BIOCHEMISTRY & MOLECULAR BIOLOGY 2021 - RESEARCH PROJECTS HONOURS, MASTERS AND PHD - School of Biomedical ...

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BIOCHEMISTRY & MOLECULAR BIOLOGY 2021 - RESEARCH PROJECTS HONOURS, MASTERS AND PHD - School of Biomedical ...
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
BIOCHEMISTRY & MOLECULAR BIOLOGY 2021 - RESEARCH PROJECTS HONOURS, MASTERS AND PHD - School of Biomedical ...
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

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BIOCHEMISTRY & MOLECULAR BIOLOGY 2021 - RESEARCH PROJECTS HONOURS, MASTERS AND PHD - School of Biomedical ...
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BIOCHEMISTRY & MOLECULAR BIOLOGY 2021 - RESEARCH PROJECTS HONOURS, MASTERS AND PHD - School of Biomedical ...
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.

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BIOCHEMISTRY & MOLECULAR BIOLOGY 2021 - RESEARCH PROJECTS HONOURS, MASTERS AND PHD - School of Biomedical ...
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.

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BIOCHEMISTRY & MOLECULAR BIOLOGY 2021 - RESEARCH PROJECTS HONOURS, MASTERS AND PHD - School of Biomedical ...
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BIOCHEMISTRY & MOLECULAR BIOLOGY 2021 - RESEARCH PROJECTS HONOURS, MASTERS AND PHD - School of Biomedical ...
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

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BIOCHEMISTRY & MOLECULAR BIOLOGY 2021 - RESEARCH PROJECTS HONOURS, MASTERS AND PHD - School of Biomedical ...
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.

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BIOCHEMISTRY & MOLECULAR BIOLOGY 2021 - RESEARCH PROJECTS HONOURS, MASTERS AND PHD - School of Biomedical ...
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BIOCHEMISTRY & MOLECULAR BIOLOGY 2021 - RESEARCH PROJECTS HONOURS, MASTERS AND PHD - School of Biomedical ...
PROJECTS

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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
                                                                                                                                         11
BATHGATE 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

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dysfunction, 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

                                                                                                                                         13
BROWN 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

14
Project: 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

                                                                                       15
COX 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
16
EDGINGTON-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

                                                                                                                                         17
GHOSAL 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

18
Project: 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

                                                                                          19
GLEESON 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.

20
This 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

                                                                                                                                          21
GOOLEY 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

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