhesin). Lymph regeneration is highly desirable. This project willthen reaches the medullary sinuses which is also work on a novel therapeutic target which ourlined by lymphatic endothelial cells and CD169+ preliminary data demonstrates is important formacrophages where the bulk of lymph-borne hepatocyte survival, and liver outcomes.soluble and particulate antigen is trapped and Project 2catabolised. Cancer cells must therefore cross this Calcium flux and beta-cell function in diabetes.lymph-tissue interface in order to invade theunderlying parenchyma. While interest has focussed Diabetes is increasingly common in Australia andon the molecular steps involved in oncogenesis and worldwide, and it is associated with increased riskstissue invasion, there has been surprisingly little of heart disease, stroke, blindness, end stage kidneyresearch on the steps involved in the establishment failure and amputations. Increased blood sugarof metastatic cancer cells once they reach the LN. levels arise when the pancreatic beta-cells are noThe project will therefore use genetic and longer able to compensate for the prevailing degreepharmacological approaches to determine the role of insulin resistance by increasing insulin secretion.of CD169+ SCS macrophages in LN metastases in Our lab works with a variety of factors whichan in vivo mouse model. These studies will involve influence beta-cell function, using a variety ofintravital two-photon microscopy and direct mouse models, and human pancreatic islets. Thisintralymphatic injection of cancer cells to monitor project will examine the role of a specific factor intheir interactions with CD169+ SCS macrophages beta-cell function and diabetes.in real-time. They will provide a molecular basis for Project 3understanding the earliest steps in LN metastases Brown fat and obesity therapy.and drive the development of novel therapeuticstrategies to prevent LN metastases not only in Over half of the Australian population is nowmelanoma but other cancers. overweight or obese. Current treatments for obesity are minimally effective, work onlySupervisor: Dr Tri Phan temporarily or have serious side effects. Brown fatE: t.phan@garvan.org.au is an important type of fat which consumes caloriesT: 02 9295 8414 to produce heat, and is associated with decreased weight in people and in animals. We have identified a drug which increases brown fat, and prevents obesity in mice. This project will examine the mechanisms behind this exciting effect. Experience with any or all of tissue immunohistochemistry, animal models, liver diseases or diabetes will be an advantage. The successful applicant must be willing to work with animals and be able to work well within a fun, collaborative lab team. Supervisor: A/Prof Jenny Gunton Diabetes and Transcription Factors Group E: j.gunton@garvan.org.au T: 02 9295 843312 IMMUNOLOGY RESEARCH PROGRAM
    • Prof David James Obesity is a major risk factor for many other diseases including diabetes, cardiovascular disease, ParkinsonsDiabetes and Obesity ResearchProgram Leader disease and cancer. This indicates that these diseases are mechanistically linked. Our program takes a very broad approach involving basic and clinical research to tackle the complexity of metabolic disease. This by definition requires interdisciplinary research so that we can integrate various layers of information that depict the behaviour of mammals as they respond to changes in their environment. We have expertise in islet, fat cell, liver and muscle biology. We use a combination of molecular, cellular, biochemical and physiological approaches to dissect the metabolic wiring in these different organs with the ultimate goal of pinpointing 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 postdoctoral fellowships in some of the best labs throughout the world. Many have gone on to successfully establish their own labs around the world. Bioenergetics in Disease Project 3 The broad aim of our projects is to understand the Energy metabolism in cancer. factors that regulate cellular energy balance under normal conditions and in disease states. Excess body It has been known for some time that cancer cells fat (obesity) is associated the development of a reprogram their metabolism to use fuel (fat, number of major diseases (e.g. type 2 diabetes and protein and glucose) in a different way to normal heart disease) and we are investigating how cells. This adaptation is thought to allow cancer different tissues and genes contribute to the way cells to make the molecular building blocks the body balances food intake and energy (proteins, DNA, lipids) they need to grow and expenditure to maintain a healthy body weight. We divide rapidly. It is also thought to allow cancer are also exploring what goes wrong with cellular cells to avoid the normal surveillance mechanisms energy metabolism in cancer. that would get rid of malfunctioning cells. In this project we are using animal and cell models to Project 1 investigate how cellular energy metabolism is Post-translational regulation of mitochondrial impacted by certain oncogenes and tumour function. suppressors and by variations in specific growth Mitochondria are the major site for fuel oxidation in factor signalling pathways. cells and strategies that stimulate mitochondria to Recent publications burn more calories may prove beneficial for 1. Wright LE, Brandon AE, Hoy AJ, Forsberg G-B, Lelliott CJ, Reznick preventing obesity and insulin resistance. Recently it J, Löfgren L, Oscarsson J, Strömstedt M, Cooney GJ & Turner N. (2011). Amelioration of lipid-induced insulin resistance in rat has emerged that post-translational modification of skeletal muscle by overexpression of Pgc-1_ involves reductions proteins in mitochondria can have major effects on in long-chain acyl-CoA levels and oxidative stress. Diabetologia the rate of mitochondrial fuel oxidation. This project 54:1417-1426. 2. Hoehn KL, Turner N (co-first author), Swarbrick MM, Wilks D, will use both genetic and pharmacological Preston E, Phua Y, Joshi H, Furler SM, Larance M, Hegarty BD, approaches to alter post-translational modifications Leslie SJ, Pickford R, Hoy AJ, Kraegen EW, James DE & Cooney GJ. (e.g. acetylation) in mitochondria and examine the (2010). Acute or chronic upregulation of mitochondrial fatty acid oxidation has no net effect on whole body energy expenditure or effect on lipid accumulation and insulin action. adiposity. Cell Metab 11: 70-76. 3. Turner N, Hariharan K, TidAng J, Frangioudakis G, Beale SM, Wright Project 2 LE, Zeng XY, Leslie SJ, Li J, Kraegen EW, Cooney GJ & Ye J. Dietary fatty acids and energy balance. (2009). Enhancement of muscle mitochondrial oxidative capacity and alterations in insulin action are lipid species-dependent: Potent tissue-specific effects of medium chain fatty acids. There is a clear relationship between excess intake Diabetes 58:2547-2554. of dietary fat (particularly animal-based fats such as 4. Turner N & Heilbronn LK. (2008). Is mitochondrial dysfunction a cause of insulin resistance? Trends Endocrinol Metab 19: 324-330. lard) and the development of obesity and insulin 5. Turner N, Bruce CR, Beale SM, Hoehn KL, So T, Rolph MS, Cooney resistance. However there are also several classes of GJ. Excess lipid availability increases mitochondrial fatty acid dietary fatty acids that appear to have beneficial oxidative capacity in muscle: evidence against a role for reduced fatty acid oxidation in lipid-induced insulin resistance in rodents. health effects, including medium chain fatty acids Diabetes. 2007 56(8):2085-92. and omega-3 fatty acids (which are rich in fish oil). This project investigates the molecular pathways that Supervisor: Dr Nigel Turner and A/Prof Greg Cooney these dietary fatty acids switch on to prevent the E: n.turner@garvan.org.au development of obesity and insulin resistance. T: 02 9295 8224 DIABETES & OBESITY PROGRAM 13
    • Regulation of Body Composition &Glucose Homeostasis by the AdaptorProtein Grb10An important risk factor for Type 2 diabetes is thedevelopment of insulin resistance. Many factorscontribute to insulin resistance including thedecrease in muscle mass associated with reducedphysical activity and ageing. Consequently,understanding how the signalling pathways involvedin insulin action and maintenance of muscle massare regulated is of major significance. We are focusingon two adapter-type signalling proteins, Grb10 andGrb14, which bind directly to the insulin receptor. Beta Cell Replacement Therapy The common forms of diabetes are characterised byWe have recently demonstrated that Grb10 gene the destruction (type 1) or an insufficiency (typeknock-out mice exhibit increased insulin signalling in 2) of insulin secreting pancreatic beta cells. We areskeletal muscle and adipose tissue. Furthermore, taking an interdisciplinary approach to devise novelGrb10-/- mice also display increased skeletal muscle strategies for beta cell replacement therapy. Ourmass and reduced adipose tissue content. primary experimental system is the zebrafish embryo, a model that is at the intersection ofSince these mice have global Grb10 ablation (ie genetic and pharmacological research.Grb10 is absent from all tissues) it is unclearwhether Grb10 has roles in both muscle and Project 1adipose tissue, or whether the effect in one tissue is Cellular reprogramming of acinar cells.an indirect consequence of its role in the other. In We are applying insights from developmentaladdition, if Grb10 is to be targeted therapeutically, biology to use the abundant pancreatic acinar cellit is important to determine whether the beneficial type as a source of progenitors for beta celleffects of ablating Grb10 require the absence of regeneration. We have established an in vivo modelGrb10 during development, or whether they can be to induce acinar cell reprogramming and track theachieved via more acute ablation of this adaptor in fate of the cells as they transition to insulinadult mice. producing beta cells. This project will focus on increasing the efficiency and specificity of cellularTo address these issues we will utilise a conditional reprogramming. We are particularly interested inGrb10 allele (Grb10fl/fl) to determine how Grb10 developing a protocol that is responsive to theablation in a tissue-specific and developmental metabolic dysfunction associated with diabetes.stage-specific manner affects phenotype.Grb10fl/fl mice will be crossed with mice Project 2expressing Cre recombinase, or tamoxifen-regulated In vivo drug screening.Cre, in muscle or adipose. This will enable us toknock-out Grb10 expression in muscle and adipose Traditional drug screens have targeted singlethroughout development and adulthood, or molecules or cell types. While the targets are oftenalternatively from a particular developmental stage well justified, it is difficult to predict how the hits(by timed addition of tamoxifen, which induces the will behave in vivo, which has contributed to thegene deletion). The resulting strains will be poor success rate for new drugs in recent years. Wecharacterised for their muscle, fat and metabolic have developed a number of transgenic models thatphenotypes, as well as for effects on signalling by allow us to monitor metabolic parameters in intactinsulin and other hormones/growth factors. This will embryos (glycemia, beta cell mass, etc.) to helpdetermine whether the effects on body identify the next generation of antidiabetic drugs.composition in Grb10-/- mice reflect autonomous Projects in this area would include assayroles for Grb10 in muscle and/or adipose, and development and screening as well as mechanisticwhether an increase in relative lean mass and analysis of hits that we have previously discovered.improvement in glucose homeostasis can be Selected Publicationsachieved by Grb10 ablation during adulthood. 1. Hesselson D, Anderson RM, Stainier DYR. (2011) Suppression of Ptf1a induces acinar-to-endocrine conversion. Current Biology 21, 712-717.Supervisor: Prof Roger Daly (Cancer Research 2. Anderson RM, Bosch JA, Goll MG, Hesselson D, Dong PDS, Shin D,Program) and A/Prof Greg Cooney (Diabetes and Chi NC, Shin CH, Schlegel A, Halpern M, Stainier DYR. (2009) LossObesity Research Program) of Dnmt1 catalytic activity reveals multiple roles for DNA methylation during pancreas development and regeneration.E: g.cooney@garvan.org.au Developmental Biology 334(1), 213-223.T: 02 9295 8209 3. Hesselson D, Anderson RM, Beinat M, Stainier DYR. (2009) Distinct populations of quiescent and proliferative pancreatic _-cells identified by HOTcre mediated labeling. PNAS 106(35), 14896-14901. Supervisor: Dr Daniel Hesselson E: d.hesselson@garvan.org.au T: 02 9295 825814 DIABETES & OBESITY PROGRAM
    • Cooper Group - Neurodegeneration, Preventing Parkinsons disease inter-neuronal progression/spread. Synuclein is a centralCell & Molecular Biology, Genetics component in PD. In its toxic misfolded form,Parkinsons Disease (PD) is a chronic and progressive Synuclein can transfer from within a degeneratingdegenerative neurological disorder that currently neuron into neighbouring healthy neurons andafflicts >6 million people worldwide and is predicted trigger their degeneration.to rapidly increase by 50% in the next 20 years asour population ages. Although predominantly Discover the role of mitochondrial dysfunction inconsidered a movement disorder, people with PD Parkinsons disease. Mitochondrial dysfunction hasalso experience significant non-motor symptoms long been observed in Parkinsons disease and weincluding sleep disturbances, olfactory dysfunction, are investigating how mitochondrial dysfunctionautonomic dysfunction and changes in cognition. contributes to neurodegeneration.Much earlier diagnosis and new treatments arecritically needed as (i) presently patients have Identification of brain specific transcripts and non-already lost ~40% of the suspectible neurons at coding RNA contributing to Parkinsons disease.time of diagnosis (ii) there is no cure and current Tremendous advances in NextGen sequencingtherapies are only partially effective at treating allow the interrogation of whole genome RNAsome of the symptoms, while progression and transcripts from PD affected regions of the brain.spread of the disease continues. The lack ofknowledge of the underlying mechanisms Identify the role of PARK9, autophagy & lysosomalresponsible for causing PD and its progression is the dysfunction in Parkinsons disease. Dysfunction inmajor impediment to therapeutic advances. To cellular proteostasis is a core contributor to PDachieve earlier diagnoses and development of and the impairment of these components are atreatments and drugs, our research centres on rapidly emerging field in Parkinsons Diseasediscovering the cascade of events causing the loss research.of neurons in Parkinsons Disease. Selected recent publicationsOur research projects utilise a wide range of 1. Gitler et al. “Alpha-synuclein is part of a diverse and highlyapproaches including genome-wide screening, Next conserved interaction network that includes PARK9 and manganese toxicity.” Nat Genet. 41:308-15 (2009). ImpactGeneration sequencing, bioinformatics, cell and Factor = 25molecular biology techniques, fluorescence 2. Cooper et al “Alpha-synuclein blocks ER-Golgi traffic and Rab1microscopy, qRT-PCR, lipodomics, proteomics, rescues neuron loss in Parkinsons models.” Science. 313:324-8. 2006. Impact Factor = 31metabolomics, siRNA knockdown, gene knockouts,FACS analysis, cell culture, primary neurons, transgenic Supervisor: A/Prof Antony Coopermice models and human PD patient brain samples. E: a.cooper@garvan.org.au T: 02 9295 8238Identifying the underlying molecular mechanism(s)of Parkinsons Disease. Whole genome functionalscreening approaches in relevant PD models haveidentified defects in major cellular signalingpathways. These will be validated using a broadarray of genetic, cell and molecular approaches toboth confirm their association with PD and identifythe underlying molecular mechanism(s) prior totesting in human brain samples. DIABETES & OBESITY PROGRAM 15
    • The Garvan Neuroscience program is an active, collaborative research community that investigates how the Prof Herbert Herzog Neuroscience Research Programbrain functions. Research undertaken by the Program looks at the brain at many different levels, from genes Leaderand molecules to synapses, neurons, brain regions and behaviour. A wide range of models from flies, mouseto humans and state-of-the-art molecular and biochemical techniques are employed to address both basicand medically relevant problems in neuroscience. The Programs goal is to understand how the brain worksand to improve understanding, diagnosis, and ultimately develop novel therapies for neurological disorders.We are particularly interested in conditions like Parkinsons Disease, Alzheimers Disease and generalconditions of dementia in which the natural ability of the brain to regenerate itself (via neuro-stem cells) iscompromised. Furthermore, we investigate the role of the nervous system in pain perception as well as howthe brain communicates with other organs and tissues in the body, for example to control bone formation;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 Neuroscience Research Program 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 energy homeostasis via interacting with NPY pathway. Therefore, this project is to 1) furtherProject investigate the mechanism by which NPFF systemNovel Neuropeptide Regulators of Energy regulates energy homeostasis; and 2) to investigateHomeostasis. how the NPFF and NPY systems interact in these regulations. To achieve this, we will examine aspectsThe worldwide prevalence of obesity is increasing at of energy homeostasis and factors in controllingalarming rate, and is a major risk factor for type 2 them in multiple mouse models where either ordiabetes and other diseases. Although the benefits both NPFF and NPY system have been geneticallyof losing excess weight are undisputed, there altered. Such mouse models include mice with NPFFcurrently exists no effective non-surgical treatment overexpression by delivering the NPFF-containingfor obesity. Body weight and body composition such adeno-associated viral vector to the adult mouseas fat tissue mass are regulated by an interactive brain, germline NPFF2R knockout mice, and micecomplex of energy homeostatic system. Thus to with adult-onset specific deletion of NPFF2R frommeet the urgent and desperate need for the NPY neurons. By Utilising cutting edgedevelopment of novel pharmacological tools for internationally competitive technology and uniquetreating obesity, researchers need not only to know germline and conditional knockout and transgenicthe identity and functions of individual molecules mouse models, this project will make highly originaland pathways involved in the regulation of energy and high-impact contributions to the understandinghomeostasis, but also to understand how these of the role of NPFF system in energy homeostasismolecules and pathways interact. Among these, and its interactions with the NPY pathway, and willneuropeptide Y (NPY), - one of the most widely demonstrate whether targeting NPFF2R couldexpressed molecule in the brain, is a known player provide the basis of novel anti-obesity treatment.critically involved in the regulation of body weight Selected recent publicationad adiposity via its control on every aspects of Zhang L et al. The neuropeptide Y system: Pathological andenergy homeostasis, such as appetite, energy implications in obesity and cancer. Pharmacol Ther. 2011expenditure, physical activity and fuel partitioning 1. Jul:131(1):91-113.Recently, our unpublished studies show thatneuropeptide FF and NPFF receptor 2 (NPFF2R) are Supervisor: Prof Herbert Herzogthe novel players in the energy homeostatic Co-Supervisor: Dr Lei Zhang andcomplex. Interestingly, our preliminary results E: h.herzog@garvan.org.ausuggest that NPFF system may exert its control on T: 02 9295 829616 NEUROSCIENCE PROGRAM
    • Major techniques involved in this project examination, cell cultures, quantitative real time-Indirect calorimetry, infrared imaging, stereotactic PCR and Western blotting, to determine the keybrain injection, oral glucose tolerance test, regulators of thermogenesis and mitochondrialintraperitoneal insulin test, dual-energy X-ray function and mechanistic central pathwaysabsorptiometry, tissue dissection, in situ possibly involved. All of the mouse models,hybridyzation, Western blotting, methods and experimental paradigms are wellimmunohistochemistry, various serum assays. established in our laboratory as demonstrated by our extensive publication record on these topics inProject highly ranked journals like Nature Medicine andAltering Thermogenesis as Weight-loss Strategy. Cell Metabolism (1,2,3,4,5).Obesity-associated cardiovascular diseases and Results from this study will provide critical newdiabetes are leading causes of death and are insights on NPYs role in the control of BAT-expected to increase as the obesity epidemic mediated energy expenditure. These results willworsens. Current weight-loss therapies mainly also provide valuable contributions to thetarget reduction of energy intake, providing only a development of potential therapeutics to increasetransient or partial solution with limited energy expenditure, likely being a more effectiveeffectiveness. Alternatives are needed to combat way for the treatment of obesity.this problem and one potential promising approachis to target the other side of the energy balance Selected recent Publications 1. Johnen H, Lin S, et al. Tumor-induced anorexia and weight loss areequation, energy expenditure. mediated by the TGF-beta superfamily cytokine MIC-1. Nat Med. 2007 Nov;13(11):1333-40.The therapeutic potential of brown adipose tissue 2. Lin S, Shi YC, et al. Critical role of arcuate Y4 receptors and the melanocortin system in pancreatic polypeptide-induced reduction(BAT) in weight reduction via the regulation of in food intake in mice. PLoS ONE. 2009;4(12):e8488.energy expenditure has emerged as a conceivably 3. Cox HM, Tough IR, et al. Peptide YY Is Critical forpromising yet underexplored area. Whilst previously Acylethanolamine Receptor Gpr119-Induced Activation of Gastrointestinal Mucosal Responses. Cell Metab. 2010 Junbelieved to be small animal-specific and exclusively 9;11(6):532-42.neonatal in mammals including humans, the 4. Shi YC, Lin S, et al. NPY-neuron-specific Y2 receptors regulate adipose tissue and tranbecular bone but not cortical boneabundance of functional BAT in adult humans has homeostasis in mice. PloS ONE. 2010;5(6):e11361been recently confirmed to be widespread by 5. Shi YC, Lin S, et al. Peripheral-specific Y2 receptor knockdownpositron emission tomography (PET) marking it a protects mice from high-fat-induced obesity. Obesity. 2011 Nov; 19(11): 2137-48promising target for anti-obesity therapy. However,little is known about the control of BAT activity and Supervisors: Dr Shu Linfunction. BAT is the main tissue that harbours Co- Supervisor: Dr Yan Shiuncoupling protein 1 (UCP1), the major component E: s.lin@garvan.org.authat is responsible for mediating metabolic T: 02 9295 8291thermogenesis. Our preliminary data demonstratesthat elevated neuropeptide Y (NPY) levels Projectspecifically in the arcuate nucleus (ARC) of the Insulin Action in the Brain.hypothalamus, which is known to be a major driverfor marked reductions in energy expenditure, also The prevalence of obesity has reached epidemicinfluences UCP1 expression in the BAT. levels and is further increasing at an alarming rate. Currently there are no effective therapeuticWe thus aim to investigate the specific role of the treatments for obesity, however it is generallyNPY system in integrating hypothalamic functions recognised that any treatment must be associatedwith energy expenditure specifically focusing on BAT with a reduction in energy intake, an increase inactivity. To achieve this, we will utilise a set of novel energy expenditure or ideally both. Therefore,and unique mouse models that allow for the defining how the central nervous systemneuron-type specific conditional deletion or over- coordinates information to regulate energy balanceexpression of NPY in an inducible adult-onset is important for understanding the pathology offashion. A wide range of laboratory techniques will obesity as well as for designing treatments tobe employed, including but not limiting to in-situ combat this disease. Insulin is a potent anabolichybridisation, immunohistochemistry, high- hormone, secreted by the pancreas in response tosensitivity infrared thermal imaging, histological NEUROSCIENCE PROGRAM 17
    • market. Therefore there is a desperate need to identify new alternative targets to treat obesity. One way to learn more about the critical pathways that control food intake and energy homeostasis is by investigating naturally occurring mutations that lead to obesity. The identification of the gene mutation in the leptin gene that causes the massive obesity in the ob/ob mouse was a landmark discovery, which has and still provides us with important information about the control of this complex system. While mutations in the leptin gene in humans are actually very rare there are other genetic variations that also lead to massive increasethe increase in blood glucose levels. Recently, insulin in appetite and the development of obesity thathas been reported to have effects not only in the have much higher frequencies like the one causingperipheral tissues, but also in the brain to regulate Prader-Willi-Syndrome (PWS), which is the mostsatiety and glucose and energy balance. Previous common known genetic cause of obesity, with astudies from our lab and others have established prevalence of 1 in 25,000 to 1 in 10,000 live births.the importance of the central neuropeptides Y(NPY) system in the regulation of food intake and PWS is characterised by severe infantile hypotoniaenergy expenditure, with hypothalamic NPY mRNA with poor suck and failure to thrive in the first 1 tolevels elevated in several rodent models of obesity. 2 years of life. This initial lack of feeding driveIncreased NPY levels contribute to the development changes then dramatically and subjects with PSWof obesity in a two-fold way by increasing food develop an obsession with food leading to an un-intake and also reducing energy expenditure. saturable appetite, which if not controlled, will leadAlthough insulin is known to influence energy to early-childhood onset obesity. PWS is due to thebalance, the precise neuronal action and absence of paternally expressed imprinted genes atpopulation(s) of neurons that mediate insulin action 15q11.2-q13. Interestingly, single deletion ofremains unknown. Thus, the major aim of this known genes in this region in mice althoughproject is to understand and define the role of showing some effects related to the PWSinsulin in NPY neurons in the regulation of energy phenotype, do not result in a phenotype that wouldhomeostasis. This research will not only help to get resemble the classical features of overeating andmore mechanistic insights in the etiology of obesity, development of obesity seen in human PWSbut also contribute to the precise understanding of subjects. Importantly, several recent studies havecentral insulin action in the NPY-ergic pathway in identified subjects with PWS that have only micro-the regulation of energy homeostasis. deletion in this locus on chromosome 15, but still show many of the major features such as increasedSpecific Aims appetite and early onset of obesity characteristic_ To generate and characterise NPY-neuron specific for this syndrome. The different deletions vary in IR-deficient mice. size but all contain the entire 27 copies of the_ To investigate the molecular mechanisms by which SNORD116 locus. central insulin action regulates energy homeostasis. Astonishingly hardly anything is known on how the genetic variations in Snord genes cause theSummary of Techniques to be Used incredible high-level of appetite and massiveConditional knockout mouse models, indirect obesity in affected individuals. Therefore the majorcalorimetry, metabolic measurements, real-time aim of this study is to identify the underlyingPCR, in situ hybridisation, western blotting, patch mechanism that leads to increased appetite andclamp electrophysiology, immuno-histochemistry. body weight of a particular mutation in this PWS locus, called Snord116 using various geneticallySupervisors: Prof Herbert Herzog: modified mouse models.h.herzog@garvan.org.auCo-Supervisor: Dr Kim Loh Specific AimsE: h.herzog@garvan.org.au _ Determine the effect of adult onset SNORD116T: 02 9295 8296 deficiency on food intake and energy homeostasis _ Investigate whether re-introduction ofProject SNORD116 can rescue the hyperphagia ofNon-coding RNAs and their role in obesity SNORD116 KO mice _ Identification of SNORD116 down streamObesity is a major global public health concern, with affecter pathwaysAustralia being one of the most affected countries.Although great effort has been placed on identifying Supervisor: Prof Herbert Herzogtreatments for obesity and critical players and E: h.herzog@garvan.org.aupathways that control appetite have been T: 02 9295 8296characterised, hardly any effective drugs are on the18 NEUROSCIENCE PROGRAM
    • ProjectAnorexia Nervosa-The Starving Brain.Anorexia 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, Inter-organ Signalling: A new level ofeating disorders programs and mental health clinics. regulatory controlClearly, new treatments for anorexia nervosa are Our laboratory has a long-standing interest indesperately required. defining the brains role in controlling and co- ordinating peripheral tissue homeostasis. UsingThe precise causes of anorexia nervosa are sophisticated genetic studies in mice, we haveunknown, but environmental and psychological demonstrated that the hypothalamus regulatesfactors often cited as playing a role. However, the behaviour of numerous organ systems, throughemerging evidence strongly suggests genetic causes modulation of specific neuropeptide pathways.for anorexia nervosa. For instance, most peoplesimply cannot diet down to an unhealthily low body Our primary focus has been upon the powerful,weight. That is because weight loss activates strong multi-system responses that surround starvationphysiological mechanisms that protect against and obesity, with a particular emphasis upon thefurther weight loss. This famine reaction is neuropeptide Y (NPY ) system. NPY is one of thetriggered by natural brain chemicals in a part of the most powerful regulators of energy homoeostasisbrain called the hypothalamus, with effects include throughout the body, and our group, inirrepressible hunger, lethargy and sharp reductions collaboration with the Eating Disorders Group, isin metabolic rate. amongst only a few in the world able to dissect the activity of this crucial pathway, through uniqueParadoxically, people with anorexia nervosa do not animal models made at the Garvan.demonstrate these expected responses to weightloss, suggesting perturbations in the natural brain Using specific tissue responses, such as adipose,chemicals responsible for the famine reaction. If we skeletal and pancreatic tissue, we have definedunderstood exactly which chemicals in the brain the mechanism whereby specific NPY pathwayswere responsible for mediating the famine reaction, from the brain act within the periphery. Thesehow they worked, as well as how these molecules pathways are extremely potent, altering fat massare perturbed in anorexia nervosa, then we could by over 4-fold and the production of bone by 7-develop novel treatment strategies to target the fold, as well as altering endocrine function throughphysical causes of this debilitating disorder, and altered production or end-organ responses.possibly therefore help people who do not respond Moreover, these signals are co-ordinated acrossto conventional treatments. many organ systems, demonstrating a level of integration between organ systems, not fullyUsing sophisticated genetic engineering techniques, appreciated previously.we have developed mice with perturbations ingenes encoding substances that act on the brain to Excitingly, during the course of these studies, wemediate the famine reaction, such as neuropeptide have uncovered unique signalling pathways, thatY, peptide YY, and dynorphins. Intriguingly, these indicate an additional layer of communication nottransgenic mice demonstrate metabolic features previously appreciated, acting between the organscharacteristic of people with anorexia nervosa, themselves. Endocrine regulation has typicallynotably an enhanced ability to lose weight and burn been viewed as a top-down process, from thebody fat. However, in order to fully investigate the hypothalamus via the pituitary to the circulation.role of these substances in the development and Our research will focus upon emerging inter-tissuetreatment of anorexia nervosa, we need to communications, defining entirely new signallinginvestigate their effects on food intake and body molecules and axes of communication.composition other eating related behaviours. Our initial studies have identified actions entirelySupervisor: Prof Herbert Herzog novel to science. For example, using tissue-specificE: h.herzog@garvan.org.au neuropeptide models, we have demonstratedT: 02 9295 8296 bones signalling to the brain to control its own production, as well as bones regulation of both adipose and glucose homeostasis. NEUROSCIENCE PROGRAM 19
    • development and healthy function of the brain, however it is hyperactivated in Bipolar Disorder and Schizophrenia. This causes disruption of many cellular functions and impairs healthy brain function, although the pathways affected are not well understood. Our goal is to discover targets of GSK3 that directly lead to the development of mood disorders and Schizophrenia, since these could become more selective and potent drug targets for improved treatment. Project We performed a bioinformatic and biochemicalPost graduate projects within the lab will involve screen to discover new targets of GSK3 in the brain.investigations of inter-organ communication, Surprisingly, we found a large cluster of GSK3concerning, but not restricted to: targets associated with clathrin-mediated_ Coordination of energy, skeletal and glucose endocytosis (CME), a process that is critical for homeostasis efficient neurotransmission in the brain. Several_ Feedback signals from bone to brain mood-stabilising drugs target CME, implicating it in_ Regulation of tumour cell growth by marrow and the pathogenesis of these disorders. Excitingly, skeletal tissue several of these have already been genetically_ Consequences of chronic obesity/leptin resistance associated with Bipolar and/or Schizophrenia,_ Neuropeptide regulation of central endocrine increasing the likelihood that they directly function contribute to the development of these disorders. This project will determine how GSK3 regulates theThese studies represent the forefront of our molecular function of these new targets, its affectunderstanding of how tissues communicate and co- on CME/neurotransmission in the brain and evaluateordinate their activities, and offer the potential for their potential to become novel therapeutic targets.entirely new modalities for disease control. Every This will be achieved using a variety of techniques,student within our lab has won at least one including protein biochemistry, recombinant DNAinternational young investigator award for oral technology, immunoflourescence microscopy andpresentation of their studies, and gone on to primary neuronal cell cultures. We will also useinternational positions. Our lab is integrated with genetically-modified flies to determine the role ofmany others within the Institute, including ongoing GSK3 targets on neurotransmission and behavioursclinical studies, and offers a rewarding, productive associated with mood disorders in a wholeand enjoyable experience for those eager to explore organism. This powerful technology is new to thethis emerging field. Garvan Institute and will be performed in collaboration with the Pain Research Group lead bySupervisor: Dr Paul Baldock Dr. Greg Neely. Opportunities exist to investigateE: p.baldock@garvan.org.au 10 new GSK3 targets already discovered, as well asT: 02 9295 8244 the opportunity to discover new targets.Neurosignalling Group Benefit Very little is known about the function of GSK3 andProject 1 its targets, especially in the brains of mood disorderDeveloping new therapies for mood disorders and Schizophrenic patients, providing greatand schizophrenia. opportunities for discovery. Many essential reagents have already been generated and are ready for use,Background greatly expediting this research. The Garvan is anMood disorders (e.g. Bipolar disorder) and exceptionally well-equipped medical researchSchizophrenia are debilitating psychiatric illnesses institute with state of the art facilities and modernthat severely impair peoples lives. They affect laboratories. Students in the Neurosignalling Group200,000 Australians, are one of the leading causes will be provided with attentive supervision, superiorof disability amongst young adults and cost the research facilities, exposure to a wide range ofcommunity over $2 billion annually. One quarter of experimental techniques and will participate inyoung adult sufferers commit suicide, therefore national/international conferences and collaborations.there is an urgent need to improve treatments formood disorder patients. Clear genetic or Project 2environmental causes have not been identified, so New transcription factors regulating neurogenesisalternative strategies for developing novel and neuroplasticity: rewiring the brain.therapeutics are needed. Our approach is todetermine how current drug treatments work, so Backgroundthat they can be improved. A key target of lithium Neurogenesis is the production and incorporation ofand other mood stabilisers is the important brain new neurons into existing circuits of the adult brain.enzyme GSK3. This protein is essential for normal This process promotes plasticity (ability of the brain20 NEUROSCIENCE PROGRAM
    • to rewire itself), facilitating learning and memorythroughout our lifetime. Neurogenesis is decreasedin several mental illnesses, including mood disorders,Alzheimers disease and age-related cognitivedecline. Therefore, a fundamental knowledge of themechanisms controlling neurogenesis could lead tonew treatments that restore healthy mentalfunction or repair the brain following injury. Weperformed a genome-wide screen in Drosophila(fruit fly) using neuronal-specific RNAi knockdownto identify genes essential for neurogenesis andbrain development. We found that knockdown of 3transcription factors in fly neurons is lethal, clearlydemonstrating a cell fate and developmental Bird and Swine Flu, Parkinsons Disease,function in the brain. All 3 genes are associated with Chronic Painhuman diseases, although their role in brain The focus of our group is to use a “systemsdevelopment has not yet been investigated. biology” approach, combining fruit fly, mouse, andOpportunities exist in the Neurosignalling Group to human genetics to identify novel conservedinvestigate any one of these novel transcription regulators of human disease. We are currentlyfactors in brain development. involved in using single nucleotide polymorphism genotyping and next generation sequencingProject technologies to identify genes and rare mutationsThis project will determine how the novel that contribute to human disease, which we thentranscription factors regulate neurogenesis, brain validate in model organism and/or human cells.development and behaviours associated withneurological disorders. More specifically, it will 1) Project 1determine how they regulate cell fate and behaviour Identification and validation of novel mutationsin genetically-modified flies (collaboration with Dr. that cause or modify Parkinsons disease (PD).Greg Neely, Pain Research Group), and 2) determinethe biochemical mechanisms by which GSK3 Therapies for neurodegenerative diseases, such asregulates their function. These goals will be PD, represent an unmet clinical need. This projectachieved using a variety of techniques, including is designed to rapidly identify novel drug targetsprotein biochemistry, recombinant DNA technology, for the treatment of PD. This project involvesimmunoflourescence microscopy and primary analysis of large genomic data sets followed byneuronal cell cultures. This will provide valuable validation of these data in model organisms. Weinsight into the mechanisms controlling have access to novel PD genomics data and areneurogenesis and is likely to reveal new therapeutic involved in collaborative efforts to genotype andavenues for improved treatment of mood disorders, sequence samples from PD patients,Alzheimers disease and age-related cognitive decline. asymptomatic close relatives, and control patients. We will then analyze these data within the contextBenefits of other genomics approaches to PD, followed byMental health is a rapidly growing research field that functional validation of these data using the fruithas recently become a health and research priority fly Drosophila melanogaster. In some cases thisin Australia and other developed nations. Many may also involve the generation and phenotypingessential reagents have already been generated and of transgenic mice when appropriate. Theare ready for use, greatly expediting this research. successful applicant will receive training in analysisThe Garvan is an exceptionally well-equipped of large genomics data sets and deep sequencingmedical research institute with state of the art efforts, basic training in animal models of PD asfacilities and modern laboratories. Students in the well as in vivo electrophysiology. Some previousNeurosignalling Group will be provided with experience with sequence analysis or genomicsattentive supervision, superior research facilities, modelling approaches will be preferred.exposure to a wide range of experimentaltechniques and will participate in national/ Project 2international conferences and collaborations. Prediction and validation of novel drugs for treatment of PD.Supervisor: Dr Adam ColeNeurosignalling Group This project is designed to directly identify newE: a.cole@garvan.org.au therapeutic approaches (i.e. small molecules) forT: 02 9295 8289 the treatment of PD. This project is a mixture of computational analysis of large genomic data sets and validation of these data in model organisms. In this project we will employ genomics approaches NEUROSCIENCE PROGRAM 21
    • to identify key genes involved in PD and will then we are still extremely limited in our ability to treatpredict small molecules that may target key PD highly pathogenic influenza infection, using most ofgenes. Finally we will functionally evaluate a short the same strategies that were employed in 1918.list of candidate small molecules in fruit fly and We have a long-standing interest in host defence tomouse models of PD. The successful applicant will pathogens, and have developed a rapid, safe, inreceive training in analysis of large genomics data vitro method for assessing the innate immunesets and deep sequencing efforts, basic training in response to bird and swine flu. In this project we willanimal models of PD, as well as training in in vivo assess and model the innate immune response toelectrophysiology, however some previous bird/swine flu infection at the genomics level, andexperience with bioinformatics analysis or use bioinformatics to predict key regulators ofelectrophysiology will be preferred. At the end of innate immunity. We will then identify candidatethis project we hope to have identified novel, FDA small molecule compounds predicted to block theseapproved therapeutics ready for trial in human key innate immune regulators and test thesepatients with PD. compounds for efficacy in suppressing the human innate immune reaction to influenza in vitro andProject 3 eventually in mice as well. The successful applicantIdentification and validation of novel mutations will receive training in analysis of large genomicscausing severe chronic pain. data sets and deep sequencing efforts, basic training in handling human peripheral blood cells andThere is currently a lack of effective therapies to instruction in assessing innate immune responses totreat chronic pain diseases such as neuropathic pain. influenza in vitro (human) and in vivo (mice). SomeIn this project, we will perform a genome-wide previous experience with bioinformatics analysis orassociation study (GWAS) for chronic pain in fruit basic tissue culture will be preferred. At the end offlies. These data will then be subject to this project we hope to have identified novel, FDAbioinformatics analysis and compared to parallel approved therapeutics ready for trial in humanunpublished human pain genomics approaches. We patients with highly pathogenic influenza infections.will then validate candidate GWAS loci using in vivotransgenic RNAi. Efforts will also be made to Recent publications 1. Neely et al. A genome-wide Drosophila screen for heat nociceptionidentify key neural circuitry required for higher order identifies _2_3 as an evolutionarily conserved pain gene. Cell. 2010pain processing in the brain. The successful applicant Nov 12;143(4):628-38.will receive training in delicate surgical manipulation 2. Neely et al, A global in vivo Drosophila RNAi screen identifies NOT3 as a conserved regulator of heart function. Cell. 2010 Aprof neural populations in live fruit flies as well as in 2;141(1):142-53.(Cover).vivo electrophysiology. 3. Pospisilik et al, Drosophila genome-wide obesity screen reveals hedgehog as a determin ant of brown versus white adipose cell fate. Cell. 2010 Jan 8;140(1):148-60.Project 4 4. Cronin et al, Genome-Wide RNAi Screen Identifies Genes Involved inIdentification of novel drugs for the treatment of Intestinal Pathogenic Bacterial Infection. Science. 2009 Jul 17;325(5938):340-3.highly pathogenic influenza infections. 5. Imai et al, Identification of oxidative stress and Toll-like receptor 4 signaling as a key pathway of acute lung injury. Cell. 2008 AprHighly pathogenic influenza, such as bird or swine 18;133(2):235-49. 6. Pospisilik et al, Targeted deletion of AIF decreases mitochondrialflu, represents a major health concern and social risk oxidative phosphorylation and protects from obesity and diabetes.to our society. The dangers of new highly Cell. 2007 Nov 2;131(3):476-91. (Cover).pathogenic and transmissible influenza is clearlyexemplified by the pandemic of 1918, killing 50- Supervisor: Dr Greg Neely100 million people or ~10% of those infected, Pain Research Groupresulting in the death of ~3% of the world E: g.neely@garvan.org.aupopulation, and this devastating outbreak occurred T: 02 9295 8297before global air travel was commonplace. Despitemajor advances in medicine over the 20th century,22 NEUROSCIENCE PROGRAM
    • Neurodegenerative Disorders Research mechanisms and role of neural regeneration is aPhD Studies in Dr Bryce Vissels group allow you the cutting edge area of research worldwide and theopportunity to learn and develop cutting edge research has significant potential to lead totechnologies and approaches that will contribute to important discoveries.a deeper understanding and treatment ofParkinsons disease, Alzheimers disease or spinal Project 2cord disorders. The group uses sophisticated The role of immune processes in Learning andapproaches to understand how synaptic dysfunction Memory, and in Parkinsons and Alzheimers disease.leads to neurodegeneration and to identify potentialapproaches to reverse the disease process. In Our labs studies are identifying a criticallyaddition to studying mechanisms of important role for inflammatory processes in brainneurodegeneration, the group studies stem cells and plasticity and disease. In our group, we arethe mechanisms underlying regeneration in the working to identify mechanisms that regulate thenervous system. The goal of this work is to identify interaction between inflammatory cells andapproaches that could drive recovery in the brain in neurones in specific brain regions, with a view todiseases such as Parkinsons and Alzheimers understand how these mechanisms ultimately leaddisease. All our projects will train you in a wide to normal bran function, or abnormal brainrange of cutting edge approaches, including function in diseases such as Parkinsons andanatomy, molecular biology, gene therapy, Alzheimers disease. The students who arephysiology, animal behaviour, cell culture, high end interested in research projects in this area will learnmicroscopy, surgery and so on. Our group is helpful, advanced techniques in the study offriendly and highly motivated. These are kinds of neurodegeneration and neuroinflamation.studies you could undertake: Techniques learned will similarly include: (1) Stereotaxic survival surgery and gene therapyProject 1 approaches, (2) Immunohistochemistry combinedNeural Regeneration Research and studies of Stem with advanced confocal microscopy andCells in Parkinsons and Alzheimers disease. stereology for analysis of regeneration. (3) Use of in vitro cell systems. (4) Sophisticated learning andStudents will have the opportunity to study neural memory and movement studies in mice (5)regeneration in our group. Adult neurogenesis is the Molecular biology. Research into mechanisms andprocess by which the brain generates new nerve role of neurodegeneration and neuro-inflamation iscells in the adult central nervous system (CNS) from another cutting edge area of research worldwidestem cells that naturally exist in the brain. and the research has significant potential to leadStimulating neurogenesis may potentially offer a to important discoveries.therapeutic approach for neurodegenerativediseases such as Parkinsons disease, Alzheimers Project 3disease, and spinal disorders. In our group, we are Post-transcriptional events that regulate neuralworking to identify mechanisms that regulate adult plasticity, memory and diseases.neurogenesis (neural repair mechanisms) in thenormal and diseased brain, to determine if We have recently identified RNA editing of specificmanipulating these mechanisms may offer neuronal RNAs as a novel mechanism that cantherapeutic potential. The students who are affect Parkinsons disease, Alzheimers disease andinterested in research projects in this area will learn behaviour in mice. This is an exciting and noveladvanced techniques in the study of neurogenesis project that offers interesting possibilities forand neural stem cells. Techniques learned will significant new insights into brain function. Theinclude: (1)Stereotaxic survival surgery and gene experiments will use similar methods to thosetherapy approaches, (2) Immunohistochemistry described for the projects above.combined with advanced confocal microscopy andstereology for analysis of regeneration. (3) Use of in Supervisor: Dr Bryce Visselvitro cell systems, including neural stem cells, for Neurodegenerative disorders researchstudying neurogenesis. (4) Behavioural testing to E: b.vissel@garvan.org.audetermine the capacity for functional recovery in T: 02 9295 8293animal models (5) molecular biology. Research into NEUROSCIENCE PROGRAM 23
    • Project 1Tinnitus, hearing loss, and frequency organisationin the inferior colliculus.Project 2Pathophysiology of hearing loss in the lateralsuperior olive.Project 3Protection from noise trauma using anti-oxidants.Our laboratory offers opportunities for students tostudy brain mechanisms of normal hearing so thatwe can better understand hearing loss and itsaccompanying brain abnormalities. In children, treated by simple amplification. In fact, hearing losshearing loss impairs speech and language has many additional adverse symptoms; speechdevelopment, which in turn undermines academic comprehension in a noisy background is lost; tinnitusachievement. In adults, it has a negative impact on or ringing of the ears often emerges; andemployment opportunities and social functioning. It sometimes there is severe loudness distortion.can create social isolation that develops into Hearing loss is not just about volume. Increasing thedepression, which in turn can lead to early onset loudness often does not improve auditorydementia. Many aspects of deteriorated hearing, perception; amplifying a fuzzy signal just gives you asuch as listening to speech in a noisy background, loud fuzzy signal.cannot be explained solely on the basis of pathologyin the inner ear. Performance on these tasks is likely Projects will be designed using mice with variableaffected by neural reorganisation or deterioration in expressions of hearing loss and will experiment withbrain circuits. intervention methods including hearing aids and acoustically enriched sound environments.Studies of experimental animals have shown that Physiological and anatomical investigations willcongenital deafness results in abnormal auditory examine changes in temporal processing andsynapses and pathologic alterations in central loudness perception and investigate theauditory pathways. Disease, head trauma, ageing, corresponding changes in synaptic structure anddrugs, and loud noise can cause hair cells to die. organisation of neural inputs to cells. Students willWhen hair cells die, they are gone forever and our be expected to learn techniques related to in vivohearing diminishes. One way to think about hearing single cell recordings, auditory brainstem responses,loss is that we lose resolution of our sound and otoacoustic emissions. Pathway tracing andenvironment. When we are young, we have high- immunocytochemistry methods using light anddensity auditory input to the brain. It is analogous to electron microscopy are also a normal part of thehaving high definition television for sight. For lab repertoire so that cell-to-cell circuits can bereasons we cant explain, ageing typically causes hair described and structure-function relationshipscells corresponding to high frequencies to die first. determined. These kinds of studies will focus on theWe might notice this loss when consonant sounds relationship between hearing loss and synapticof speech, such as s, f and th, become difficult to organisation of the auditory system.distinguish. As receptor cells die, our soundenvironment “pixilates” and hearing loss worsens. Supervisor: Prof David RyugoYou can hear sounds but the details are blurry. Many E: d.ryugo@garvan.org.aupeople wrongly assume that hearing loss can be T: 02 9295 828824 HEARING RESEARCH UNIT
    • Prof Peter Croucher Research at the Osteoporosis and Bone Biology Program is focused on understanding the causes andOsteoporosis and Bone BiologyProgram Leader development 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 edge technology in genomics, proteomics and contemporary imaging approaches are being applied to address critical clinical questions in skeletal medicine. Students in the Program have made fundamental discoveries that are having a real impact in skeletal medicine. Garvan researchers were the first to show the importance of genes in regulating the skeleton; have identified critical molecular pathways that regulate bone; and recently discovered the importance of neurological control of bone. Work undertaken at the Garvan has also led to the development of new approaches to predicting who will fracture their bones, an example of laboratory discoveries being translated directly into the clinic for patient benefit. Research from the Osteoporosis and Bone Biology Program has been published in high ranking journals such as Nature, Nature Genetics, Blood, JAMA, & N.Engl J. Med. PhD students participate and present their work at major international scientific meetings and attracted numerous awards. Our postgraduate students are highly regarded, gaining their own fellowships and have established their own independent scientific careers often at prestigious Institutes and Universities in the US, UK and Europe. The Croucher labs research interests are in the Bassett at Imperial College London, we have major diseases of the skeletal system, particularly in screened knockout mice from the Wellcome Trust diseases such as osteoporosis and tumours that Sanger Institute Mouse Genetics Programme and grow in bone, including multiple myeloma, or those identified strains with increased bone strength that metastasise to bone, such as breast and resulting from deletion of genes not previously prostate cancer. Our research interests are in known to have a role in the skeleton. This project understanding the cellular and molecular will establish the role of these pathways in mechanisms that lead to these conditions with the controlling bone strength and identify new aim of developing new approaches for clinical therapeutic targets for treating osteoporosis. intervention. In recent years we have developed new screening tools that have allowed us to identify Project 2 new genes that control bone strength and Targeting metastasis initiating cells in breast and developed new approaches to increasing bone prostate cancer. mass. We have also developed novel high-resolution imaging technologies that allow us to visualise Bone metastases are a devastating clinical individual metastasis-initiating cells as they colonise consequence for patients with breast and prostate the skeleton. Building upon these discoveries we are cancer. The mechanisms leading to their now Utilising the latest next generation genomic development are poorly defined, and approaches technology, bioinformatic and systems biology to prevention and treatment limited. We have approaches, and the latest high-resolution imaging developed new high-resolution imaging to taking these projects forward. We have a number technology that allows us to visualise the tumour of projects available in the following areas: initiating cells, at a single cell resolution, in the skeleton. Projects in this area will use the latest Project 1 imaging technology and next generation genetic New gene targets for anabolic therapy in and bioinformatic tools to establish a genetic and osteoporosis. molecular fingerprint of these tumour-initiating cells and utilise this knowledge to develop new Treatments for osteoporosis prevents further bone therapeutic approaches to preventing the loss but have a limited ability to restore bone mass development of bone metastasis. so patients continue to fracture. In collaboration with Professor Graham William and Dr Duncan OSTEOPOROSIS & BONE BIOLOGY PROGRAM 25
    • Project 3 Specific projects included, but not limited to:Defining the tumour initiating cells in multiplemyeloma. Project 1 Analysis of gene-gene and gene-environmentalMultiple myeloma is a B-cell neoplasm interactions on bone phenotypes.characterised by the growth of tumour cells in theskeleton and the development of a devastating Gene-gene interaction or epistasis is abone disease. We have developed novel in vivo phenomenon whereby the effect of one gene on aimaging technology to study single myeloma cells phenotype is modified by the presence of anotherand their interactions with bone in vivo and gene in the same or different chromosomes. Thediscovered new molecules implicated in myeloma presence of epistasis presents a challenge in thebone disease. We will use this new technology and analysis of genetic association studies. We arenext generation genetic and bioinformatic interested in an Bayesian approach to detect geneapproaches to define a genetic and molecular - phenotype association in human populations arefingerprint of these cells, establish the role of not sensitive enough to detect epistasis inosteoblasts in regulating their behaviour and utilise osteoporosis phenotypes.this knowledge to develop new therapeuticapproaches. Project 2 Development of clinico-genetic prognosticSupervisor: Prof Peter Croucher models for individualising fracture risk.E: p.croucher@garvan.org.auT: 02 9295 8243 We have developed a risk factor based model for predicting fracture risk. We want to refine theGenetics and Epidemiology Group model by including genetic data. With a rapidOsteoporosis is a systemic skeletal disease improvement in genotyping technology, nextcharacterised by low bone mass and degenerative generation of GWAS will be adding more variantsmicroarchitectural deterioration of bone tissue at a low frequency to cover as many SNPs aswhich consequently increase bone fragility and possible. We are interested in the integration ofsusceptibility to fracture risk. The chance that a 50- genetic profiling into the existing prognostic modelyear old woman has a hip fracture during her to improve the predictive accuracy of fracture risklifetime is about 12%, which is equivalent to or for an individual.higher than her risk of having breast cancer.Fracture is a serious event because it is associated Project 3with reduced life expectancy. Development and validation of a composite outcome that captures all clinical aspects ofOur group is primarily interested in translational osteoporosis.science of osteoporosis. We are interested inidentifying genetic and environmental risk factors Patients with an existing fracture have anthat contribute to fracture susceptibility and increased risk of subsequent fracture andmortality risk. We are actively working on the mortality. The hypothesis is that fracture, re-concept of individualised prognosis of osteoporosis fracture, and mortality collectively provide aby using genes, hormones, bone turnover markers, better outcome that reflects the underlyingand bone strength related parameters. clinico-pathology of osteoporosis. The primary aim of this proposed project is therefore to develop aWe have carried out genetic association studies, “composite outcome” for osteoporosis to captureincluding participating in genomewide association fracture and its adverse outcomes.studies (GWAS). We also perform a genome-widelinkage study to discover novel genes that areinvolved in the regulation of bone phenotypes andfracture risk. This line of research requires expertisein clinical medicine, genetics, and bioinformatics.26 OSTEOPOROSIS & BONE BIOLOGY PROGRAM
    • Project 4 Genetics & Epidemiology GroupRole of biochemical markers of bone turnover in Neuropeptide activity in the initiation andthe prognosis of fracture risk. maintenance of Anorexia Nervosa?This project seeks to determine the short-term Anorexia nervosa (AN) is the most lethal psychiatricwithin-subject variability of bone turnover markers, condition, with up to 20% mortality over 20 years.and develop a sensitive longitudinal algorithm for Sadly, AN is an increasing health issue, with patientsdetermining the actual value for an individual and presenting at younger ages and with increasingscreening for significant changes in those markers frequency. To date, treatment options are severelywithin an individual patient. limited, however, recovery and survival rates are markedly improved (70% recovery at 12 months) ifProject 5 refeeding is included with normal psychiatric care.Relationship between sarcopenia and osteoporosis. This is clear evidence for the importance of refeeding to this condition, formerly treated as aSarcopenia is a condition characterised by loss purely psychiatric disease.muscle mass and reduced muscle strength. Thisproject is aimed at defining the gender-specific Our laboratory, in collaboration with therelationship between muscle properties (i.e., muscle Neuroscience Division, using genetic mouse models,mass, muscle strength, and muscle quality) and has been instrumental in examining the action of afragility fracture in men and women. The project will family of neuropeptides, the Neuropeptide Y (NPY)also develop clinically based criteria for the system. These neuropeptides have been shown todiagnosis of sarcopenia that can be applied to the exert powerful actions on fat and bone mass. Onegeneral population. of the peripheral members of this family, PYY which is produced in the gut in response to food intake, isResources an extremely powerful modulator of appetite andOur group is one of the worlds leading osteoporosis bone mass. It has been shown to be abnormal inresearch centres, with extensive experience in the states of altered body weight such as Anorexiagenetics of osteoporosis. Our work has been Nervosa and obesity.published in Nature, Nature Genetics, New EnglandJournal of Medicine, Lancet, JAMA. More than 10 In Anorexia Nervosa, PYY is elevated which ispapers from our group are among the highly cited consistent with the loss of fat mass and bone masspapers in the world. By joining our group, students in these patients. It is our hypothesis that elevatedwill not just have access to leading experts, but also PYY alters the signalling of critical pathways in theto extensive scientific resources, including brain that control feeding, behaviour, hormonesophisticated genetic and bone analytical production and bone mass, thereby producing aequipments, and high performance computing. cascade critical to the persistence and possibly even aetiology of AN.Supervisor: Prof Tuan NguyenGenetics and Epidemiology Group This project will combine both basic and clinicalE: t.nguyen@garvan.org.au aspects of research, the proportion of which can beT: 02 9295 8277 altered depending on the interests of the student. The basic research will dissect the central and peripheral actions of PYY in an effort to isolate a target for therapeutic intervention. The clinical research will involve collaboration with the Childrens Hospital at Westmead who have a large intake of acute Anorexia Nervosa and all the tools in OSTEOPOROSIS & BONE BIOLOGY PROGRAM 27
    • place for assessment of changes in weight and bone range of molecular biology techniques includingin conjunction with serum levels of PYY among other mass spectrometry and quantitative PCR. Isoformsrelated hormones. There is also the potential for a and newly-discovered post-translationalgenetic study examining the role of PYY in the first modifications of FPP synthase, and their relevancedegree relatives of subjects with Anorexia Nervosa. to differences in drug responsiveness between patients, will be analysed using a variety of state-Supervisor: A/Prof Jackie Center of-the-art next-generation sequencing,Genetics and Epidemiology Group bioinformatic and proteomic approaches.E: j.center@garvan.org.auT: 02 9295 8271 Project 2 Proteomics and the Role of Prenylated Proteins inMolecular Pharmacology Group Tumour Cells.Bisphosphonates are a “blockbuster” class of drugsused worldwide for the treatment of common bone This project will:diseases such as post-menopausal osteoporosis, _ Optimise new, highly sensitive proteomiccancer-induced bone loss and Pagets disease. My techniques to identify lipid modified (prenylated)lab is a world-leader in characterising how these small GTPase signalling proteins.drugs work at the cellular and molecular level. We _ Use these techniques to profile the expression ofmade the breakthrough discovery a few years ago prenylated small GTPases in normal cells andthat most of these drugs work by inhibiting FPP cancer cells and identify potential mechanismssynthase, a critical enzyme involved in the involved in tumour growth and spread.biosynthesis of cholesterol and a variety of lipidintermediates necessary for the lipid modification We have begun to develop an exciting new(prenylation) and hence normal function of essential technique to identify prenylated proteins, utilisingsignalling proteins. Several PhD projects will be biochemical and 2D electrophoretic methods andavailable in my lab, addressing clinically important mass spectrometry. Together with other state-of-questions about the pharmacology and biological the-art proteomic methods such as DIGE andactions of these drugs and the role of prenylated SILAC, we have identified some changes in theproteins in cancer cells. levels of prenylated Rab GTPases, involved in vesicular trafficking, in cancer cells. This project willProject 1 develop these observations to further study theModelling the Mevalonate Pathway in the role of Rab proteins and other small GTPases in theTreatment of Bone Diseases. spread of tumour cells to the skeleton. ReferencesIn this project we will seek to understand: 1. Rogers, M.J., Crockett, J.C., Coxon, F.P., Monkkonen, J. (2011)._ How inhibition of FPP synthase by bisphosphonate Biochemical and molecular mechanisms of action of drugs affects upstream and downstream bisphosphonates. Bone 49 (S1), 34-41. 2. Itzstein C, Coxon FP, Rogers MJ. (2011). The regulation of metabolites and enzymes of the mevalonate osteoclast function and bone resorption by small GTPases. Small pathway, leading to adverse drug effects; GTPases 2, 117-130._ How different isoforms and modifications of the 3. Coxon, F.P., Taylor, A., Stewart, C.A., Baron, R., Seabra, M, Ebetino, F.H. & Rogers, M.J. (2011). The gunmetal mouse reveals Rab FPP synthase enzyme might affect the geranylgeranyl transferase to be the major molecular target of responsiveness of patients to bisphosphonate drugs. phosphonocarboxylate analogues of bisphosphonates. Bone 49 (S1), 111-121. 4. Roelofs, A.J., Jauhiainen, M., Mönkkönen, H., Rogers, M.J.,The accumulation of lipid metabolites directly Mönkkönen, J. & Thompson, K. (2009). Zoledronic acid causesupstream of FPP synthase is the cause of a accumulation of IPP/DMAPP selectively in peripheral blood monocytes due to efficient drug uptake. Br. J. Haematol. 144,common flu-like side-effect of bisphosphonate 245-50.drugs. A mathematical model of the pathway thatwe have developed will be tested, in well- Supervisor: Dr Mike Rogersestablished cell and organ culture models, to predict E: m.j.rogers@hotmail.co.ukthe effect of bisphosphonates and other drugs on T: 02 9295 8272lipid metabolites and enzyme expression using a28 OSTEOPOROSIS & BONE BIOLOGY PROGRAM
    • 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 Garvans 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.General Research Project Areas and scientific literature databases. Very largeThe sequencing of the human genome took 10 datasets from genome sequencing require highyears and cost almost $3 billion. Now with performance computing infrastructure, and wemassively parallel sequencing were able to have recently installed such a system. Thesequence a genome in days for only a few thousand successful candidate will develop tools to harnessdollars, and this has brought whole genome this infrastructure.sequencing into the hands of individual researchersand have spawned the viability of genome medicine. Required BackgroundFrom the time of the sequencing of the first human These positions could be filled by students fromgenome over 10 years ago, genome biology has, a range of backgrounds, including bioinformatics,and continues, to rewrite our understanding of biochemistry, chemistry, physics, or computerbiology, so that today we see the genome as an scientists.exquisitely regulated machine. We are interested inunderstanding this exquisite regulation in the For the Genome Informatics a keen interest incontext of diseases being studied at Garvan. For biology, and genome biology in particular is vital.further details contact w.kaplan@garvan.org.au. Students with good scripting language skills especially in Python and the R-language would beThe Garvan has recently started a new group an advantage, as would some familiarity with Java.focused on developing methods and tools for An interest in GPGPU programming and map-reducevisualising biological data. Jointly associated with techniques like Hadoop would also be very helpful.CSIRO, the group focuses primarily on usingprinciples of usability, data visualisation, human- For the visualisation projects and an interest incomputer interfaces, and graphic design to develop using data visualisation, human computerstate-of-the-art methods and tools that address interaction, usability, or design to address keycutting edge challenges in biological and biomedical challenges in basic biomedical research. Ofresearch. A second focus of the team is on using particular interest would be students with strongthese methods to analyse experimental datasets in JavaScript or Java3D skills, as well as a strongcollaboration with groups at the Garvan. Projects interest in using HTML 5 to build the next-will include the VIZBI initiative (http://vizbi.org), the generation of visualisation tools for analysingReflect system for enhancing scientific literature omics datasets for systems biology. There is also(http://reflect.ws), and developing methods for scope for students wishing to focus not on toolintegrating macromolecular 3D structures with development, but on applying visualisationgenomics, proteomics, and other systems biology techniques to data from various disease areas,data. For further details see http://odonoghuelab.org/. possibly in collaboration with other groups at Garvan.Techniques Used Supervisor: Dr Warren Kaplan and Dr SeánBioinformatics software development, graphics ODonoghuedesign, 3D graphics, 3D animation, Human- E: w.kaplan@garvan.org.aucomputer interface development. Applications to T: 02 9295 8146data from genomics, proteomics, systems biology GARVAN BIOINFORMATICS 29
    • Applications are submitted online at: Noteswww.garvan.org.au/education. All applicationsare considered by the Garvan Higher DegreesCommittee (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:www.grs.unsw.edu.au/futurestudents/apply.html.As part of this process, you will need to haveagreed a potential research project with yoursupervisor.