Garvan PhD_projects_2013


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Garvan PhD_projects_2013

  1. 1. 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 26Garvan Bioinformatics 29How to Apply 30
  2. 2. 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 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 for further Garvan Institute can provide, please email information. or visit POSTGRADUATE STUDIES AT THE GARVAN 01
  3. 3. 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: 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
  4. 4. 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: 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
  5. 5. 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: T: 02 9295 833304 CANCER RESEARCH PROGRAM
  6. 6. 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. ( 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: 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: 02 9295 8327 CANCER RESEARCH PROGRAM 05
  7. 7. 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 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, 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: cancer phenotype. T: 02 9295 831506 CANCER RESEARCH PROGRAM
  8. 8. 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 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: 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
  9. 9. 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: 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
  10. 10. 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: 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
  11. 11. 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: 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: T: 02 9295 832610 CANCER RESEARCH PROGRAM
  12. 12. 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 Poject 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 Poject 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 Poject 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: 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 by made 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 Poject 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: 02 9295 8414 IMMUNOLOGY RESEARCH PROGRAM 11
  13. 13. 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 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: 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: T: 02 9295 843312 IMMUNOLOGY RESEARCH PROGRAM
  14. 14. 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: development of obesity and insulin resistance. T: 02 9295 8224 DIABETES & OBESITY PROGRAM 13
  15. 15. 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 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: 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: T: 02 9295 825814 DIABETES & OBESITY PROGRAM
  16. 16. 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 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: 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
  17. 17. 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: that NPFF system may exert its control on T: 02 9295 829616 NEUROSCIENCE PROGRAM
  18. 18. 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) 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: 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