BIOCHEMISTRY & MOLECULAR BIOLOGY 2021 - RESEARCH PROJECTS HONOURS, MASTERS AND PHD - School of Biomedical ...
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
BIOCHEMISTRY &
M O L E C U L A R B I O LO G Y
2021
R E S E A R C H P R OJ E C TS
H O N O U R S , M A ST E R S
AND PHD
WELCOME
The Department of Biochemistry and Molecular Biology is a teaching and
research Department of the School of Biomedical Sciences, Faculty of Medicine,
Dentistry and Health Sciences based on the main campus at Parkville.
The Department of Biochemistry The Department has expertise in a broad
and Molecular Biology has teaching range of technologies: cryo-electron
responsibilities to medical, biomedicine tomography, flow cytometry, genetic
and science students and has very active manipulation of primary cells and whole
research programs with strong graduate organisms, viral delivery systems, animal
research training. models, DNA and RNA sequencing,
CRISPR/Cas9 gene modification, high-
The Biochemistry and Molecular Biology
resolution fluorescence imaging, light
department houses 20+ research groups
microscopy imaging, mass spectrometry,
working in the areas of biophysics,
proteomics, metabolomics, nuclear
cell biology, chemical biology,
magnetic resonance spectroscopy,
computational biology, drug design
bioinformatics, cryo-electron
and resistance, genomics, immunology,
microscopy, small-angle X-ray scattering
metabolism, proteomics and structural
and X-ray crystallography.
biology. Disease focus includes
infection, cancer, neurodegeneration The Department has a dynamic research
and genetic diseases. We place a strong profile and has established an extensive
emphasis on research and research set of collaborations with other
training with over 70 graduate research University Departments both within and
students currently enrolled. outside the Bio21 Molecular Science and
Biotechnology Institute.
The Department is situated within the
University of Melbourne’s Bio21 Molecular The School of Biomedical Sciences is
Science and Biotechnology Institute, part of the Faculty of Medicine Dentistry
a multidisciplinary research centre and Health Sciences. It comprises
specialising in medical, agricultural the Departments of Anatomy and
and environmental biotechnology Neuroscience, Biochemistry and
which supports major technology Molecular Biology, Microbiology and
platforms around mass spectrometry Immunology, Pharmacology and
(proteomics/metabolomics/ analytical), Therapeutics, and Physiology.
advanced electron and fluorescence
Situated on the University’s Parkville
microscopy, NMR and protein structural
Campus in a rich medical and research
characterization.
precinct the School has much to offer
students, research and teaching staff
alike.
“Our job as artists is to get people to think, get
them to feel, and to show them their true potential.”
Budi Miller
Head of Acting
2
3
HOW TO APPLY
HONOURS
What is Honours? How long is Honours? STEP 3: Project Preference
Honours is a fourth-year undergraduate Honours is a one-year course consisting Once you have submitted an online course
course that consists of a combination of a of 75 points of research and 25 points application, you will receive an email
research project and coursework subjects. of coursework, that commences mid- within 3 working days with your personal
The course is designed to develop the February and finish in November. Mid-year login details to access the Honours
student’s capacity to solve problems, to entry is also possible, commencing in July Project Preference System - SONIA.
analyse data, to read and think critically, and finishing in June the following year. Please follow the instruction in the email
and to communicate clearly. to set up your password and select your
How to apply
Honours can give you a taste of what preferences for projects offered within
STEP 1: Contact Potential Supervisor(s)
working as a scientist would be like as MDHS departments. You may select up
a career, allows you to demonstrate Decide which departments, institutes, to 4 project preferences in Round 1 or 3
academic excellence in an area of special supervisors and projects you wish to apply project preferences in Round 2, 3 and mid
interest to you, and provides an entry for and make contact with the relevant year. You must only preference projects
point for further research higher degree supervisor. after making contact with the relevant
study (i.e. PhD). These skills are highly supervisor(s). You are allowed to log into
Applicants must contact potential
sought after by employers in biological, SONIA to change your preferences any
supervisors either before or soon after
medical and industrial areas. time by the closing date.
submitting an online application for entry
What are the entry requirements? to an MDHS Honours course. Department More information including application
and Institute Honours project booklets dates and online application:
To be considered for entry, applicants
and websites, the individual information mdhs-study.unimelb.edu.au/degrees/
must have completed a suitable
sessions held by departments and honours/apply-now
undergraduate degree (Bachelor of
institutes are ways of helping you to
Biomedicine, Bachelor of Science or biomedicalsciences.unimelb.edu.au/
make contact with potential Honours
equivalent) with a major in a relevant departments/biochemistry/study/
supervisors.
discipline with a WAM (weighted average honours-and-masters
mark) of at least H3 (65%) or equivalent. STEP 2: Online Application
Students who have completed or are due Lodge an online application
to complete a Bachelor of Biomedicine
1. Apply online and select either the
at the University of Melbourne should
‘Returning Applicants’, ‘Current
apply to complete Biomedicine Honours.
Students and Previous Students’ or
Students who have completed or are due
‘First Time Applicants’. Do not select
to complete a Bachelor of Science at the
the ‘First Time Applicants’ option if
University of Melbourne or an equivalent
you have previously completed study
course at another institution should apply
or applied to any program at The
to complete Science or Biomedicine University of Melbourne.
Honours.
2. Select ‘MDHS Specialisations’ as
Meeting the minimum Faculty level is not a requirement response in the online
guarantee of admission and students must application form.
be accepted by a supervisor before entry 3. Provide original or certified
into the course. transcript(s) for any study not
undertaken at The University of
Melbourne. You are not required
to provide transcripts for study
undertaken at this university.
4
MASTER OF BIOMEDICAL SCIENCE
What is the Master of Biomedical Notes How to apply
Science? 1. Apply online and select either Current
• Quotas may be applied to the
The Master of Biomedical Science at the degree as a whole, or to individual Students and Previous Students or
University of Melbourne is a coursework disciplines, and preference may be First Time Applicants. Do not select
master’s degree incorporating a given to applicants with evidence of the First Time Applicants option if
substantial research project. This course appropriate preparation or potential you have previously completed study
is an alternative to Honours as a PhD to undertake research. or applied to any program at The
pathway. Students undertake a major • Entry is subject to the capacity University of Melbourne.
research project and discipline-specific of a participating department to 2. Provide original or certified
coursework subjects. In addition, a suite of provide adequate supervision in a transcript(s) for any study not
professional business and communication research project appropriate to the undertaken at The University of
subjects are offered to complement and interests and preparation of the Melbourne.
enhance the research undertaken and to individual student, and is subject to
progress students’ career opportunities. the agreement of an academic staff
Selecting a Project
member to supervise the project. Once you have submitted an online course
The course encourages students to think
• Students entering this course are application, you will receive an email with
innovatively and provides an awareness
expected to organise an academic your personal login details to access the
of the health and economic benefits of
supervisor in the relevant academic Master of Biomedical Science Project
biomedical research. Graduates of this
unit, and select a research project, as Preference System - SONIA. Please follow
course gain an understanding of the
part of the application process. You the instruction in the email to set up your
research process, specialist knowledge
will be provided with a list of current password and review projects offered
and professional skills that are attractive
projects once your application has within MDHS departments. You must make
to employers.
been assessed and deemed eligible. direct contact with the supervisor and
What are the entry requirements? The theme and scope of the research obtain permission to work on their project
To be considered for entry, applicants project is negotiated between the before submitting your project preference.
must have completed a suitable student and supervisor prior to Once your project has been endorsed, you
undergraduate degree with a major in a commencement of the course. will be allocated to this project in SONIA.
relevant discipline with a WAM (weighted More information including application
How long is the Master of Biomedical
average mark) of at least H3 (65%) or dates and online application:
Science?
equivalent. Meeting this requirement does study.unimelb.edu.au/find/courses/
not guarantee selection. The Master’s is a two-year (full time) graduate/master-of-biomedical-science/
course consisting of 125 points of research how-to-apply/
and 75 points of coursework. The course
can be commenced at the start of the year biomedicalsciences.unimelb.edu.au/
or at mid-year. departments/biochemistry/study/
honours-and-masters
Difference between Honours and the Master of Biomedical Science
Honours Masters
Duration 1 year (full time) 2 years (full time), part time available
Level Undergraduate Graduate
CSP (commonwealth supported places) Yes Limited
available?
PhD Scholarship scoring Considers marks from 3rd year of Only Masters marks are considered
Bachelor’s degree and Honours marks
International Market recognition Australian Honours degrees may not be Recognised as a graduate master’s
recognised overseas, as many countries do degree
not have an equivalent degree.
5
6
RESEARCH HIGHER DEGREES
What is a PhD? What are the entry requirements? Choosing a supervisor and research
A PhD (Doctor of Philosophy) is a To be considered for entry into a PhD, area
three-year supervised research degree applicants must have completed A critical element of success is choosing
with the possibility of up to 12 months a research area that interests you.
• a four-year bachelor’s degree
extension. A candidate may be required Departmental websites have information
(BSc Hons, BBiomed Hons) in a
to supplement their research with on the range of research areas on offer, as
relevant discipline which includes
enrolment in additional subjects if well as areas of interest of academic staff
a substantial research component
considered necessary. The research is members who can supervise your project.
equivalent to at least 25% of one
written up as a thesis (80,000 – 100,000 year full time study and achieved a It is very important for you to talk to
words) and examined by external experts minimum WAM of 80% (University of supervisors as well as current or previous
in the field. Melbourne) or equivalent; or students. It is one thing to be interested in
What is a MPhil? • a master’s degree in a relevant the project but you need to get along with
A MPhil (Master of Philosophy) is similar discipline which includes a your supervisor too.
to a PhD but carried out over 18 months substantial research component
equivalent to at least 25% of one For future information regarding Research
to 2 years. The research work is written Higher Degrees:
up as a thesis (30,000 – 40,000 words) year of full time study and achieved
which demonstrates your knowledge and a minimum weighted average of study.unimelb.edu.au/find/courses/
contribution to the field of research. 80% (University of Melbourne) or graduate/doctor-of-philosophy-medicine-
equivalent. dentistry-and-health-sciences/
To be considered for entry into a MPhil, study.unimelb.edu.au/find/courses/
applicants must have completed graduate/master-of-philosophy-mdhs-
biomedical-science/
• a four-year bachelor’s degree
(BSc Hons, BBiomed Hons) in a biomedicalsciences.unimelb.edu.au/
relevant discipline which includes departments/biochemistry/research/
a substantial research component graduate-research-opportunities
equivalent to at least 25% of one How to apply
year full time study and achieved a
minimum WAM of 75% (University of 1. Review the list of prospective projects
Melbourne) or higher; or and supervisors in this handbook or
• a master’s degree in a relevant online.
discipline which includes a 2. Identify projects of interest and
substantial research component contact the project supervisor to
equivalent to at least 25% of one explain your research interests and
year of full-time study and achieved provide your curriculum vitae (CV)
a minimum weighted average of 75% and academic transcripts.
(University of Melbourne) or higher. Once confirmed a project and supervisor
apply online at https://study.unimelb.edu.
au/how-to-apply/graduate-research
7
SCHOLARSHIPS
Honours Graduate degrees
Honours applicants who accept and enrol The Melbourne Scholarships Program
in an Honours course will automatically is one of the most generous and
be considered for available Honours comprehensive in Australia, with a
Scholarships. These are awarded on wide range of scholarships available for
academic merit. domestic and international students.
There are many different types of
Highly ranked full-time students who have
scholarships available, with some
enrolled in an MDHS program through
varying in value, duration and eligibility.
the Bachelor of Biomedicine (Degree with
Most University of Melbourne graduate
Honours) and the Bachelor of Science
students have scholarships to aid with
(Degree with Honours) and demonstrated
living expenses and course fees. Some
a level of financial needs will automatically
scholarships also assist with relocation
be considered for an Frances Elizabeth
fees and insurance costs whilst studying at
Thomson Trust Scholarship. The
the University of Melbourne.
Scholarship will award eligible students
with a one-off payment of $5,000. Graduate Research Scholarships for
mdhs.unimelb.edu.au/study/ domestic and international students
scholarships/n/frances-elizabeth- are awarded on a competitive basis. If
thomson successful, students must also meet
the entry requirements for a Doctoral
A scholarship of $5,000 is available to any
degree at the University of Melbourne.
full-time student enrolled in Department
More details on the different types
of Biochemistry and Molecular Biology
of scholarships available, what they
Honours with a third year WAM > 85 (not
cover and eligibility can be found here:
including University of Melbourne Breadth
scholarships.unimelb.edu.au/awards/
subjects or equivalent) undertaking
graduate-research-scholarships
Honours in a laboratory located at Bio21
Institute.
The highest ranked Department of
Biochemistry and Molecular Biology
Honours student for each year will be
awarded the Grimwade Honours prize
of $2,000.
8
9
PROJECTS 10
ASCHER GROUP
Contact: A/Prof David Ascher Drug Design and
Computational Biology
Location: Bio21 Molecular Science and Resistance
Biotechnology Institute
Genomics Personalised Medicine
Email: david.ascher@unimelb.edu.au
Weblink: Click here Structural Biology
The Ascher group develops new computational tools to investigate and understand the relationship
between protein sequence, structure and function and phenotype. The lab uses these to drive
improvements in and personalisation of patient treatment, and to guide drug discovery.
Project: Treating the person not Project: Finding clarity within Project: small molecules for BIG
the disease a blizzard- guiding the solution targets- Targeting protein-protein
We have developed a range of of cryo-EM structures interactions with fragments
computational tools to deconvolute the The recent explosion in the power of cryo- Most proteins work within a network of
molecular mechanisms of a mutation electron microscopy has revolutionised interactions with other proteins, and
giving rise to different phenotypes. In the structural biology field, especially the ability to selectively target specific
collaboration with clinical partners we the characterisation of large protein interactions, modulating protein function
have shown that even though patients complexes. This is helping us tackle very and providing the opportunity to develop
may present the same disease, they may important biological problems in a way more selective and effective drugs. But
arise from many different mutations that that they could never before. There are, while drugs are usually around 100 Å,
alter a patient’s outcome or how they however, inherent limitations that not only proteins interact tightly using way larger
may respond to a particular treatment. By pose difficulties to the structure solving protein-protein interfaces, ranging from
analysing these mutations and predicting stage, i.e., properly positioning a protein 1000-6000 Å. This raises the challenge of
their effects on protein structure and chain within an electron density map, how we can use a small molecule to affect
function we are trying to revolutionise but also potentially introducing errors an interface many times larger, which
treatment strategies, an important that might be propagated to the refined until recently was considered to be flat
step towards personalised medicine. structure. This is especially relevant for and undruggable. We and others have
We are currently working on a range medium resolution structures (4-8 Å). The had success using fragment-based drug
of diseases including genetic diseases problem is analogous to looking through discovery to identify novel protein-protein
(Alkaptonuria, Urea cycle disorders, VHL), blurry (or drunk) glasses and, without interaction modulators. This allows us to
cancer (renal carcinomas), and drug/ good points of reference, not being able take advantage of hot-spots within the
vaccine resistance (TB, cancer, malaria, to orientate yourself. To improve this protein interfaces that mediate a large
HIV, influenza). These projects combine procedure, we can leverage the power of proportion of the binding energy, growing
both computational (bioinformatics) our existing structural and evolutionary the molecule to improve binding affinity
and experimental (protein expression, knowledge accumulated over decades and drug like properties. The crystal
biophysics, structural biology) and deposited in structural databases structures of many protein interface
approaches to unravel the molecular in order to help guide the proposal of a modulators with their targets have been
mechanisms driving these mutations and more effective methods for this molecule solved, which opens up the possibility for
derive novel predictive methods. This placement. This project will use structural us to ask: what are the major components
information is then used to help identify bioinformatics and machine learning to of binding affinity? and can we use this
and guide the development of novel develop novel computational tools to information to predict fragments likely to
therapies to treat these conditions. One aid cryo-EM and low-resolution crystal bind to a given interface? Using structural
of the ultimate goals of these projects structure solving, analysing protein bioinformatics and machine learning,
will be the development of webservers residue environments, protein interaction these questions will be answered, leading
enabling the rapid analysis of mutations interfaces, and protein functional sites. to the development of novel programs.
to help guide clinical decisions These methods will be brought together The students will then also have the
into an integrated platform for the opportunity to test these experiments in
Project supervisor
evaluation and validation of medium the lab, using biophysical and structural
A/Prof David Ascher
resolution protein structures. approaches to test fragment binding.
Project availability
Project supervisor Project supervisor
• PhD A/Prof David Ascher A/Prof David Ascher
• Master of Biomedical science
Project availability Project availability
• Honours
• PhD • PhD
• Master of Biomedical science • Master of Biomedical science
• Honours • Honours
11BATHGATE GROUP
Contact : Professor Ross Bathgate Drug Design and
Location: The Florey Institute of Resistance
Neuroscience and Mental Health
Structural Biology
Email: bathgate@florey.edu.au
Weblink: Click here Cell signalling
The Bathgate lab focusses on understanding the interactions of peptide ligands with their G protein-
coupled receptor (GPCR) targets for the development of peptide-based drugs and utilizing structure-based
drug design to develop novel therapeutics. He works closely with a number of pharmaceutical companies
interested in the clinical development of drugs targeting receptors for peptides of the relaxin family.
Projects are available on multiple therapeutically relevant GPCR targets with training in various techniques
including peptide mimetic design, cell signalling assays, molecular pharmacology, structural biology and
structure-based drug design.
Project: Targeting peptide G protein- A complete understanding of the Project: Peptidomimetic drug design
coupled receptors (GPCRs) for novel mechanism of ligand binding and targeting G protein-coupled receptors
drug development activation is required to design drugs Currently available drugs in the market
The largest single class of drug targets is targeting these receptors. Furthermore, fall broadly into two categories. There are
the G Protein-Coupled Receptor (GPCR) we are utilizing novel protein engineering ‘small molecule’ drugs (molecular weight
family, which were targets for ~30% of techniques that enable these normally of 5000 Da) with no oral
a small proportion of the GPCR family advanced protein NMR techniques, bioavailability. Due to their small size,
and peptide GPCRs, although showing crystallography and Cryo-EM (also see small molecule drugs often suffer from
great potential as targets for treating projects from Dr Daniel Scott, Prof Paul reduced target specificity and toxicity.
many diseases, are poorly targeted with Gooley). Our studies are complemented Large biologics, on the other hand, are
drugs. Modern GPCR drug development by peptide drug development projects highly target-specific and thus less toxic
is encumbered by a lack of information and small molecule screening projects than small molecules. Therefore, the
about the molecular structure underlying with collaborators. Additionally, we are compounds that fit between these two
GPCR function and the reliance on working with pharmaceutical industry molecular weights (500 Da-5000 Da)
cell-based assays that are prone to partners (eg. Takeda and Novartis) to and possess the advantages of both the
false positives in drug screening. While facilitate drug development efforts. small molecule (e.g. bioavailability and
the past 10 years have seen advances Projects are available on multiple stability) and larger biologics (e.g. highly
in our knowledge of GPCR structures GPCR targets with training in various target specific) are of great interest.
peptide GPCRs, especially those with techniques as outlined above. Peptidomimetics are such compounds
large structured ectodomains (ECDs), Project supervisor that fall into this category.
remain poorly understood. This is mainly Prof Ross Bathgate Relaxin family peptides have complex-
because the flexibility of linkers joining
Project co-supervisors two chain and three disulfide bonded
the ECDs to the transmembrane domains
Dr Daniel Scott, Prof Paul Gooley, structure and our laboratory has
(TMDs) impedes crystallization. Hence
A/Prof Mike Griffin recently developed peptidomimetics
the study of complex peptide receptors
of human relaxin 2 (B7-33), relaxin
requires different approaches. Our Project availability
3 (stapled peptide), and insulin-like
laboratory targets peptide GPCRs for • PhD peptide 5 (analogue 13). Projects are
drug development utilizing state-of-the- • Master of Biomedical science available to further develop these
art molecular pharmacology, biochemical
• Honours peptidomimetic ligands as molecular
and Nuclear magnetic resonance (NMR)
probes and drug leads that target their
techniques. These techniques enable us
GPCR targets, relaxin family peptide
to map the native peptide binding sites
(RXFP) receptors RXFP1, RXFP3 and
of these receptors and determine the
RXFP4. These receptors are potential
mechanisms of receptor activation as
drug targets for cardiovascular
well their cell signalling characteristics.
disease, neurological disorders and gut
12dysfunction, respectively. Our laboratory Project: Drug discovery: investigation cellular compartments in real time. This
utilizes multidisciplinary cutting-edge of signalling by GPCRs using novel project will examine a range of GPCR
technologies including modern solid cellular biosensors signalling pathway with a particular focus
phase peptide synthesis, molecular GPCRs are the targets for ~30% of all on the effect of diverse drugs. A complete
pharmacology, and animal physiology currently used therapeutic drugs. It understanding of the mechanisms
to carry out these projects. Importantly, is critical to understand how these of GPCR activation and signalling
we are working with pharmaceutical receptors are activated, how they alter complexity is crucially important for drug
industry partners (eg. Takeda and cellular function, how such responses development targeting these receptors.
Novartis) to develop peptidomimetics are switched off, and how other cellular We work with multiple GPCR targets and
therapeutically. Projects are available components can modulate their activity. collaborate with pharmaceutical industry
on multiple additional GPCR targets with GPCRs interact with a range of other partners including Novartis and Takeda.
training in various techniques as outlined proteins and these interactions govern Projects are available on multiple GPCR
above. their function and modulation. Our targets with training in molecular and cell
laboratory has a range of advanced biology and numerous BRET techniques
Project supervisor
cutting-edge technologies available for to study GPCR interactions and cellular
Prof Ross Bathgate
the study of GPCRs allowing interacting signalling.
Project availability
partners and signalling profiles to Project supervisor
• PhD be determined. These include novel Prof Ross Bathgate
• Master of Biomedical science Bioluminescence Resonance Energy
Project co-supervisors
• Honours Techniques (BRET)-based biosensors.
Dr Martina Kocan
BRET is a technology that places light-
emitting labels on proteins, enabling Project availability
their interactions to be examined in • PhD
living cells, and is uniquely suited to the • Master of Biomedical science
study of integral membrane proteins
• Honours
such as GPCRs (Figure). BRET-based
biosensors allow us to closely monitor
intermolecular signalling in diverse
13BROWN GROUP
Contact : Doctor Kristin Brown
Cancer Cell signalling
Location: Peter MacCallum Cancer Centre
Email: kristin.brown@petermac.org Drug Design and
Metabolism
Resistance
Weblink: Click here
Cell Biology
Deregulated cellular metabolism is a well-established hallmark of cancer. The Brown group uses a range of
molecular biology, cell biology and biochemistry techniques to investigate the ways in which deregulated
cellular metabolism contributes to cancer initiation, cancer progression and therapy resistance. The
knowledge gained from these studies is applied to the pre-clinical development of novel anticancer
therapies.
Project: Fueling chemotherapy driving chemotherapy resistance in Project: Cutting off the Fuel Supply to
resistance in triple-negative breast TNBC and establish combination therapy Starve Cancer: Identifying metabolic
cancer strategies with potential to have a major vulnerabilities in cancer
Triple-negative breast cancer (TNBC) is impact on patient survival. Students A universal characteristic of all cancer
a molecularly heterogeneous group of will gain experience in mammalian cell cells is the reprogramming of cell
diseases defined by the lack of estrogen culture, molecular biology techniques, metabolism to provide the energy
receptor (ER), progesterone receptor metabolomics and stable-isotope and building blocks necessary to
(PR) and absence of human epidermal labelling techniques. support proliferation and survival.
growth factor receptor-2 (HER2) Project supervisor Reprogramming of cell metabolism
amplification. Consequently, TNBCs are Dr Kristin Brown occurs as a consequence of oncogenic
impervious to therapies commonly used mutations and renders cancer cells
in other breast cancer subtypes and Project availability dependent on a unique set of nutrients. It
treatment options are largely limited • PhD is now widely recognized that the altered
to conventional chemotherapy agents. • Master of Biomedical science metabolic activity of cancer cells provides
Approximately 30% of TNBC patients • Honours a window of opportunity to develop
respond to chemotherapy. Unfortunately, tumour-specific anticancer therapies.
the long-term prognosis for the majority Using transcriptomic and metabolomic
of patients with residual disease after approaches, the aims of this project
chemotherapy is poor. Identification will be to: (1) compare and contrast
of novel and actionable strategies to metabolic reprogramming induced by
sensitize cancer cells to chemotherapy well-described oncogenes; (2) compare
would represent a major advance for the and contrast the nutrient requirements of
management of TNBC. cancer cells dependent on well-described
oncogenes and (3) identify and validate
Cancer cells exhibit dramatic alterations
key metabolic vulnerabilities that can be
in cell metabolism, which support cell
targeted for the preclinical development
growth, proliferation and survival.
of novel anticancer strategies. Students
Indeed, metabolic reprogramming is a
will gain experience in mammalian cell
recognized hallmark of cancer induced
culture, molecular biology techniques,
by numerous genetic or epigenetic
metabolomics and stable-isotope
alterations. Our recent studies suggest
labelling techniques.
that reprogramming of cellular
metabolism is also a component of Project supervisor
the highly coordinated response to Dr Kristin Brown
chemotherapy exposure. The aims Project co-supervisor
of this project will be to 1) identify Dr Andrew Cox
adaptive metabolic reprograming
events triggered upon chemotherapy Project availability
exposure, and 2) identify novel • PhD
therapeutic approaches to exploit • Master of Biomedical science
adaptive metabolic reprogramming • Honours
events and sensitize TNBC cells to
chemotherapy. This research will lead to
the identification of critical mechanisms
14Project: Unravelling the partners of SGK1 is extremely limited.
oncogenic activities of serum- and In this project, students will identify
glucocorticoid-regulated kinase 1 SGK1 substrates and interacting proteins
(SGK1) using the proximity-dependent biotin
The phosphoinositide 3-kinase (PI3K) identification (BioID) method. Students
pathway has emerged as a master will gain experience in mammalian
regulator of numerous cellular cell culture and proteomics (mass
phenotypes associated with cancer spectrometry) techniques. Targets
including cell survival, proliferation, identified in the BioID screen will be
growth, altered metabolism and validated using a variety of biochemical
malignant transformation. Deregulation and molecular biology techniques.
of the PI3K pathway is implicated in Project supervisor
virtually all human cancers and the Dr Kristin Brown
pathway has been aggressively targeted
Project availability
for cancer therapy. Although most
work has focused on the Akt kinase • PhD
family as major downstream effectors • Master of Biomedical science
of PI3K, the closely related serum- and • Honours
glucocorticoid-regulated kinase (SGK)
family of serine/threonine kinases has
by comparison received little attention.
The SGK1 isoform was initially discovered
as a gene transcriptionally responsive to
serum and glucocorticoids in mammary
tumour cells. More recently, SGK1 has
been shown to play a critical role in
driving the expansion of tumour cells and
promoting resistance to conventional
chemotherapy and targeted therapy
agents. However, the molecular
mechanisms that enable SGK1 to elicit
such oncogenic activities are unknown.
This is largely because information
regarding the substrates and interaction
15COX GROUP
Contact : Doctor Andrew Cox
Cell Biology Metabolic Disease
Location: Peter MacCallum Cancer
Centre
Cancer
Email: andrew.cox@petermac.org
Weblink: Click here Metabolism
In the Cox laboratory, we use zebrafish (Danio rerio) as a model system to study pathways that
regulate liver growth during development, regeneration and cancer. Our lab is especially interested in
understanding the mechanisms by which metabolism is reprogrammed in cancer. We employ a wide range
of techniques including multiphoton microscopy, metabolomics and transcriptomics in zebrafish models
of liver regeneration and cancer. Our ultimate goal is to identify critical metabolic vulnerabilities that can
be exploited for the development of therapies to combat cancer.
Project: Fishing for metabolic clues: Project: Metabolic rewiring in liver
Role of the Hippo/Yap pathway in cancer: Role of oxidative stress and
reprogramming metabolism in liver the Nrf2 pathway.
cancer. Many of the major risks factors for
The Hippo/Yap pathway is an developing liver cancer such as alcohol,
evolutionarily conserved cascade that obesity, smoking and toxin exposure
plays a fundamental role in governing share in common a role for oxidative
organ size control, stem cell homeostasis stress. Nrf2 is a transcription factor
and cancer. The Hippo/Yap pathway is activated by oxidative stress that
regulated by a range of environmental orchestrates an adaptive response
cues including nutrient status. Although remodeling metabolism and promoting
many of the inputs into the Hippo cytoprotection. Recent studies have
pathway have been identified, less identified that the Nrf2 pathway is
is known about the Yap target genes frequently mutated in liver cancer
responsible for tissue growth. Using (~12% tumors), causing activation of
a combination of metabolomic and the pathway in the absence of oxidative
transcriptomic approaches in zebrafish, stress. We have used transcriptomic
we have discovered that Yap reprograms and metabolic profiling in Nrf2-/-
glutamine metabolism in vivo to zebrafish to examine the role Nrf2
stimulate nucleotide biosynthesis and plays in remodeling metabolism during
fuel premalignant liver growth. Building liver development and regeneration.
on this initial investigation, we currently Building on these preliminary studies,
have research projects that aim to 1) we currently have research projects
Examine how Yap coordinates nutrient that aim to 1) Generate a gain of
sensing to metabolic output in the liver. function Nrf2 mutant (Nrf2D29H),
2) Elucidate the mechanisms by which frequently recovered in cancer, and
Yap reprograms metabolism to fuel liver characterize the effect the mutation
growth in the context of regeneration has on metabolic reprogramming.
and cancer. The students will use a 2) Examine how deregulation of Nrf2
combination of innovative biochemical, remodels metabolism to stimulate liver
genetic and imaging approaches in tumorigenesis. The students will use a
zebrafish to identify the metabolic combination of innovative biochemical,
dependencies of tissue growth during genetic and imaging approaches in
regeneration and cancer. zebrafish to identify the metabolic
dependencies of tissue growth in liver
Project supervisor
regeneration and cancer.
Dr Andrew Cox
Project availability Project supervisor
Dr Andrew Cox
• PhD
• Master of Biomedical science Project availability
• Honours • PhD
• Master of Biomedical science
• Honours
16EDGINGTON-MITCHELL GROUP
Contact: Doctor Laura Edgington-Mitchell
Location: Bio21 Molecular Science and Immunology Chemical Biology
Biotechnology Institute
Email: laura.edgingtonmitchell@ Cell Biology
unimelb.edu.au
Cancer
The Protease Pathophysiology Lab uses a chemical biology approach to understand the mechanisms by
which enzymes called proteases contribute to normal cellular function and how these mechanisms can
go wrong to cause disease. Our overarching goals are to establish proteases as diagnostic or prognostic
biomarkers for inflammation and cancer and as novel drug targets for the treatment of these diseases.
Project: Development of Novel To detect the formation of this bond, Project: Understanding the
Chemical Tools to Measure Protease and thus measure protease activity, Contribution of Proteases to Oral
Activation ABPs are tagged with fluorophores that Cancer Pathology
Proteases are enzymes that cleave emit light only after protease cleavage. Oral squamous cell carcinoma is the
peptide bonds of proteins. To prevent This fluorescence can be visualised most common head and neck cancer. It
cleavage at the wrong place or time, and using a number of optical imaging is an extremely painful disease for which
thus protect the body from aberrant applications, including whole animal treatments are limited. Oral cancer often
proteolysis, most proteases are and tissue imaging, flow cytometry, spreads to cervical lymph nodes, and
synthesised as inactive proteins called confocal microscopy, and SDS-PAGE once metastasis occurs, patient survival
zymogens. They become activated in (in-gel fluorescence). The identity of the rates drop below 40%. Current methods
response to a conformational change, probe’s targets can then be confirmed to predict the spread of oral cancer
which can be mediated by alterations in by immunoprecipitation with protease- are ineffective; thus, most patients
pH or cleavage by other proteases. Once specific antibodies or proteomic undergo radical elective neck dissection
activated, proteases are also subject methods. to remove all cervical lymph nodes
to spatial and temporal regulation by This project will involve collaboration prior to the appearance of metastatic
endogenous inhibitors such as cystatins. with chemists to develop novel activity- lesions. Our laboratory is investigating
As a result of these complex modes based probes for cysteine and serine the contribution of proteases to oral
of post-translational modification, proteases. cancer pain and metastasis. Proteases
traditional biochemical methods that are a large family of enzymes that
survey total protein levels rarely reflect Project supervisor function as tiny molecular scissors to cut
the pool of active, functional enzymes. Dr Laura Edgington-Mitchell proteins. This process facilitates protein
The ability to specifically measure and Project availability degradation and turnover, but also
modulate the activity of a protease in its • PhD contributes to many cellular signalling
native environment is therefore required events that underlie the growth and
• Master of Biomedical science
to define its precise proteolytic functions metastasis of oral cancer. This project
during health and disease. • Honours aims to understand the functions of key
proteases that are activated in human
To achieve this, efforts from our team
oral cancers using in vitro assays and in
and others have focussed on developing
vivo mouse models. We will evaluate the
activity-based probes (ABPs) for
utility of protease activity as a biomarker
diverse cysteine and serine proteases.
for predicting metastasis and as a
These tools capitalise on the catalytic
potential drug target for the treatment of
mechanism of proteolysis, combining
this deadly disease.
a protease recognition sequence with
a reactive functional group called a Project supervisor
warhead. When the catalytic residue of an Dr Laura Edgington-Mitchell
active protease attacks this warhead, a Project availability
covalent, irreversible bond forms.
• PhD
• Master of Biomedical science
• Honours
17GHOSAL GROUP
Contact : Dr Debnath Ghosal
Location: Bio21 Molecular Science and Structural Biology Pathogens
Biotechnology Institute
Email: debnath.ghosal@unimelb.edu.au Discovery Research Cell Biology
Weblinks: Click here Drug Design and
Biophysics
Resistance
We are interested in host-pathogen interaction particularly, how bacterial and viral pathogens utilize
complex molecular machines to mediate infection. We use a range of structural (e.g. cryoEM, X-ray
crystallography etc) and cell biology techniques to elucidate the structure and function of these molecular
machines in situ, in their native context, inside ‘living’ cells.
Project: Structure and function of Project: Structural biology in situ: at subnanometer resolution. We are
bacterial cytoskeletal filaments by Structure and function of bacterial harnessing this unique power of cryo-
cryo-EM secretion systems by cryo-EM ET and combining it with correlative
Until early 1990s, cytoskeletal proteins Bacteria harbour at least nine different light and electron microscopy (CLEM),
were believed to be the hallmarks of types of secretion systems to transfer and Focused Ion Beam (FIB) milling to
eukaryotic cells. However, in the last macromolecules across cellular envelope. elucidate the structure and function of
three decades, the discovery of bacterial These are sophisticated multi-protein different bacterial injection modules at
homologs of eukaryotic actin, tubulin nanomachines that secrete myriads molecular resolution.
and intermediate filament proteins have of substrates including proteins, Project supervisor
dramatically changed our perception. nucleoprotein complexes and variety Dr Debnath Ghosal
One of the key emerging difference of small molecules and are central
between the bacterial and the eukaryotic to pathogenesis of multiple human Project availability
cytoskeletal systems is that each of the diseases. For example, many pathogenic • PhD
bacterial filaments seem to perform bacteria utilize the Type III Secretion • Master of Biomedical science
one dedicated function while eukaryotic System (T3SS) to cause diseases • Honours
ones, by virtue of their interaction with such as dysentery (Shigella), typhoid
a repertoire of adapters and regulatory (Salmonella), plague (Yersinia) etc. Other
proteins, perform numerous tasks. We human pathogens employ the Type IV
are trying to understand how prokaryotic Secretion System (T4SS) to mediate
cytoskeleton was customised for multi- gastric cancer (Helicobacter), brucellosis
functionality during the evolution of (Brucella), typhus and spotted fevers
complex eukaryotic cells. (Rickettsia), as well as Legionnaires’
disease (Legionella). The T4SS is also
Project supervisor
associated with the spread of antibiotic
Dr Debnath Ghosal
resistance, which currently presents a
Project availability major threat to public health. Therefore,
• PhD these molecular machines are attractive
• Master of Biomedical science targets for drug developments to enrich
our present repertoire of antibiotics.
• Honours
Structural studies with these molecular
machines are extremely challenging due
to their large number of components,
flexibility and tight integration into
the bacterial cell envelope. Electron
cryotomography (cryo-ET) has unrivalled
power to visualize the native structure of
macromolecules in situ. In recent years,
improvement in software, detectors and
implementation of improved subvolume
averaging methods have allowed us
to investigate macromolecules in situ
18Project: The Role of Bacterial methods have allowed us to investigate
Secretion Systems in Virulence and in macromolecules in situ at subnanometer
Antibiotic Resistance resolution. We are harnessing this unique
Bacteria harbour at least nine different power of cryo-ET and combining it with
types of secretion systems to transfer correlative light and electron microscopy
macromolecules across cellular envelope. (CLEM), and Focused Ion Beam (FIB)
These are sophisticated multi-protein milling to elucidate the structure and
nanomachines that secrete myriads function of different bacterial injection
of substrates including proteins, modules at molecular resolution.
nucleoprotein complexes and variety Project supervisor
of small molecules and are central Dr Debnath Ghosal
to pathogenesis of multiple human
Project availability
diseases. For example, many pathogenic
bacteria utilize the Type III Secretion • PhD
System (T3SS) to cause diseases such as • Master of Biomedical science
dysentery (Shigella), typhoid (Salmonella), • Honours
plague (Yersinia) etc. Other human
pathogens employ the Type IV Secretion
System (T4SS) to mediate gastric cancer
(Helicobacter), brucellosis (Brucella),
typhus and spotted fevers (Rickettsia), as
well as Legionnaires’ disease (Legionella).
The T4SS is also associated with the
spread of antibiotic resistance, which
currently presents a major threat to
public health. Therefore, these molecular
machines are attractive targets for drug
developments to enrich our present
repertoire of antibiotics. Structural
studies with these molecular machines
are extremely challenging due to their
large number of components, flexibility
and tight integration into the bacterial
cell envelope. Electron cryotomography
(cryo-ET) has unrivalled power to visualize
the native structure of macromolecules
in situ. In recent years, improvement in
software, detectors and implementation
of improved subvolume averaging
19GLEESON GROUP
Contact : Professor Paul Gleeson
Location: Bio21 Molecular Science and Cell Biology Proteomics
Biotechnology Institute
Email: pgleeson@unimelb.edu.au Organelles Neurodegeneration
Weblinks: Click here
Immunology Biophysics
Membrane trafficking underpins many cell processes, including secretion, receptor signalling, endocytosis,
antigen presentation, and neural networking. Many diseases arise from defects in membrane trafficking,
including Alzheimer’s disease. Our aim is to understand the molecular basis of membrane and protein
sorting in the secretory and endocytic pathways in a variety of physiological processes using cultured cells
and differentiated primary cells, and to exploit this knowledge for the design of new therapeutics.
Project: Intracellular trafficking in We have established a powerful new Project: The Golgi Apparatus: a
neurons and Alzheimer’s disease approach to synchronize and analyse new hub for the regulation of mTOR
Alzheimer’s disease is characterized by the trafficking of newly synthesized signaling and autophagy in health
the accumulation of amyloid plaques in membrane cargoes BACE1 and APP in real and disease
the brain consisting of an aggregated time. The project will incorporate this Vertebrates have evolved mechanisms
form of β-amyloid peptide (Aβ) derived new approach with immunofluorescence, for joining the individual Golgi stacks
from sequential amyloidogenic FACS and live cell imaging, together with into a ribbon, typically found in a
processing of the Amyloid Precursor the use of photoactivatable fluorescent juxtanuclear location in interphase cells.
Protein (APP) by membrane-bound probes to track the itineraries of these The organization of the Golgi apparatus
proteases BACE1 and γ-secretase. The membrane cargoes. In addition, the role is highly dynamic and the Golgi ribbon
initial processing of APP by BACE1 of specific transport machinery in APP can dissociate and re-organize under
is regulated by intracellular sorting and BACE1 transport will be assessed a variety of conditions, for example,
events of the enzyme, which is a prime by silencing transport machinery using during mitosis and to reposition the
target for therapeutic intervention. lentivirus to deliver RNAi. A wide range Golgi to accommodate a number of
We are interested in defining the of other biochemical and cell biological processes, including directed secretion
intracellular trafficking pathways of APP approaches will also be employed and pathogen invasion. Surprisingly, and
and BACE1 and the sorting signals of Project supervisor despite our knowledge of Golgi dynamics,
these membrane proteins that define Prof Paul Gleeson the fundamental biological relevance
their itineraries. We have mapped the of the “ribbon” structure of the Golgi in
itineraries of these cargos in cultured Project co-supervisor vertebrates has remained a mystery. The
human cell lines and our findings show Dr Lou Fourriere classic functions of the Golgi, namely
that the distinct trafficking pathways of Project availability membrane transport and glycosylation,
APP and BACE1 provides the capacity to do not require a ribbon structure and the
• PhD
finely regulate their co-localization and relevance of the Golgi ribbon structure
thereby regulating APP processing and • Master of Biomedical science has been elusive. We have developed
Aβ production. There is considerable • Honours a cell-based system to explore the
evidence that dysregulation of membrane biological functions of the Golgi ribbon
trafficking events is associated with an and have recently discovered that the
increased risk of Alzheimer’s disease. We Golgi represents a major intracellular hub
are now defining the itineraries of APP for control of the mTOR signaling pathway
and BACE1 in primary neurons, the cell and in regulating autophagy. mTOR
type relevant for this disease. The project signaling regulates many fundamental
will map the post-Golgi anterograde cell processes including growth and
transport pathways of APP and BACE1 metabolism. Neurodegenerative
in neurons, determine the selective diseases and cancer are often associated
trafficking routes to axons and dendrites, with changes in Golgi morphology and
and assess the impact of neuronal we have shown that the Golgi-localized
signaling on these trafficking pathways. mTOR signaling pathway are likely to
contribute to these diseases.
20This project will investigate the role of Project: Extending the serum half-life of transport machinery, to dissect the
the Golgi on the higher order functions of novel therapeutic proteins pathway of ligand internalization and
of metabolism and autophagy in range The neonatal Fc receptor (FcRn) plays recycling, the kinetics of recycling using
of condition, including stress. A wide a critical role in regulating the half-live quantitative biochemical assays, as well
range of technologies will be used in this of a range of serum proteins, including as mass spec analysis of the recycled
project including viral transduction, high IgG and albumin, in the adult individual. ligands to determine if the itinerary of
resolution light microscopy, electron The Fc receptor protects these serum recycling has resulted in post-translational
microscopy, flow cytometry, quantitative proteins from degradation by binding modifications which may impact on
immunoblotting, proteomics and to IgG and albumin in endosomes after function.
metabolic analysis. internalization by cells and releasing the Project supervisor
Project supervisor proteins back into the plasma. There is Prof Paul Gleeson
Prof Paul Gleeson considerable interest in exploiting this
Project availability
protective pathway to prolong the life
Project availability time of engineered therapeutic proteins • PhD
• PhD by attaching the FcRn ligand binding motif • Master of Biomedical science
• Master of Biomedical science to recombinant therapeutic proteins. • Honours
• Honours In collaboration with CSL at Bio21, this
project will define the membrane recycling
pathway of the FcRn, and the itinerary
of albumin-based ligands, information
which is critical for the optimizing the
life span of therapeutic proteins. The
project will analyse the role of FcRn in
specific cell types including macrophages,
dendritic cells and endothelial cells which
are considered to be the major sites for
recycling in the body. Both cultured
and primary cells, derived from FcRn
engineered mice, will be employed. A
wide variety of biochemical and cell
biological methods will be used including
transfection cell systems, trafficking
assays, coupled with RNAi silencing
21GOOLEY GROUP
Contact: Professor Paul Gooley
Location: Bio21 Molecular Science and Structural biology Drug Design
Biotechnology Institute
Email: prg@unimelb.edu.au Biophysics Pathogens
Weblinks: Click here
Protein receptors
The Gooley group uses structural biology and physical biochemistry methods to study how proteins work
normally and in disease. Our current interests are proteins involved in viral-host cell interactions and the
mechanisms of ligand-recognition and activation of G protein-coupled receptors.
Project: Defining the host-viral Project: The complex binding mode Project supervisor
molecular interactions of rabies of the peptide hormone H2 relaxin to Prof Paul Gooley
proteins. its receptor.
Project co-supervisors
Symptomatic infection by rabies virus The insulin-like hormone relaxin has Dr Daniel Scott, Prof Ross Bathgate,
causes an incurable and invariably lethal received recent clinical interest as a A/Prof Mike Griffin
disease. The virus manipulates the treatment for acute heart failure. The
immune response of the host cell to avoid biological processes involving relaxin Project availability
detection during replication. To achieve generally are through the activation • PhD
this viral proteins interact with and of the G-protein coupled receptor, • Master of Biomedical science
manipulate the function of proteins of the RXFP1. However, the molecular details • Honours
host cell. Key to this process is the rabies of how relaxin interacts and activates
virus P-protein whose full functions are RXFP1 are unclear. In part this is due
not understood. P-protein interacts with to the complex multidomain structure
other viral proteins, including the rabies of RXFP1: an N-terminal LDLa module
L- and N-proteins, for viral replication, essential for activation, a large leucine
but it also is known to bind the immune- rich repeat (LRR) domain that is known
signalling transcription factors STAT1 to contain a relaxin binding site, and a
and STAT2, preventing them from C-terminal transmembrane domain that
entering the nucleus to activate antiviral contains critical regions for activation.
in response to interferons. The regions Structurally, we have only characterized
and amino acid residues of P-protein the LDLa module. However, we have
that are involved in these processes recently discovered that the 32-residue
are unclear, and the full extent of host linker between the LDLa module and
protein/P-protein interactions remain to the LRR domain contains a second
be resolved. This project broadly aims to relaxin binding site, and therefore we
understand the molecular interactions hypothesize that relaxin binds to both
of P-protein with its multiple targets and this linker and the LRR domain to induce
includes techniques such as mutagenesis a conformational change, possibly of the
to perturb specific interactions, and linker, that reorients the LDLa module so
characterization of these mutants by it can effectively bind and activate the
cell-based assays. Mutants that lose transmembrane domain. This hypothesis
(or gain) function will be structurally requires proving and opens opportunities
characterized and the impact on their in understanding receptor activation
molecular interactions determined using and the design of novel agonists and
an array of techniques. These studies will antagonists. There are multiple projects
lead towards the design of novel anti- available involving mutagenesis of
virals and vaccines. RXFP1 and relaxin, peptide synthesis
and cell-based assays to monitor
Project supervisor
binding and activation of these mutants/
Prof Paul Gooley
analogues; expression and purification
Project availability of the domains of RXFP1, structural
• PhD determination of these domains and
• Master of Biomedical science characterization of their molecular
interactions.
• Honours
22You can also read
