2. Postgraduate Studies at the Garvan 01
Why Choose the Garvan 01
Garvan PhD Open Day 21st of August 2012 01
Cancer Research Program 02
Colon Cancer Genetics & Biology Group 02
Ovarian Cancer Group 03
Tyrosine Kinase Signalling Networks in Human Cancers 04
Mitotic Control Group 05
Pancreatic Carcinogenesis Group 05
Epigenetic Laboratory Cancer Program 06
Cancer Bioinformatics Group 10
Immunology Research Program 11
B Cell Biology Laboratory 11
Diabetes & Transcription Factors Group 12
Diabetes & Obesity Research Program 13
Bioenergetics in Disease 13
Regulation of Body Composition & Glucose Homeostasis
by the Adaptor Protein Grb10 14
Beta Cell Replacement Therapy 14
Cooper Group - Neurodegeneration,
Cell & Molecular Biology, Genetics 15
Neuroscience Research Program 16
Eating Disorders Group 16
Inter-organ Signalling: A new level of regulatory control 19
Bird and Swine Flu, Parkinson's Disease, Chronic Pain 21
Neurodegenerative Disorders Research 23
Hearing Research Unit 24
Osteoporosis & Bone Biology Research Program 25
Genetics and Epidemiology Group 26
Garvan Bioinformatics 29
How to Apply 30

3. Prof John Mattick In partnership with the University of New South Wales, Garvan Institute provides a learning and
Executive 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 world's leading medical research institutes with programs in cancer, diabetes and obesity,
immunology, neuroscience and osteoporosis, Garvan is playing a leadership role in translating the
amazing developments in modern biomedical research into real improvements in health care and
quality of life. The joint initiative with St Vincent's Hospital in establishing The Kinghorn Cancer Centre
will enable Garvan's 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

4. 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 Leader
most highly regarded cancer research teams in Australia and internationally. With complementary skills in
cancer genomics, cancer epigenomics, cancer molecular and cellular biology, cancer biomarker and
therapeutic target identification & validation and translational research, the program is focussed on
understanding the causes of and developing new diagnostic, prognostic treatment and prevention strategies
for 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 the
pathophysiology of breast and prostate cancers, with over 350 primary publications in top ranking
multidisciplinary and specialist journals. Among the many successful PhD graduates are Directors of major
research institutes and academic departments, professorial heads of independent research groups and
clinical units, and recipients of prestigious NHMRC and ARC Fellowships.
Colon Cancer Genetics and Biology Group These two major findings have provided many
How can an arthritis drug cause colon cancer in the different avenues for further research. The projects
mouse? Dissecting the origins of carcinogenesis. can be tailored to suit the expertise and interests of
the PhD candidate - ranging from cell culture
Project 1 models to sulindac and the knockout mouse.
We have made the unexpected discovery that an
arthritis drug sulindac that is also used to prevent Supervisor: A/Prof Maija Kohonen-Corish
colon cancer in people with high-risk genes, can Colon Cancer Genetics and Biology Group
actually cause cancer in the mouse. Sulindac has E: m.corish@garvan.org.au
opposite effects in different parts of the mouse T: 02 9295 8336
colon - either preventing or causing cancer. We
References
have shown that sulindac triggers a molecular 1. Kohonen-Corish MR, Sigglekow ND, et al 2007. Promoter
pathway in the mouse that may be informative for methylation of the mutated in colorectal cancer gene is a frequent
understanding 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 NSAID
Project 2 Sulindac is chemopreventive in the mouse distal colon but
We 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 in
the development - and potentially treatment - of colorectal cancer' (MCC) is a novel target of the UV-induced DNA
damage response. Genes & Cancer 1:917-926
colon cancer. We have identified new biological
functions for this gene, including a role in the DNA
damage response. We now want to pursue these
functions further in a model that is relevant for the
disease in humans, our newly engineered MCC
knockout mouse, which allows us to determine the
factors that are important in initiating and
promoting cancer.
02 CANCER RESEARCH PROGRAM

5. Ovarian Cancer Group Project 2
Ovarian cancer is the most lethal gynaecological Effect of cMET pathway and its inhibitor INC280
cancer. Every year in Australia, approximately 1200 in ovarian cancer.
women are diagnosed with ovarian cancer and 800
women die from the disease. The poor prognosis for cMet, a receptor tyrosine Kinase, and its ligand
women with ovarian cancer is mainly due to an HGF are both mis-regulated in ovarian cancer, with
inability 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 enhance
ovarian cancers are diagnosed at an advanced cell migration, adhesion and proliferation in cancer
stage, when the 5-year survival rate is 20%. In cells. Inhibitors of receptor tyrosine kinases
addition, this poor prognosis is due in part to the (including cMET) have been shown to be effective
development of chemotherapy resistance in women against ovarian cancer, thereby making it
following surgery and several rounds of treatment. imperative to examine new therapeutic agents
The Ovarian Cancer Research Group at the Garvan such as INC280. We hypothesize that targeting
Institute 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
References
Available projects include: 1. Samimi, G., B. Z. Ring, et al. (2012). "TLE3 Expression Is
Associated with Sensitivity to Taxane Treatment in Ovarian
Project 1 Carcinoma." Cancer Epidemiol Biomarkers Prev 21(2): 273-279.
2. Montavon, C., B. S. Gloss, et al. (2012). "Prognostic and
Evaluation of TLE as a biomarker for response to diagnostic significance of DNA methylation patterns in high grade
taxane-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 stromal
surgery 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 predictive
respond to this regimen, 75% of treated women for outcome in advanced ovarian cancer identifies a survival
eventually relapse. Thus it is imperative that we factor: microfibril-associated glycoprotein 2." Cancer Cell 16(6):
521-532.
identify biomarkers that can predict women who
are likely to respond to treatment, thereby
significantly improving patient management. We
have demonstrated that transducin-like enhancer of
split 3 (TLE3) expression is associated with
progression-free survival in taxane-treated ovarian
cancer patients. In our study, TLE3 expression was
associated with a favourable outcome only in
patients who had received a taxane as part of their
treatment regimen. These findings warrant an
independent evaluation of TLE3 as a potential
therapeutic response marker for taxane-based
chemotherapy in ovarian cancer. Studies are also
necessary to determine whether and by what
mechanisms TLE3 may serve as a functionally-
based biomarker in determining response.
CANCER RESEARCH PROGRAM 03

6. Tyrosine Kinase Signalling Networks in Examples of PhD projects available within the Signal
Transduction Group are:
Human Cancers
Tyrosine kinases function in key signalling pathways
Project 1
regulating fundamental cellular processes such as
characterisation of how the cellular 'kinome' is
proliferation, survival, metabolism and motility.
regulated by the proto-oncogene Src in basal
Importantly, aberrant signalling by these proteins
breast cancer cells.
underpins many human cancers, and tyrosine
kinases represent major targets for drug
We have recently identified that a particularly
development. Research in my group is aimed at
aggressive form of breast cancer, termed basal
characterising tyrosine Kinase signalling mechanisms
breast cancer, exhibits a prominent Src-regulated
and 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 in
Recent developments in mass spectrometry-based
basal breast cancer cells.
proteomics, coupled with affinity-based enrichment
strategies, now allow 'global' characterisation of
Project 2
particular types of intracellular signalling event, such
Identification of 'sensitizers' to Src inhibitors in
as tyrosine phosphorylation. In other words, we can
basal breast cancer.
identify and quantitate all of the signalling events
happening in a cell at any given point in time. In
Despite the presence of a prominent Src signalling
addition, they enable the majority of kinases
network in basal breast cancer cells, Src Kinase
expressed by the cell (the 'kinome') to be co-
inhibitors exert only modest effects on these cells in
ordinately 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 functional
allow us to obtain global 'snapshots' of signalling in
screen of the human 'druggable' genome in order to
particular types of cancer cell, and importantly,
identify genes whose knockdown sensitizes basal
compare cell types, such as normal and cancer cells,
breast cancer cells to Src Kinase inhibitors, thereby
or drug-sensitive and -resistant cells. My group has
identifying candidate combination therapies for this
established these technology platforms and is
disease subtype.
currently using them to address key questions in
cancer cell signalling research, such as:
Project 3
characterisation of the signalling networks that
Identification of kinases and signalling proteins that
distinguish different breast cancer subgroups;
mediate prostate cancer metastasis.
whether pancreatic cancer can be subclassified
based on tyrosine phosphorylation patterns; and
It is possible to grow primary human prostate
whether changes in cellular signalling networks can
cancers as tumours in mice (xenografts). We have
identify markers and mediators of therapeutic
access to xenografts that differ in their ability to
responsiveness, such as to docetaxel in prostate
spread (metastasize). Quantitative MS-based
cancer. In order to functionally interrogate the large
proteomics will be used to screen these xenografts
numbers of kinases and signalling proteins identified
in order to identify signalling proteins that mediate
by these approaches, we are also implementing
cancer metastasis.
siRNA screens that characterise the roles of
identified candidates in regulation of cell
Supervisor: Professor Roger Daly
proliferation and migration.
Signal Transduction Group
E: r.daly@garvan.org.au
T: 02 9295 8333
04 CANCER RESEARCH PROGRAM

7. Mitotic Control Group Pancreatic Carcinogenesis Group
The Mitotic Control Group sits within the Cell Cycle Pancreatic Cancer is the fourth leading cause of
group (Prof. Liz Musgrove) of the Garvan's Cancer cancer death in our society. Almost 90% of the
Research 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 which
we demonstrated that correct mitotic progression preneoplastic lesions are present.
was dependent on maintaining a tightly regulated
balance between the activities of the phosphatase The Pancreatic Carcinogenesis team is focused on
PP2A, and Kinase CDK1 [1,2]. Further, we identified identifying key drivers and biomarkers of
the novel mitotic Kinase Greatwall as the master pancreatic cancer through studying the earliest
regulator of this balance [3,4]. These results changes in exocrine cell differentiation and
dramatically altered our understanding of mitosis proliferation using pancreas specific models (in
and opened up several new and exciting research vitro and in vivo).
pathways. The primary aim of the lab is to further
explore and characterise these pathways, to identify The Pancreatic Carcinogenesis group sits within
new 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 the
Project 1 International Cancer Genome Consortium
Mapping the Human Mitotic Exit Pathway. (www.icgc.org). The APGI aims to fully
During mitotic exit certain CDK1 substrates need to characterise the genomic, epigenomic and
remain phosphorylated while others must be transcriptomic aberrations in tumor samples of
dephosphorylated to ensure the highly ordered pancreatic cancer patients using the latest next
events of mitotic exit occur in the correct sequence. generation sequencing technologies. As such, the
However, currently very little is known about how APGI provides a unique resource to investigate
this order of dephosphorylation is achieved in molecular mechanisms involved in pancreatic
mammalian cells. This project aims to identify the carcinogenesis, to eventually reveal new targets
order 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, advanced
biochemistry 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 1
may identify novel targets for future chemotherapies. Investigating the expression and the role of
candidate gene aberrations identified by APGI in
Project 2 models of early pancreatic cancer; genetically
Preventing 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 to
target mitosis as a means of selectively killing
define the functional consequences and molecular
cancer cells. Unfortunately, many cancer cells are
mechanisms of these novel gene aberrations in
resistant to these drugs. Furthermore, it is very
model systems of early pancreatic cancer.
difficult to currently predict which cancers will be
sensitive or resistant. This project aims to identify a
Project 2
common signature of proteins that promote and
Investigating ENU-induced mutagenesis mouse
inhibit mitosis and determine if these can be used to
models, including forward screens to identify new
predict response, and if subsequent targeting of
genes that can impact on exocrine pancreas cell
these proteins improves current chemotherapies.
differentiation and proliferation and reverse
This project will utilise multiple cancer cell line
screens where the effects of a known mutation in
models, immunohistochemistry, and advanced live-
a gene of our interest (as identified by APGI) are
cell imaging. The outcomes will hopefully provide a
further investigated for a contribution to
critical predictive tool and help further our
pancreatic carcinogenesis.
understanding of why cancer cells are sensitive or
resistant to mitotic poisons.
Supervisor: Dr. Ilse Rooman
References Pancreatic Carcinogenesis Group
1. Burgess A et al. (2010), Proc Natl Acad Sci USA 107: 12564-12569.
E: i.rooman@garvan.org.au
2. 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 8372
4. Vigneron S, et al. (2009) EMBO J 28: 2786-2793.
Supervisor: Dr Andrew Burgess
Mitotic Control Group
E: a.burgess@garvan.org.au
T: 02 9295 8327
CANCER RESEARCH PROGRAM 05

8. Epigenetic Laboratory Cancer Program Overall Aim
To integrate chromatin modification marks, DNA
Project 1 methylation and RNA expression across the genome
Modelling epigenomic change during early breast in order to investigate the relationship between
carcinogenesis using in vitro and in vivo model changes in the epigenomic landscape and the
systems. biology of early breast cancer.
Epigenetic deregulation is an early and crucial event Aim 1: Epigenome Profiling
in carcinogenesis so at diagnosis, tumours already To utilise our in vitro and in vivo HMEC model
contain many genetic and epigenetic aberrations. systems of early breast cancer to further develop
Therefore, identifying the early epigenetic changes and generate epigenome maps of early breast cancer.
in cancer is challenging, as it is difficult to separate
the drivers of carcinogenesis from epigenetic lesions Aim 2: Integration
that are secondary passengers of carcinogenesis. To To integrate epigenomic and transcriptional maps of
identify early epigenetic lesions in malignancy, our pre- and post-selection cells in the in vitro and in
laboratory is exploiting a Human Mammary vivo HMEC systems to identify epigenetic
Epithelial Cell (HMEC) culture system as an in vitro modifications and biological (regulatory) pathways
model 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, unlike
other normal cells, HMECs are able to overcome Aim 3: Prediction
this replicative barrier and enter into a second To utilise our newly acquired understanding of
exponential growth phase. Cells from this second epigenetic remodelling in the HMEC system and its
phase exhibit a much more aggressive phenotype role in driving early tumourigenesis from Aims 1 and
and these post-selection cells are considered to 2 for prediction of early methylation changes as
share features with pre-malignant basal breast biomarkers of breast cancer.
cancer cells. Recently, we have extend this in vitro
model to an in vivo mouse model system that can PhD Project
generate abnormal breast lesions that mimic human We seek a motivated PhD candidate to be actively
ductal carcinoma in situ (DCIS). In this PhD project, involved in generation and analysis of epigenetic
we intend to utilise the in vitro and in vivo HMEC maps. The project can be tailored to the interests
systems to deliver a detailed and integrated and/or strengths of the candidate. For more
epigenomic map of very early breast cancer. We Bioinformatically oriented candidates there is an
will use these maps to identify potential early excellent opportunity to be involved in developing
biomarkers for breast cancer detection, and to of new techniques for processing and integration of
derive new understanding of the biology and next generation sequencing data.
sequential epigenetic events that occur in early
References
breast 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 crucial
event in breast carcinogenesis and epigenetic
Supervisor: Prof Susan Clark
aberrations occurring early during pre-malignancy
Co Supervisor: Dr Elena Zotenko
shape the fate of the cancer epigenome and
E: s.clark@garvan.org.au
subsequent cancer phenotype.
T: 02 9295 8315
06 CANCER RESEARCH PROGRAM

9. Project 2
Epigenetic mechanism: how does aberrant
acetylation of the histone variant H2A.Z drive
gene activation in cancer?
Epigenetic gene regulation is important in normal
cell growth and differentiation and is commonly
deregulated in many diseases, including cancer.
Epigenetic processes include DNA methylation,
post-translational histone modification, exchange of
histone variants and alterations in nucleosome
positioning. Our laboratory is interested in the role
of histone variants in deregulation of gene
Aim 2: Identify the molecular machinery involved
transcription in cancer cells, as the mechanisms
in acetylation of H2A.Z.
associated with exchange and post-translational
modification of histone variants are still unclear.
We will perform mass spectrometry assays to
H2A.Z is an evolutionarily conserved H2A histone
identify the complexes bound to acH2A.Z before
variant. We recently reported for the first time that
and after androgen treatment. This approach will
the acetylation of H2A.Z (acH2A.Z) is associated
allow us to identify the factors involved in H2A.Z
with gene deregulation in prostate cancer; activated
acetylation. We will then perform knock down
oncogenes gain acH2A.Z and down-regulated
experiments to down-regulate these factors and
tumour suppressor genes lose acH2A.Z at the
assay the changes in gene expression and H2A.Z
transcription start site (TSS). This exciting discovery
acetylation. These studies will identify the
provides an entirely new dimension to the “histone
complexes responsible for promoting acetylation
code”. We hypothesize that acetylation of H2A.Z is
of H2A.Z.
an important chromatin modification that drives
active transcription in normal cells but aberrant
Aim 3: Determine if acetylation of H2A.Z alters
H2A.Z acetylation leads to transcriptional
nucleosome occupancy.
deregulation in cancer. There are however many
unresolved and key questions concerning the
Changes in genome-wide nucleosome occupancy
mechanism of how H2A.Z acetylation promotes
by acH2A.Z will be analysed by an innovative
gene activation. The PhD project will address the
approach where we will combine two state of the
following questions, (1) Is H2A.Z acetylation a
art techniques: gNOMe-seq assay2 [AI: Prof
cause or consequence of gene activation? 2) What
Jones] and ChIP-seq. This technique will allow us
is the mammalian enzyme(s) responsible for H2A.Z
to directly interrogate the nucleosomes containing
acetylation? 3) Does H2A.Z acetylation alter
acH2A.Z to detect changes in nucleosome
nucleosome positioning?
localisation upon androgen treatment. This approach
will address how acH2A.Z affects the chromatin
Overall Aim
structure by altering promoter nucleosome
To understand how acetylation of H2A.Z regulates
positioning to activate gene transcription.
gene activation in cancer.
Significance and outcome: The project will address
Aim 1: Determine how acetylation of H2A.Z
for the first time the mechanism that promotes
changes gene transcription.
acetylation of H2A.Z and its role in gene
activation. The outcome will directly determine if
To identify if acetylation of H2A.Z directly promotes
H2A.Z acetylation is a key epigenetic regulator of
or is a consequence of gene activation using LNCaP
gene transcription in cancer, and will identify the
prostate cancer cells treated with androgens as a
molecular targets that control acH2A.Z activity.
model system of cancer gene activation. Using
ChIP-seq we will study the genome-wide
Supervisor: Prof Susan Clark
alterations in H2A.Z/acH2A.Z occupancy and gene
Co Supervisor: Dr Fatima Valdes-Mora
expression upon androgen treatment. We will
E: s.clark@garvan.org.au
address whether transcriptional changes occur after
T: 02 9295 8315
over- or under-expressing H2A.Z and/or acH2A.Z
to determine the temporal and sequential molecular References
events 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 unresolved
mechanistic role of acH2A.Z in promoting
regulation of gene expression.
CANCER RESEARCH PROGRAM 07

10. Project 3 Aim 2: To map epigenetic modifier-mediated
Establishing the importance of enhancer epigenetic enhancer/promoter interactions.
reprogramming and atypical long-range
interactions in cancer cells. The structure of the genome is three-dimensional
and complex interactions ensure that the correct
Cancer is extraordinarily complex and the result of gene expression patterns are established and
widespread genetic and epigenetic reprogramming. maintained. Using an innovative technology
The phenomenon of epigenetic reprogramming (Chromatin Interactions by Paired End Tag
(atypical silencing and activation achieved through Sequencing; ChIA-PET) we will delineate how
altered patterns of DNA methylation, histone enhancers and promoters interact through
composition, histone modifications and nucleosome epigenetic modifiers, RAD21 (cohesin, facilitates
positions) at gene promoters is a hallmark of cancer looping) and CTCF (blocks interactions), in normal
cells, as we previously described. However, our and cancer cells. We will produce long-range
existing knowledge is compartmentalised and does interaction maps for normal and prostate cancer
not yet adequately extend beyond promoters cells and address how DNA looping networks may
despite increasing evidence that suggests that the be disrupted.
transcriptional profile of a cell is equally determined
by the activity of distal regulatory elements (eg. Aim 3: To define functional roles of epigenetic
enhancers and insulators). Exciting data from our modifiers in enhancer/promoter interactions.
most recent work has challenged the views of the
field; that is, enhancers with an unexpectedly We propose that in cancer cells, atypical
“active” epigenetic signature can regulate enhancer/promoter interactions are directed by
transcriptionally repressed promoters. We found aberrant DNA methylation or binding of key DNA
that the purpose of such enhancers was to ensure modifying proteins. RAD21, CTCF and DNA
the correct tissue-specific gene expression methyltransferases are all disrupted in cancer.
patterns, whilst retaining epigenetic flexibility that Therefore, we will manipulate their expression in
allows 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 structural
rendered resistant to reprogramming when organisation of chromatin (gNOMe-seq). At
enhancers are epigenetically silenced. completion, we will understand how RAD21, CTCF
and DNMTs contribute to atypical long-range
In this new PhD study, we emphasise the necessary interactions characteristic of cancer cells.
and dynamic functions of enhancers; raising the
possibility that epigenetic reprogramming of distal Supervisor: Prof Susan Clark
regulatory elements could contribute to cancer Co Supervisor: Dr Phillippa Taberlay
establishment and progression. We hypothesize that E: s.clark@garvan.org.au
epigenetic reprogramming alters the three- T: 02 9295 8315
dimensional structure of the chromatin:DNA
complex. Imminent interest in distal regulatory References
1. Coolen, M.W. et al Clark SJ. Nature cell biology 12, 235-46
elements 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 enhancer
epigenetic reprogramming in cancer cells.
We will investigate the extent to which enhancer
epigenetic reprogramming occurs genome-wide in
prostate cancer compared to normal prostate
epithelial cells. At completion, we will understand
how epigenetic reprogramming pertains to distal
regulatory elements in cancer.
08 CANCER RESEARCH PROGRAM

11. Project 4 Overall Aim
Role of epigenetic modifiers MBD2 and TET proteins To understand the role of MBD2 and TET2&3
in 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 MBD2
hypomethylation of gene promoters (including in promoting DNA methylation and/or its loss in
oncogenes) and repeat DNA sequences. While the promoting demethylation and transcriptional
vast 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 of
methylated state. Critical, yet unanswered questions TET2&3 in promoting 5hmC and potential DNA
in cancer biology remain regarding the balance of demethylation and its aberrant function in
hyper- and hypo-methylation in normal and cancer transcriptional deregulation in cancer.
cells and the potential role that CpG binding
proteins play in controlling the DNA methylation Aim 3: To identify potential binding partners of
landscape. We previously developed an in vitro MBD2 and TET2&3 and the associated complexes
prostate cancer cell model system, where we which determine differential specificity.
showed that the methyl binding domain protein
MBD2 plays a critical role in aberrant de novo DNA Outcome and significance
methylation and that gene silencing precedes The findings from this project will have a major
epigenetic remodelling. We now have significant impact on understanding the key steps involved in
new data showing that loss of MBD2 promotes both de novo DNA methylation and demethylation
DNA demethylation. The mechanisms leading to in cancer and will demonstrate sets of genes that
DNA demethylation are still hotly debated, but are coordinately deregulated in cancer. These new
recently a new family of TET proteins that understandings may provide routes to use MBD2
enzymatically convert 5-methylcytosines (5mC) to and/or TET proteins as pharmalogical targets in
5-hydroxymethylcytosines (5hmC) has been cancer treatment.
characterised. Hydroxy-methylation of cytosine
residues may be a critical facilitator of DNA Supervisor: Prof Susan Clark
demethylation, and regulation of DNA methylation Co Supervisor: Dr Clare Stirzaker
fidelity. Of particular interest, is that both MBD2 E: s.clark@garvan.org.au
and TET proteins share similar DNA binding domains T: 02 9295 8315
and preferentially bind CpG sites in CpG islands.
References
1. Song, J. Z.; Stirzaker, C.; et al Clark, S. J., Oncogene 2002, 21, (7),
Hypothesis 1048-61
In a normal cell there is a dynamic balance between 2. Stirzaker, C et al Clark, S. J., Cancer Res 2004, 64, (11), 3871-7
MBD2-mediated de novo methylation and TET-
mediated demethylation at CpG islands to ensure
that the methylation state of CpG islands are
faithfully maintained. We propose that in cancer, this
balance is disrupted, due to the potential differential
binding of these factors or factor-associated
complexes, promoting alterations in DNA
methylation, epigenetic instability and changes in
gene expression.
CANCER RESEARCH PROGRAM 09

12. 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 generate
Project 5 comprehensive catalogues of genomic,
Integrated methods for the analysis of genomic transcriptomic and epigenomic changes in multiple
and epigenomic data. different tumour types. In collaboration with
Pancreatic Cancer group (Prof. Andrew Biankin) and
Epigenetics Signal Transduction group (Prof. Roger Daly) within
Genetics is the study of the DNA sequence and how Garvan, and Prof. Sean Grimmond's group at
it effects gene expression and function. Epigenetics University of Queensland's Institute for Molecular
is the study of how gene expression is controlled Bioscience, we have the chance to integrate the
independently of the DNA sequence through pre-processed data at multiple molecular level for
chemical modifications such as DNA methylation, ~400 individual pancreatic cancers (ongoing)
chromatin modifications and expression of ncRNAs. including somatic mutations, copy number
This area of biological research is rapidly growing. abberations, methylation sites, mRNA expression,
Extremely large quantities of data are being protein expression and phosphorylation. Although a
generated daily, presenting new computing and preliminary version of an in-house integrating
analysis challenges that require strong analytical platform (InterOmics) has been developed to
skills. Additionally, over the course of the last few automate the analysis and facilitate hypotheses
years it has become increasingly apparent that no generation, we need to improve the platform by
single (epi)genomic experiment will provide answers including multiple significant important new
to all biological and clinical questions. One of the functions on data annotation, data query, data
major challenges facing biologists and computational mining and user interface. This platform will be also
scientists is to integrate the knowledge from useful to quickly integrate and analyze the publicly
various genomic and epigenomic experimental available data from other ICGC and TCGA projects.
approaches in order to gain insight into the biological
mechanisms that underlie complex diseases. Project 2
Protein-protein interaction network analysis.
(Epi)Genomic Data Integration
Our research concerns the development and use of We have previously developed a Protein Interaction
novel statistical and bioinformatics methods in order Network Analysis (PINA) platform, which is a
to gain a better understanding of the factors comprehensive web resource, including a database
involved in disease. Projects would involve of unified protein-protein interaction data integrated
developing new methods for the initial processing from six manually curated public databases, and a
and 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 of
are interested in investigating new statistical and protein interactions at a network level, by including
bioinformatics approaches to analyse the data multiple collections of interaction modules identified
generated at each stage of a genomic or epigenomic by different clustering approaches from the whole
experiment and the integration of several layers of network of protein interactions ('interactome') for
regulatory data with clinical information. six model organisms. There are still many interesting
problems left including: 1) Utilising protein-protein
Supervisor: Dr Nicola Armstrong interaction network and pathway model to help the
E: 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 8326
10 CANCER RESEARCH PROGRAM

13. A/Prof Robert Brink The work of the research team at the Garvan Immunology Program is divided between studying how a
Immunology Research Program
Leader
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: 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 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.phan@garvan.org.au
T: 02 9295 8414
IMMUNOLOGY RESEARCH PROGRAM 11

14. 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 mortality
The role of subcapsular sinus (SCS) macrophages rate of ~33-50% with intensive support including
in LN melanoma metastases. liver transplantation. The commonest cause in
Australia is paracetamol overdose. Other causes
The primary function of the lymph node (LN) is to include alcohol, drug reactions, surgery and sepsis.
filter the lymph to trap and degrade any pathogens
and cancer cells that may have infiltrated the host With the exception of N-acetyl cysteine, there are
organism. Afferent lymph enters the SCS which no proven therapies. Many treatments including
forms an anatomical and functional barrier to the corticosteroids, heparin, insulin, glucagon, blood or
free diffusion of lymph borne particles. This barrier plasma exchange and prostaglandins have been
is formed by lymphatic endothelial cells and tissue- trialled without success. A therapy that diminishes
resident macrophages that express the sialic acid- hepatocyte death or enhances replacement through
binding C-type lectin CD169 (sialoadhesin). Lymph regeneration is highly desirable. This project will
then reaches the medullary sinuses which is also work on a novel therapeutic target which our
lined by lymphatic endothelial cells and CD169+ preliminary data demonstrates is important for
macrophages where the bulk of lymph-borne hepatocyte survival, and liver outcomes.
soluble and particulate antigen is trapped and Project 2
catabolised. Cancer cells must therefore cross this Calcium flux and beta-cell function in diabetes.
lymph-tissue interface in order to invade the
underlying parenchyma. While interest has focussed Diabetes is increasingly common in Australia and
on the molecular steps involved in oncogenesis and worldwide, and it is associated with increased risks
tissue invasion, there has been surprisingly little of heart disease, stroke, blindness, end stage kidney
research on the steps involved in the establishment failure and amputations. Increased blood sugar
of metastatic cancer cells once they reach the LN. levels arise when the pancreatic beta-cells are no
The project will therefore use genetic and longer able to compensate for the prevailing degree
pharmacological 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 which
an in vivo mouse model. These studies will involve influence beta-cell function, using a variety of
intravital two-photon microscopy and direct mouse models, and human pancreatic islets. This
intralymphatic injection of cancer cells to monitor project will examine the role of a specific factor in
their interactions with CD169+ SCS macrophages beta-cell function and diabetes.
in real-time. They will provide a molecular basis for
Project 3
understanding the earliest steps in LN metastases
Brown fat and obesity therapy.
and drive the development of novel therapeutic
strategies to prevent LN metastases not only in Over half of the Australian population is now
melanoma but other cancers. overweight or obese. Current treatments for
obesity are minimally effective, work only
Supervisor: Dr Tri Phan temporarily or have serious side effects. Brown fat
E: t.phan@garvan.org.au is an important type of fat which consumes calories
T: 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 8433
12 IMMUNOLOGY RESEARCH PROGRAM

15. Prof David James Obesity is a major risk factor for many other diseases including diabetes, cardiovascular disease, Parkinson's
Diabetes and Obesity Research
Program 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

16. Regulation of Body Composition &
Glucose Homeostasis by the Adaptor
Protein Grb10
An important risk factor for Type 2 diabetes is the
development of insulin resistance. Many factors
contribute to insulin resistance including the
decrease in muscle mass associated with reduced
physical activity and ageing. Consequently,
understanding how the signalling pathways involved
in insulin action and maintenance of muscle mass
are regulated is of major significance. We are focusing
on two adapter-type signalling proteins, Grb10 and
Grb14, which bind directly to the insulin receptor. Beta Cell Replacement Therapy
The common forms of diabetes are characterised by
We have recently demonstrated that Grb10 gene the destruction (type 1) or an insufficiency (type
knock-out mice exhibit increased insulin signalling in 2) of insulin secreting pancreatic beta cells. We are
skeletal muscle and adipose tissue. Furthermore, taking an interdisciplinary approach to devise novel
Grb10-/- mice also display increased skeletal muscle strategies for beta cell replacement therapy. Our
mass and reduced adipose tissue content. primary experimental system is the zebrafish
embryo, a model that is at the intersection of
Since these mice have 'global' Grb10 ablation (ie genetic and pharmacological research.
Grb10 is absent from all tissues) it is unclear
whether Grb10 has roles in both muscle and Project 1
adipose 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 developmental
addition, if Grb10 is to be targeted therapeutically, biology to use the abundant pancreatic acinar cell
it is important to determine whether the beneficial type as a source of progenitors for beta cell
effects of ablating Grb10 require the absence of regeneration. We have established an in vivo model
Grb10 during development, or whether they can be to induce acinar cell reprogramming and track the
achieved via more 'acute' ablation of this adaptor in fate of the cells as they transition to insulin
adult mice. producing beta cells. This project will focus on
increasing the efficiency and specificity of cellular
To address these issues we will utilise a conditional reprogramming. We are particularly interested in
Grb10 allele (Grb10fl/fl) to determine how Grb10 developing a protocol that is responsive to the
ablation 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 2
expressing Cre recombinase, or tamoxifen-regulated In vivo drug screening.
Cre, in muscle or adipose. This will enable us to
'knock-out' Grb10 expression in muscle and adipose Traditional drug screens have targeted single
throughout development and adulthood, or molecules or cell types. While the targets are often
alternatively 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 the
gene deletion). The resulting strains will be poor success rate for new drugs in recent years. We
characterised for their muscle, fat and metabolic have developed a number of transgenic models that
phenotypes, as well as for effects on signalling by allow us to monitor metabolic parameters in intact
insulin and other hormones/growth factors. This will embryos (glycemia, beta cell mass, etc.) to help
determine whether the effects on body identify the next generation of antidiabetic drugs.
composition in Grb10-/- mice reflect autonomous Projects in this area would include assay
roles for Grb10 in muscle and/or adipose, and development and screening as well as mechanistic
whether an increase in relative lean mass and analysis of hits that we have previously discovered.
improvement in glucose homeostasis can be Selected Publications
achieved 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) Loss
Obesity 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 8258
14 DIABETES & OBESITY PROGRAM

17. Cooper Group - Neurodegeneration, Preventing Parkinson's disease inter-neuronal
progression/spread. Synuclein is a central
Cell & 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 degenerating
degenerative neurological disorder that currently
neuron into neighbouring healthy neurons and
afflicts >6 million people worldwide and is predicted
trigger their degeneration.
to rapidly increase by 50% in the next 20 years as
our population ages. Although predominantly
Discover the role of mitochondrial dysfunction in
considered a movement disorder, people with PD
Parkinson's disease. Mitochondrial dysfunction has
also experience significant non-motor symptoms
long been observed in Parkinson's disease and we
including sleep disturbances, olfactory dysfunction,
are investigating how mitochondrial dysfunction
autonomic dysfunction and changes in cognition.
contributes to neurodegeneration.
Much earlier diagnosis and new treatments are
critically 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 Parkinson's disease.
time of diagnosis (ii) there is no cure and current
Tremendous advances in NextGen sequencing
therapies are only partially effective at treating
allow the interrogation of whole genome RNA
some of the symptoms, while progression and
transcripts from PD affected regions of the brain.
spread of the disease continues. The lack of
knowledge of the underlying mechanisms
Identify the role of PARK9, autophagy & lysosomal
responsible for causing PD and its progression is the
dysfunction in Parkinson's disease. Dysfunction in
major impediment to therapeutic advances. To
cellular proteostasis is a core contributor to PD
achieve earlier diagnoses and development of
and the impairment of these components are a
treatments and drugs, our research centres on
rapidly emerging field in Parkinson's Disease
discovering the cascade of events causing the loss
research.
of neurons in Parkinsons Disease.
Selected recent publications
Our research projects utilise a wide range of 1. Gitler et al. “Alpha-synuclein is part of a diverse and highly
approaches including genome-wide screening, Next conserved interaction network that includes PARK9 and
manganese toxicity.” Nat Genet. 41:308-15 (2009). Impact
Generation sequencing, bioinformatics, cell and Factor = 25
molecular biology techniques, fluorescence 2. Cooper et al “Alpha-synuclein blocks ER-Golgi traffic and Rab1
microscopy, qRT-PCR, lipodomics, proteomics, rescues neuron loss in Parkinson's models.” Science. 313:324-8.
2006. Impact Factor = 31
metabolomics, siRNA knockdown, gene knockouts,
FACS analysis, cell culture, primary neurons, transgenic Supervisor: A/Prof Antony Cooper
mice models and human PD patient brain samples. E: a.cooper@garvan.org.au
T: 02 9295 8238
Identifying the underlying molecular mechanism(s)
of Parkinson's Disease. Whole genome functional
screening approaches in relevant PD models have
identified defects in major cellular signaling
pathways. These will be validated using a broad
array of genetic, cell and molecular approaches to
both confirm their association with PD and identify
the underlying molecular mechanism(s) prior to
testing in human brain samples.
DIABETES & OBESITY PROGRAM 15

18. The Garvan Neuroscience program is an active, collaborative research community that investigates how the Prof Herbert Herzog
Neuroscience Research Program
brain functions. Research undertaken by the Program looks at the brain at many different levels, from genes Leader
and molecules to synapses, neurons, brain regions and behaviour. A wide range of models from flies, mouse
to humans and state-of-the-art molecular and biochemical techniques are employed to address both basic
and medically relevant problems in neuroscience. The Program's goal is to understand how the brain works
and to improve understanding, diagnosis, and ultimately develop novel therapies for neurological disorders.
We are particularly interested in conditions like Parkinson's Disease, Alzheimer's Disease and general
conditions of dementia in which the natural ability of the brain to regenerate itself (via neuro-stem cells) is
compromised. Furthermore, we investigate the role of the nervous system in pain perception as well as how
the 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 Australian
Postgraduate Awards or NHMRC scholarships, and have received numerous presentation awards and travel
fellowships 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) further
Project investigate the mechanism by which NPFF system
Novel Neuropeptide Regulators of Energy regulates energy homeostasis; and 2) to investigate
Homeostasis. how the NPFF and NPY systems interact in these
regulations. To achieve this, we will examine aspects
The worldwide prevalence of obesity is increasing at of energy homeostasis and factors in controlling
alarming rate, and is a major risk factor for type 2 them in multiple mouse models where either or
diabetes and other diseases. Although the benefits both NPFF and NPY system have been genetically
of losing excess weight are undisputed, there altered. Such mouse models include mice with NPFF
currently exists no effective non-surgical treatment overexpression by delivering the NPFF-containing
for obesity. Body weight and body composition such adeno-associated viral vector to the adult mouse
as fat tissue mass are regulated by an interactive brain, germline NPFF2R knockout mice, and mice
complex of energy homeostatic system. Thus to with adult-onset specific deletion of NPFF2R from
meet the urgent and desperate need for the NPY neurons. By Utilising cutting edge
development of novel pharmacological tools for internationally competitive technology and unique
treating obesity, researchers need not only to know germline and conditional knockout and transgenic
the identity and functions of individual molecules mouse models, this project will make highly original
and pathways involved in the regulation of energy and high-impact contributions to the understanding
homeostasis, but also to understand how these of the role of NPFF system in energy homeostasis
molecules and pathways interact. Among these, and its interactions with the NPY pathway, and will
neuropeptide Y (NPY), - one of the most widely demonstrate whether targeting NPFF2R could
expressed 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 publication
ad adiposity via its control on every aspects of Zhang L et al. The neuropeptide Y system: Pathological and
energy homeostasis, such as appetite, energy implications in obesity and cancer. Pharmacol Ther. 2011
expenditure, physical activity and fuel partitioning 1. Jul:131(1):91-113.
Recently, our unpublished studies show that
neuropeptide FF and NPFF receptor 2 (NPFF2R) are Supervisor: Prof Herbert Herzog
the novel players in the energy homeostatic Co-Supervisor: Dr Lei Zhang and
complex. Interestingly, our preliminary results E: h.herzog@garvan.org.au
suggest that NPFF system may exert its control on T: 02 9295 8296
16 NEUROSCIENCE PROGRAM

19. Major techniques involved in this project examination, cell cultures, quantitative real time-
Indirect calorimetry, infrared imaging, stereotactic PCR and Western blotting, to determine the key
brain injection, oral glucose tolerance test, regulators of thermogenesis and mitochondrial
intraperitoneal insulin test, dual-energy X-ray function and mechanistic central pathways
absorptiometry, tissue dissection, in situ possibly involved. All of the mouse models,
hybridyzation, Western blotting, methods and experimental paradigms are well
immunohistochemistry, various serum assays. established in our laboratory as demonstrated by
our extensive publication record on these topics in
Project highly ranked journals like Nature Medicine and
Altering Thermogenesis as Weight-loss Strategy. Cell Metabolism (1,2,3,4,5).
Obesity-associated cardiovascular diseases and Results from this study will provide critical new
diabetes are leading causes of death and are insights on NPY's role in the control of BAT-
expected to increase as the obesity epidemic mediated energy expenditure. These results will
worsens. Current weight-loss therapies mainly also provide valuable contributions to the
target reduction of energy intake, providing only a development of potential therapeutics to increase
transient or partial solution with limited energy expenditure, likely being a more effective
effectiveness. Alternatives are needed to combat way for the treatment of obesity.
this problem and one potential promising approach
is 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 are
equation, 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 for
promising yet underexplored area. Whilst previously Acylethanolamine Receptor Gpr119-Induced Activation of
Gastrointestinal Mucosal Responses. Cell Metab. 2010 Jun
believed 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 bone
abundance of functional BAT in adult humans has homeostasis in mice. PloS ONE. 2010;5(6):e11361
been recently confirmed to be widespread by 5. Shi YC, Lin S, et al. Peripheral-specific Y2 receptor knockdown
positron emission tomography (PET) marking it a protects mice from high-fat-induced obesity. Obesity. 2011 Nov;
19(11): 2137-48
promising target for anti-obesity therapy. However,
little is known about the control of BAT activity and
Supervisors: Dr Shu Lin
function. BAT is the main tissue that harbours
Co- Supervisor: Dr Yan Shi
uncoupling protein 1 (UCP1), the major component
E: s.lin@garvan.org.au
that is responsible for mediating metabolic
T: 02 9295 8291
thermogenesis. Our preliminary data demonstrates
that elevated neuropeptide Y (NPY) levels
Project
specifically in the arcuate nucleus (ARC) of the
Insulin Action in the Brain.
hypothalamus, which is known to be a major driver
for marked reductions in energy expenditure, also
The prevalence of obesity has reached epidemic
influences UCP1 expression in the BAT.
levels and is further increasing at an alarming rate.
Currently there are no effective therapeutic
We thus aim to investigate the specific role of the
treatments for obesity, however it is generally
NPY system in integrating hypothalamic functions
recognised that any treatment must be associated
with energy expenditure specifically focusing on BAT
with a reduction in energy intake, an increase in
activity. 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 system
neuron-type specific conditional deletion or over-
coordinates information to regulate energy balance
expression of NPY in an inducible adult-onset
is important for understanding the pathology of
fashion. A wide range of laboratory techniques will
obesity as well as for designing treatments to
be employed, including but not limiting to in-situ
combat this disease. Insulin is a potent anabolic
hybridisation, immunohistochemistry, high-
hormone, secreted by the pancreas in response to
sensitivity infrared thermal imaging, histological
NEUROSCIENCE PROGRAM 17