Cell-cell interactions in tumour progression - The University of Sydney
Cell-cell interactions in tumour progression - The University of Sydney
Cell-cell interactions in tumour progression - The University of Sydney
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Pathology Discipl<strong>in</strong>e<br />
Honours Year Students<br />
Summary <strong>of</strong> Requirements
ENTRY REQUIREMENTS<br />
Must have a WAM <strong>of</strong> 65 or<br />
greater<br />
Must approach a supervisor<br />
obta<strong>in</strong> permission to<br />
undertake his/her Honours<br />
project
Why a WAM <strong>of</strong> 65 or greater?<br />
Faculty <strong>of</strong> Science rule that WAM must be >65<br />
<strong>The</strong> Faculty <strong>of</strong> Science may consider applicants <strong>in</strong> the<br />
range 63-65 on special application, with support from the<br />
Discipl<strong>in</strong>e<br />
WAM < 68 - difficult to achieve Honours 1<br />
<strong>The</strong> m<strong>in</strong>imum score for Honours I is 80<br />
Pathology constra<strong>in</strong>ed by Faculty <strong>of</strong> Science (average Honours<br />
marks <strong>in</strong> each Dept must not exceed average WAM + 10).<br />
NOTE: <strong>The</strong> current cut-<strong>of</strong>f for a post-graduate<br />
scholarship for a PhD is:<br />
WAM ~72/Hons ~82 (local students)
NOTE !<br />
It is NOT necessary to have completed<br />
<strong>Cell</strong> Pathology 3.
REQUIREMENTS OF CANDIDATES<br />
General<br />
Recommended students start by February 1st.<br />
Courses:<br />
Animal Handl<strong>in</strong>g Course.<br />
Radiation Safety Course.<br />
Laboratory Safety Course
REQUIREMENTS OF CANDIDATES<br />
Sem<strong>in</strong>ars<br />
Department Presentations:<br />
Project overview & research plan<br />
March (10 m<strong>in</strong>).<br />
F<strong>in</strong>al sem<strong>in</strong>ar<br />
November (20 m<strong>in</strong>)<br />
Weekly Research Techniques Sem<strong>in</strong>ars &<br />
Journal Club: - Semester 1<br />
Attendance at formal research sem<strong>in</strong>ars (x4).
REQUIREMENTS OF CANDIDATES<br />
Assessment<br />
Mark breakdown:<br />
Literature Review (May) 5%<br />
F<strong>in</strong>al Sem<strong>in</strong>ar (Nov) 10%<br />
<strong>The</strong>sis (Nov) 75%<br />
Coursework (Sem 1) 10%<br />
(Includ<strong>in</strong>g all aspects <strong>of</strong> sem<strong>in</strong>ar<br />
participation)
How to apply for Honours<br />
Step 1: Select a research project/s. Lists <strong>of</strong> projects are available at<br />
this session and at:<br />
Pathology Discipl<strong>in</strong>e website:<br />
http://sydney.edu.au/medic<strong>in</strong>e/pathology/students/honours/<strong>in</strong>dex.php<br />
Searchable database for Science Honours projects <strong>in</strong> the Faculty <strong>of</strong> Medic<strong>in</strong>e:<br />
http://sydney.edu.au/medic<strong>in</strong>e/future-students/honours/<strong>in</strong>dex.php<br />
Step 2: Discuss the research project with the supervisor/s and<br />
obta<strong>in</strong> permission to undertake the project/s<br />
Step 3: Submit application form to Pathology Discipl<strong>in</strong>e Front<br />
Office (Pathology Dept website)<br />
http://sydney.edu.au/medic<strong>in</strong>e/pathology/students/honours/<strong>in</strong>dex.php<br />
Step 4: Submit application form to Faculty <strong>of</strong> Science<br />
http://sydney.edu.au/science/fstudent/undergrad/course/honours/<strong>in</strong>dex.shtml
Pathology Honours Website
Searchable database for Science Honours<br />
projects <strong>in</strong> the Faculty <strong>of</strong> Medic<strong>in</strong>e<br />
http://sydney.edu.au/medic<strong>in</strong>e/future-students/honours/<strong>in</strong>dex.php
Students consider<strong>in</strong>g Medic<strong>in</strong>e<br />
or Dentistry<br />
It is possible and encouraged to defer<br />
admission <strong>in</strong>to Medic<strong>in</strong>e or Dentistry to<br />
undertake Honours (and later a PhD)
<strong>University</strong> <strong>of</strong> <strong>Sydney</strong><br />
Honours Merit Scholarships<br />
Awarded on the basis <strong>of</strong> academic merit and<br />
personal attributes such as leadership and<br />
creativity<br />
$6,000 for one year !<br />
Applications close early January<br />
http://www.usyd.edu.au/scholarships/prospective/honours.shtml
Marfan Syndrome (MFS)<br />
Hambly Lab<br />
Marfan syndrome (MFS) is an autosomal dom<strong>in</strong>ant <strong>in</strong>herited<br />
genetic connective tissue disease with the estimated<br />
<strong>in</strong>cidence <strong>of</strong> 1 / 3000 ~ 5000.<br />
MFS patients are extremely tall and slim with multi-system<br />
symptoms.<br />
Skeletal: long slim limbs and f<strong>in</strong>gers, scoliosis, pectus<br />
excavatum or car<strong>in</strong>atum and abnormal jo<strong>in</strong>t flexibility and<br />
so on.<br />
Ocular: ectopia lentis (most obvious symptom)<br />
Cardiovascular: mitral valve prolapse, ventricular<br />
dilatation and thoracic aortic aneurysm<br />
Possible pathogenesis<br />
MFS patients <strong>in</strong>herited an abnormal fibrill<strong>in</strong> mutation<br />
from their parents or may generate a new somatic<br />
mutation<br />
MFS patients produce abnormal fibrill<strong>in</strong>, compromis<strong>in</strong>g<br />
micr<strong>of</strong>ibril formation<br />
Fibrill<strong>in</strong>-1+ latent TGF-β → control TGF-β signall<strong>in</strong>g<br />
21 May 2012
Abnormal elasticity<br />
- STIFF WALL (echo)<br />
Abnormal fibrill<strong>in</strong><br />
Excessive wall stress<br />
dur<strong>in</strong>g heart pump<strong>in</strong>g<br />
Inflammation<br />
- cytok<strong>in</strong>es<br />
- MMPs<br />
Cystic Medial Necrosis<br />
Thoracic aortic aneurysm<br />
Failure <strong>of</strong> sequestration <strong>of</strong> TGF-β<br />
- Increased fibrosis<br />
- STIFF WALL (echo)<br />
21 May 2012
Plasma TGFβ and MMPs <strong>in</strong> Human Heritable Aortopathy<br />
600<br />
400<br />
200<br />
15<br />
10<br />
5<br />
0<br />
0<br />
TGFβ ng/ml x 10 NS<br />
Control Marfan MASS FTAD<br />
MMP3 (ng/ml)<br />
*<br />
Control Marfan MASS TAAD<br />
*<br />
600<br />
400<br />
200<br />
0<br />
150<br />
100<br />
50<br />
0<br />
MMP2 ng/ml<br />
*<br />
Control Marfan MASS FTAD<br />
MMP9 (ng/ml)<br />
Control Marfan MASS TAAD<br />
Lu et al unpublished data 2012<br />
*<br />
NS
Supervisor: Dr Danuta Kal<strong>in</strong>owski<br />
Co‐Supervisor: Pr<strong>of</strong> Des Richardson
Fe<br />
Oxidative Phosphorylation DNA Synthesis<br />
‐ Cancer <strong>cell</strong>s require higher levels <strong>of</strong> iron for proliferation and are<br />
more sensitive to iron depletion than normal <strong>cell</strong>s.
• <strong>The</strong>refore, drugs that can b<strong>in</strong>d iron (iron chelators)<br />
represent a novel chemotherapeutic treatment avenue.
Vehicle Control<br />
(15% Propylene<br />
glycol <strong>in</strong> Sal<strong>in</strong>e)<br />
Dp44mT<br />
(0.4 mg/kg)<br />
SK-Mel-28 Tumour Implants after 7 weeks <strong>of</strong> Treatment – IV <strong>in</strong>jection once a day
• This project will assess the anti‐cancer activity and<br />
the mechanisms <strong>of</strong> action <strong>of</strong> novel iron chelators<br />
developed <strong>in</strong> our group.<br />
‐ Structure‐Activity Relationships<br />
‐ Pharmacology<br />
‐ Routes <strong>of</strong> <strong>Cell</strong>ular Uptake<br />
‐ Selectivity <strong>in</strong> Target<strong>in</strong>g Cancer
Ascorbate<br />
Iron Metabolism & Chelation (IMC) Program<br />
Department <strong>of</strong> Pathology<br />
<strong>The</strong> <strong>University</strong> <strong>of</strong> <strong>Sydney</strong>
Iron (Fe) is an essential metal for all mammalian<br />
<strong>cell</strong>s<br />
Fe is required for oxygen transport, mitochondrial<br />
respiration, DNA synthesis, etc.<br />
Although necessary, Fe is potentially toxic to <strong>cell</strong>s<br />
and must be carefully delivered<br />
Almost all Fe <strong>in</strong> plasma is bound to the serum Fe<br />
transport prote<strong>in</strong>, transferr<strong>in</strong> (Tf)<br />
<strong>The</strong> Tf‐to‐<strong>cell</strong> cycle is the major Fe uptake route<br />
used by most <strong>cell</strong>s, and <strong>in</strong> particular dur<strong>in</strong>g red<br />
blood <strong>cell</strong> production<br />
<strong>The</strong> follow<strong>in</strong>g honours project exam<strong>in</strong>es some<br />
basic unanswered questions <strong>in</strong> <strong>cell</strong>ular Fe biology
Andrews N C Blood 2008;112:219-230
Transferr<strong>in</strong>-Fe<br />
complex<br />
<strong>Cell</strong><br />
Transferr<strong>in</strong><br />
without Fe<br />
•<strong>Cell</strong>s <strong>in</strong> the body take up<br />
almost all their iron (Fe)<br />
from the transferr<strong>in</strong> (Tf)-to<strong>cell</strong><br />
cycle<br />
•Vitam<strong>in</strong> C (ascorbate)<br />
stimulates this process by<br />
an unknown mechanism
•<strong>Cell</strong>s <strong>in</strong> the body take up<br />
almost all their iron (Fe)<br />
from the transferr<strong>in</strong> (Tf)-to<strong>cell</strong><br />
cycle<br />
•Vitam<strong>in</strong> C (ascorbate)<br />
stimulates this process by<br />
an unknown mechanism<br />
•<strong>The</strong> Tf-to-<strong>cell</strong> cycle can<br />
be regulated by hypoxia<strong>in</strong>ducible<br />
factors (HIFs)<br />
•Your project can<br />
exam<strong>in</strong>e how ascorbate<br />
regulates <strong>cell</strong> Fe uptake<br />
via HIFs.
Relevance to understand<strong>in</strong>g basic <strong>cell</strong>ular<br />
and systemic iron metabolism, which is<br />
central to a wide range <strong>of</strong> disease types.<br />
Relevance to cancer <strong>cell</strong> metabolism as the<br />
metabolic phenotype <strong>in</strong> cancer <strong>cell</strong>s is<br />
frequently associated with <strong>in</strong>creased<br />
expression <strong>of</strong> HIF1α and decreased <strong>cell</strong>ular<br />
ascorbate
Please contact either:<br />
Darius Lane<br />
darius.lane@sydney.edu.au<br />
Des Richardson<br />
d.richardson@sydney.edu.au
N<br />
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ONO OUR RS S PRROOJE<br />
ECTTS<br />
Hea aded bby:<br />
Pr<strong>of</strong>es P ssor Des D Riicharddson<br />
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Iron is essential for f life and gr rowth. While it is well kno own that ironn<br />
deficiency ccan<br />
lead to annaemia<br />
it is geenerally<br />
not<br />
appreeciated<br />
that iron i is critica al for the grow wth <strong>of</strong> all <strong>cell</strong> ls, particularlly<br />
cancer <strong>cell</strong> lls. <strong>The</strong> Iron MMetabolism<br />
aand<br />
Chellation<br />
Progra am is concern ned with unde erstand<strong>in</strong>g the<br />
basic proceesses<br />
<strong>of</strong> how t<strong>tumour</strong><br />
<strong>cell</strong>s utilise and trransport<br />
iron.<br />
This knowledge will w lead to the<br />
developmen nt <strong>of</strong> therapie es that can seelectively<br />
starrve<br />
<strong>tumour</strong> ceells<br />
<strong>of</strong> iron annd<br />
<strong>in</strong>hibit<br />
theirr<br />
growth. In addition, a we are a study<strong>in</strong>g the t mechanis sms <strong>in</strong>volved <strong>in</strong> iron load<strong>in</strong>ng<br />
<strong>in</strong> the <strong>in</strong>hherited<br />
diseasees<br />
β-<br />
thalaassaemia<br />
and d Friedreich's s ataxia.<br />
1. Deevelopment<br />
t <strong>of</strong> New Iro on Chelators s as Novel Drugs D Aga<strong>in</strong>nst<br />
Cancer<br />
Primmary<br />
supervis sor: Pr<strong>of</strong>. Des<br />
Richardson;<br />
Co-supervi isors: Dr. Davvid<br />
Lovejoy, Dr. Danuta KKal<strong>in</strong>owski.<br />
This project will use u a comb<strong>in</strong>a ation <strong>of</strong> techn niques that are e implemented<br />
<strong>in</strong> chemistrry,<br />
biochhemistry,<br />
phy ysiology, mole ecular biology y and pharma acology to dessign<br />
and asseess<br />
the activityy<br />
<strong>of</strong> noovel<br />
drugs for r the treatmen nt <strong>of</strong> cancer. Your Y project will w be multi- faceted and wwill<br />
<strong>in</strong>volve<br />
groww<strong>in</strong>g<br />
human tu umour <strong>cell</strong>s <strong>in</strong> n tissue cultur re and assessi <strong>in</strong>g the effectss<br />
<strong>of</strong> chelators on gene<br />
expreession.<br />
This will w be done us<strong>in</strong>g u Western n analysis, RT T-PCR and mmicroarray<br />
anaalysis.<br />
<strong>The</strong> labb<br />
has cconsiderable<br />
experience e <strong>in</strong> these cutt<strong>in</strong>g g-edge techniq ques and you will be taughht<br />
the<br />
<strong>in</strong>triccacies<br />
<strong>of</strong> their r use. Feel fre ee to contact Dr. D David Lov vejoy (david. lovejoy@syddney.edu.au)<br />
and DDr.<br />
Danuta Kal<strong>in</strong>owski<br />
(da anutak@med. .usyd.edu.au) to have a chaat<br />
about whetther<br />
the projecct<br />
matches yoour<br />
<strong>in</strong>terests.<br />
2. Tra ansport <strong>of</strong> nitric n oxide <strong>in</strong> <strong>cell</strong>s andd<br />
its <strong>in</strong>teracttion<br />
with iroon<br />
conta a<strong>in</strong><strong>in</strong>g prote<strong>in</strong>s<br />
<strong>in</strong> tumoour<br />
<strong>cell</strong>s<br />
Prima ary superviso or: Pr<strong>of</strong>. Des Richardson.<br />
Nitric oxide (NO) functions f as a natural iron chelator and is <strong>of</strong>ten secreeted<br />
by<br />
macro ophages to des stroy cancer c<strong>cell</strong>s.<br />
This prooject<br />
<strong>in</strong>volvess<br />
exam<strong>in</strong><strong>in</strong>g tthe<br />
method by y<br />
which NO is able to o <strong>in</strong>duce the ssecretion<br />
<strong>of</strong> irron<br />
from canccer<br />
<strong>cell</strong>s. Thiss<br />
project will<br />
use a comb<strong>in</strong>ation c <strong>of</strong> o techniquess<br />
that are usedd<br />
<strong>in</strong> biochemistry,<br />
physioloogy,<br />
<strong>cell</strong><br />
biolog gy, molecular biology and ppharmacologgy.<br />
Feel free too<br />
contact Pr<strong>of</strong>.<br />
Des<br />
Richar rdson (d.richa ardson@med. .usyd.edu.au) ) to have a chat<br />
about whetther<br />
the<br />
projec ct matches you ur <strong>in</strong>terests.<br />
3. Thhe<br />
Role <strong>of</strong> Iron I <strong>in</strong> the Pathogenesi<br />
P is <strong>of</strong> the Cri ippl<strong>in</strong>g Neurrodegeneraative<br />
Diseasee,<br />
Friedreichh's<br />
Ataxia<br />
Primmary<br />
supervis sor: Pr<strong>of</strong>. Des<br />
Richardson;<br />
Co-supervi isors: Dr. Micchael<br />
Huang, Dr. Yohan SSuryo<br />
Rahmannto.<br />
Frieddreich’s<br />
Ataxi ia is a neurod degenerative disease d cause by the accummulation<br />
<strong>of</strong> iroon<br />
<strong>in</strong> the enerrgy<br />
produuc<strong>in</strong>g<br />
macrop phages. This condition c <strong>of</strong>te en results <strong>in</strong> cardiac c hyperttrophy,<br />
muscuular<br />
atrophy aand<br />
earlyy<br />
death. <strong>The</strong> current c project t will exam<strong>in</strong> ne both the pat thophysiologgy<br />
<strong>of</strong> Friedreicch’s<br />
ataxia annd<br />
a<br />
potenntial<br />
new ther rapy that <strong>in</strong>vo olves iron chelation.<br />
This project will use u a comb<strong>in</strong>a ation <strong>of</strong> techn niques that are e used <strong>in</strong> biocchemistry,<br />
phyysiology,<br />
pharmmacology<br />
and d molecular biology. b Feel free f to contac ct Dr. Michaeel<br />
Huang<br />
(mihuuang@med.u<br />
usyd.edu.au) to t have a chat t about wheth her the projectt<br />
matches youur<br />
<strong>in</strong>terests.<br />
4. MMolecular<br />
Re egulation <strong>of</strong> f eIF3a <strong>in</strong> Cancer C <strong>Cell</strong> Motility M andd<br />
Invasion<br />
Primmary<br />
supervis sor: Pr<strong>of</strong>. Des<br />
Richardson;<br />
Co-supervi isors: Dr. Fedderica<br />
Saletta.<br />
eIF3a is the largest su ubunit <strong>of</strong> the eeukaryotic<br />
<strong>in</strong>iitiation<br />
factorr<br />
3 (eIF3) andd<br />
plays a role<br />
as a regu ulator <strong>of</strong> a sub bset <strong>of</strong> mRNAAs<br />
encod<strong>in</strong>g pprote<strong>in</strong>s<br />
<strong>in</strong>vollved<br />
<strong>in</strong> the <strong>cell</strong><br />
cycle, <strong>cell</strong><br />
prolifera ation and <strong>cell</strong> mobility. Thiis<br />
project aimms<br />
to identify new targets o<strong>of</strong><br />
eIF3a<br />
<strong>in</strong>volved d <strong>in</strong> enhanced cancer <strong>cell</strong> mmobility<br />
and i<strong>in</strong>vasion.<br />
A vaariety<br />
<strong>of</strong> techhniques<br />
will<br />
be used <strong>in</strong>clud<strong>in</strong>g: i cel ll culture, revverse-transcripptase-PCR<br />
annd<br />
quantitative<br />
PCR,<br />
Western blott<strong>in</strong>g, imm mun<strong>of</strong>luorescent<br />
sta<strong>in</strong><strong>in</strong>g, ggene<br />
knockdoown,<br />
drug treeatment<br />
etc.<br />
This study is impo ortant for und derstand<strong>in</strong>g th he pathologica al role <strong>of</strong> eIF33a<br />
<strong>in</strong> the exprression<br />
<strong>of</strong> mettastasis<br />
regulaators<br />
and for<br />
devellop<strong>in</strong>g<br />
novel therapeutics target<strong>in</strong>g t eIF3 3a and its dow wnstream signnal<strong>in</strong>g.<br />
Our sttudies<br />
are cruucial<br />
for deepeen<strong>in</strong>g<br />
our<br />
knowwledge<br />
about cancer <strong>cell</strong> bi iology and de evelop<strong>in</strong>g exp ploitable treatmments<br />
for canncer.<br />
Feel freee<br />
to contact DDr.<br />
Federica<br />
Salettta<br />
(fsaletta@med.usyd.edu<br />
u.au) to have a chat about whether w the pproject<br />
matchhes<br />
your <strong>in</strong>tereests.
5. Innvestigat<strong>in</strong>g<br />
g <strong>cell</strong>ular res sponse to iron-depletion<br />
by exam<strong>in</strong>n<strong>in</strong>g<br />
the miitogen-activated<br />
prote<strong>in</strong>n<br />
k<strong>in</strong>ases<br />
(MAAPK)<br />
signall l<strong>in</strong>g pathwa ay<br />
Primmary<br />
supervis sor: Pr<strong>of</strong>. Des<br />
Richardson;<br />
Co-supervi isors: Dr. Yu Yu.<br />
Iron-depletion<br />
ca an cause mmultiple<br />
effeccts<br />
<strong>in</strong>clud<strong>in</strong>gg<br />
<strong>in</strong>hibition <strong>of</strong> the iron n-<br />
IRON DEPLETION<br />
conta<strong>in</strong><strong>in</strong>g<br />
enzym me, ribonuclleotide<br />
reduuctase<br />
whichh<br />
is importaant<br />
for DNA A<br />
TTrx<br />
Trx<br />
synth hesis, <strong>cell</strong> cyc cle arrest andd<br />
apoptosis. RRecently,<br />
the rrole<br />
<strong>of</strong> signall<strong>in</strong>g<br />
pathways<br />
AASK1<br />
ASKK1-<br />
P<br />
<strong>in</strong> th he regulation <strong>of</strong> <strong>cell</strong>ular iroon<br />
metabolismm<br />
is becom<strong>in</strong>ng<br />
<strong>in</strong>creas<strong>in</strong>glly<br />
recognized d.<br />
<strong>The</strong> aim <strong>of</strong> this pr roject is to eluucidate<br />
the mmolecular<br />
signnall<strong>in</strong>g<br />
pathwaay<br />
<strong>in</strong>volved <strong>in</strong> n<br />
MKK4/7<br />
MKK3/6<br />
iron-depletion<br />
by y exam<strong>in</strong><strong>in</strong>gg<br />
the mitogeen-activated<br />
prote<strong>in</strong> k<strong>in</strong>aases<br />
(MAPK K)<br />
DUSPP<br />
1<br />
DDUSP<br />
1 signa all<strong>in</strong>g pathwa ay which funcctions<br />
to l<strong>in</strong>k extra<strong>cell</strong>ularr<br />
signals to regulate<br />
diverse<br />
DUSPP<br />
10<br />
DUSPP<br />
16<br />
JNK- P<br />
p38- P DDUSP<br />
10<br />
DDUSP<br />
16 <strong>cell</strong>u ular processes.<br />
<strong>The</strong> projeect<br />
will <strong>in</strong>vollve<br />
multiple techniques i<strong>in</strong>clud<strong>in</strong>g<br />
cel ll<br />
cultu ures, RNA tr ransfection, rreverse-transccriptional-PCCR,<br />
Western blott<strong>in</strong>g, cel ll<br />
p53- P<br />
ATF2- P proli iferation assa ays, etc. <strong>The</strong> rresults<br />
will bee<br />
vital for ouur<br />
understandi<strong>in</strong>g<br />
<strong>of</strong> <strong>cell</strong>ula ar<br />
signa all<strong>in</strong>g aspect ts <strong>of</strong> iron-deficiency<br />
and d the molecuular<br />
pharmacoology<br />
<strong>of</strong> iron n<br />
APOPTOSIS<br />
chela ation. Contac ct Dr. Yu Yuu<br />
(yuyu@medd.usyd.edu.auu)<br />
to have a cchat<br />
about the<br />
proje ect.<br />
HS<br />
HS<br />
S<br />
S<br />
6. Cancer<br />
<strong>The</strong>ra apeutics and<br />
Target<strong>in</strong>g g (Multi-Dru ug Resistannce)<br />
Primmary<br />
supervis sor: Dr. Patri ic Jansson; Co o-supervisor rs: Pr<strong>of</strong>. Des RRichardson.<br />
Multtidrug<br />
resistan nce (MDR) is a phenomeno on <strong>in</strong> which cancer c <strong>cell</strong>s arre<br />
resistant too<br />
the cytotoxicc<br />
effects <strong>of</strong> vaarious<br />
chemmotherapeutic<br />
agents. One major mechan nism by whic ch this occurss<br />
is through thhe<br />
over--expression<br />
<strong>of</strong><br />
ATP-dependent<br />
drug effl flux transporte ers such as thhe<br />
P-glycoprotte<strong>in</strong><br />
(Pgp) ) and multidrug<br />
resistance-associated<br />
pr rote<strong>in</strong> (MRP) ). <strong>The</strong> hypoxiia-<strong>in</strong>ducible<br />
fa factor<br />
(HIF)-1<br />
is a maste er transcriptio onal activator <strong>of</strong> oxygen-re egulated geness<br />
and HIF-1 iis<br />
consttitutively<br />
up regulated r <strong>in</strong> several<br />
tumou ur types under r hypoxic connditions<br />
and HHIF<br />
mighht<br />
thus be imp plicated <strong>in</strong> tum mour therapy resistance.<br />
This Honours proj ject will <strong>in</strong>vestigate<br />
wheth her iron chelat tion, HIF-1 acctivation,<br />
hyppoxia<br />
and PPgp<br />
is important<br />
for how novel n iron che elators overco ome drug resisstance.<br />
This project will use u a comb<strong>in</strong>a ation <strong>of</strong> cutt<strong>in</strong> ng-edge techn niques <strong>in</strong>cludi<strong>in</strong>g:<br />
<strong>cell</strong> cultuure,<br />
westeern<br />
blott<strong>in</strong>g, siRNA, s cytoto oxicity detect tion and fluor rescent/confoccal<br />
microscoppy<br />
etc. PPlease<br />
contact t Dr. Patric Ja ansson (patric c.jansson@sy ydney.edu.au) to discuss thhis<br />
projeect.<br />
7. Thhe<br />
Role <strong>of</strong> Melanotrans<br />
M sferr<strong>in</strong> <strong>in</strong> Melanoma M Growth G and Metastasis<br />
Primmary<br />
supervis sor: Dr. Yoha an Suryo Rah hmanto; Co-su upervisors: PPr<strong>of</strong>.<br />
Des Ricchardson,<br />
Dr. Yu Yu, Dr. ZZakl<strong>in</strong>a<br />
Kovaacevic.<br />
Melaanoma<br />
is the fourth f most co ommon cance er <strong>in</strong> NSW an nd Australia aand<br />
new<br />
Iron homeostasis /<br />
metabolism<br />
treatmments<br />
are urg gently required.<br />
Melanotran nsferr<strong>in</strong> (MTf f) is a molecuule<br />
that is<br />
highlly<br />
expressed <strong>in</strong> i melanoma (for review see<br />
Oncogene 26:6113-24) . <strong>The</strong><br />
Epithelial septal<br />
Angiogenesis<br />
MTf<br />
junction<br />
aim o<strong>of</strong><br />
this project t is to exam<strong>in</strong> ne the hypothe esis that MTf f plays roles <strong>in</strong>n<br />
<strong>cell</strong><br />
cyclee<br />
<strong>progression</strong>, , growth and melanoma m me etastasis. This<br />
is importantt<br />
as<br />
<strong>Cell</strong> prroliferation,<br />
migration and<br />
<strong>tumour</strong>igenesis<br />
melaanoma<br />
<strong>in</strong>ciden nce is <strong>in</strong>creasi <strong>in</strong>g worldwid de and metasta atic melanomma<br />
is<br />
almoost<br />
completely y resistant to every e known therapy. Laboratory<br />
technniques<br />
<strong>in</strong>volveed:<br />
animal haandl<strong>in</strong>g,<br />
mammmalian<br />
<strong>cell</strong><br />
cultuure,<br />
molecular r clon<strong>in</strong>g, <strong>cell</strong> l transfection, , RNA and pr rote<strong>in</strong> extractiion,<br />
RT-PCR,<br />
Western bloott<strong>in</strong>g,<br />
<strong>cell</strong> bioology<br />
assay<br />
and aanalysis,<br />
flow w cytometry an nd immunohi istochemistry.<br />
Contact Dr. Yohan Suryoo<br />
Rahmanto<br />
(yohaan.suryorahm<br />
manto@sydney y.edu.au) to have h a chat ab bout this projeect.<br />
8. MMolecular<br />
regulation<br />
<strong>of</strong> ERp29 <strong>in</strong> epithelial<br />
can ncer <strong>cell</strong> plaasticity<br />
Primmary<br />
supervis sor: Dr. Daoh hai Zhang; Co o-supervisor rs: Pr<strong>of</strong>. Des RRichardson<br />
Endooplasmic<br />
retic culum prote<strong>in</strong> n 29 (ERp29) is a novel mo olecule that <strong>in</strong>nduces<br />
epithelial-mesenchyymal<br />
reverse transition and d<br />
epithhelial<br />
<strong>cell</strong> mor rphogenesis. This T project aims a to understand<br />
the funcctions<br />
and moolecular<br />
mechhanisms<br />
<strong>of</strong> ERRp29<br />
<strong>in</strong><br />
estabblish<strong>in</strong>g<br />
epithe elial architect ture <strong>in</strong> cancer r <strong>cell</strong>s. A variety<br />
<strong>of</strong> techniqques<br />
that will be used <strong>in</strong>cluude<br />
<strong>cell</strong> cultuures,<br />
3-<br />
dimeensional<br />
<strong>cell</strong> system, s revers se-transcriptio onal-PCR, Western W blott<strong>in</strong>ng,<br />
immun<strong>of</strong>luuorescent<br />
stai<strong>in</strong><strong>in</strong>g,<br />
prote<strong>in</strong>n-prote<strong>in</strong><br />
<strong>in</strong>teraaction,<br />
gene knockdown, k etc e . This stud dy is importan nt for understaand<strong>in</strong>g<br />
the paathological<br />
fuunction<br />
<strong>of</strong> ERpp29<br />
as a<br />
noveel<br />
<strong>tumour</strong> supp pressive mole ecule and for develop<strong>in</strong>g novel n therapeuutics<br />
target<strong>in</strong>gg<br />
ERp29 and its downstreaam<br />
signal<strong>in</strong>g.<br />
1
9. Diissect<strong>in</strong>g<br />
the e role <strong>of</strong> NDR RG-1 <strong>in</strong> regu ulat<strong>in</strong>g endo oplasmic retiiculum<br />
stress<br />
and cancerr<br />
<strong>cell</strong> survivaal<br />
Primmary<br />
supervis sor: Dr. Daoh hai Zhang; Co o-supervisor rs: Pr<strong>of</strong>. Des RRichardson.<br />
N-myyc<br />
downstrea am regulated gene g 1 (NDRG G1) is a meta astasis suppressor<br />
that is<br />
<strong>in</strong>vollved<br />
<strong>in</strong> <strong>cell</strong> di ifferentiation, , carc<strong>in</strong>ogenesis,<br />
survival, and metastasis.<br />
It is sensittive<br />
to thee<br />
redox status s <strong>of</strong> the <strong>cell</strong>s and a the <strong>in</strong>trac <strong>cell</strong>ular calciu um concentrattion.<br />
Disruption<br />
<strong>of</strong> caalcium<br />
homeo ostasis with<strong>in</strong> endoplasmic reticulum (E ER) system is associated wiith<br />
the EER<br />
stress response<br />
that repr resents an ada aptive mechan nism supporti t<strong>in</strong>g survival aand<br />
chemmoresistance<br />
<strong>of</strong> o tumor <strong>cell</strong>s s. This project t aims to disse ect how NDRRG1<br />
expressioon<br />
moduulates<br />
ER stre ess and to und derstand the biological b con nsequences. TThis<br />
study willl<br />
use<br />
<strong>cell</strong> cculture,<br />
immu unoblott<strong>in</strong>g, gene g silenc<strong>in</strong>g g, <strong>cell</strong>-based functional f anaalysis,<br />
phospphatase<br />
assay y, drug treatm ment and <strong>cell</strong> apoptosis, a etc.<br />
Feel free to contact Dr.<br />
Daohhai<br />
Zhang (da aohai.zhang@ @sydney.edu.a au) to have a chat c about thiis<br />
project.<br />
10. HHow<br />
does vi itam<strong>in</strong> C (as scorbate) re egulate iron n uptake by <strong>cell</strong>s? <strong>The</strong> rrole<br />
<strong>of</strong> HIFss.<br />
Primmary<br />
supervis sor: Dr. Dariu us Lane; Co- supervisors: Pr<strong>of</strong>. Des Riichardson.<br />
Iron (Fe) is essen ntial for life and it has long l been re ecognised thaat<br />
vitam<strong>in</strong> C (ascorbate)- deficiency caauses<br />
anemia a.<br />
Normmally,<br />
circulat<strong>in</strong>g<br />
Fe is bou und to the Fe e-b<strong>in</strong>d<strong>in</strong>g prote<strong>in</strong>,<br />
transferrr<strong>in</strong><br />
(Tf), withh<br />
Tf-Fe uptakke<br />
be<strong>in</strong>g the mmajor<br />
route <strong>of</strong> o<br />
Fe uuptake<br />
by ma ammalian <strong>cell</strong>s.<br />
<strong>Cell</strong>ular hypoxia h (low w oxygen tenssion)<br />
stimulaates<br />
Tf-Fe upptake<br />
by up-rregulat<strong>in</strong>g<br />
the<br />
expreession<br />
<strong>of</strong> prote<strong>in</strong>s<br />
<strong>in</strong>volve ed <strong>in</strong> the classical<br />
Tf-to-ce ell cycle for FFe<br />
delivery ( (e.g., the Tf rreceptor;<br />
TfRR1).<br />
We have<br />
recenntly<br />
identified d that ascorb bate, which is s abundant <strong>in</strong> n vivo but typpically<br />
absent nt <strong>in</strong> standardd<br />
<strong>cell</strong> culture,<br />
dramatically y<br />
stimuulates<br />
Fe upta ake from Tf-F Fe, although th he molecular mechanism iis<br />
unknown.<br />
<strong>The</strong> aim <strong>of</strong> this project p is to determ<strong>in</strong>e d ho ow ascorbate <strong>in</strong>teracts i withh<br />
HIFs to reggulate<br />
<strong>cell</strong>ularr<br />
Fe uptake. TThis<br />
will have<br />
impoortant<br />
ramifica ations for the treatment <strong>of</strong> f diseases rang g<strong>in</strong>g from anaaemia<br />
to canccer.<br />
Feel free to contact Drr.<br />
Darius Lane<br />
(dariuus.lane@sydn<br />
ney.edu.au) to o have a chat about whethe er the project matches youur<br />
<strong>in</strong>terests.<br />
11. HHow<br />
do astr rocytes proc cess iron? Role R <strong>of</strong> GPI-l<strong>in</strong>ked<br />
Cp.<br />
Primmary<br />
supervis sor: Dr. Dariu us Lane; Cosupervisors: Pr<strong>of</strong>. Des Riichardson.<br />
<strong>The</strong> bbra<strong>in</strong><br />
has a high<br />
requirement<br />
for iron (Fe), ( which is s essential forr<br />
life, yet the mechanisms by which Fee<br />
enters and is<br />
proceessed<br />
by the bra<strong>in</strong> b rema<strong>in</strong>s s a mystery. With<strong>in</strong> W the bra a<strong>in</strong>, astrocytes<br />
(‘star-shapeed’<br />
glial <strong>cell</strong>s that are at leeast<br />
equivalen nt<br />
<strong>in</strong> nuumber<br />
to neur rones) are tho ought to be important i <strong>in</strong> process<strong>in</strong>g p annd<br />
re-distribuut<strong>in</strong>g<br />
Fe <strong>in</strong> thhe<br />
bra<strong>in</strong>. Astrrocytes<br />
extend d<br />
long processes that<br />
ensheathe the bra<strong>in</strong> cap pillaries and help to form m the BBB. Inntrigu<strong>in</strong>gly,<br />
thhe<br />
ends <strong>of</strong> thhese<br />
processes<br />
(i.e., the ‘end-feet t’) express a special s form <strong>of</strong> o the Fe oxid dis<strong>in</strong>g enzymme,<br />
ceruloplasmm<strong>in</strong><br />
(Cp). Thhis<br />
prote<strong>in</strong> is ttethered<br />
to the<br />
exterrnal<br />
surface <strong>of</strong> o the plasma membrane by b a glycopho osphatidyl<strong>in</strong>ossitol<br />
(GPI) annchor.<br />
<strong>The</strong> roole<br />
<strong>of</strong> astrocyyte<br />
GPI-l<strong>in</strong>ked d<br />
Cp iss<br />
unknown.<br />
<strong>The</strong> aim <strong>of</strong> this project p is to determ<strong>in</strong>e the<br />
role <strong>of</strong> GPI I-l<strong>in</strong>ked Cp <strong>in</strong>n<br />
astrocytic FFe<br />
process<strong>in</strong>gg.<br />
This will hhave<br />
importan nt<br />
ramiffications<br />
for the t understan nd<strong>in</strong>g and trea atment <strong>of</strong> neu urodegeneratiive<br />
diseases tthat<br />
are assocciated<br />
with abbnormal<br />
bra<strong>in</strong> n<br />
Fe metabolism, such as Alzheimer’s A<br />
and Park<strong>in</strong> nson’s diseaases.<br />
Feel free to coontact<br />
Dr. Darius Lane<br />
(dariuus.lane@sydn<br />
ney.edu.au) to o have a chat about whethe er the project matches youur<br />
<strong>in</strong>terests.<br />
12. EExam<strong>in</strong><strong>in</strong>g<br />
the t Molecul lar Mechanisms<br />
Beh<strong>in</strong>d d the Anti-TTumour<br />
Acttivity<br />
<strong>of</strong> NDDRG1<br />
<strong>in</strong> Panncreatic<br />
Cancer<br />
Primmary<br />
supervis sor: Pr<strong>of</strong>. Des<br />
Richardson;<br />
Co-supervi isor: Dr. Zakll<strong>in</strong>a<br />
Kovacevvic.<br />
Pancreatic<br />
cancer is a highly ag ggressive dise ease with a po oor response tto<br />
current<br />
theraapies.<br />
<strong>The</strong> metastasis<br />
suppr ressor N-myc c down-stream m regulated geene<br />
1 (NDRGG1)<br />
has bbeen<br />
shown to o effectively <strong>in</strong>hibit i pancre eatic cancer by y reduc<strong>in</strong>g prrimary<br />
tumouur<br />
growwth,<br />
metastasis s and angioge enesis.<br />
This project will <strong>in</strong>volve<br />
exami <strong>in</strong><strong>in</strong>g the mol lecular functio ons <strong>of</strong> NDRGG1<br />
to elucidatte<br />
the<br />
mechhanisms<br />
that are a <strong>in</strong>volved <strong>in</strong> i its anti-tum mour activity. Moreover, thhe<br />
project will<br />
also<br />
examm<strong>in</strong>e<br />
a novel class c <strong>of</strong> anti-cancer<br />
agents that are able to t markedly uup-regulate<br />
NDRRG1<br />
expressio on <strong>in</strong> cancer and a may be a potential new w therapeutic strategy for<br />
pancrreatic<br />
cancer treatment.<br />
A rannge<br />
<strong>of</strong> experim mental techni iques <strong>in</strong>clud<strong>in</strong> ng tissue cultu ure, western bblot<br />
analysis,<br />
immuunohistochem<br />
mistry and dru ug treatments will be performed.<br />
Feel frree<br />
to contact Dr.<br />
Zakli<strong>in</strong>a<br />
Kovacevic<br />
(zakl<strong>in</strong>a.kov vacevic@syd dney.edu.au) to t have a chatt<br />
about whethher<br />
the<br />
projeect<br />
matches yo our <strong>in</strong>terests.
2013 Honours Projects<br />
SYDNEY MEDICAL SCHOOL<br />
Neuropathology<br />
Dr Greg Sutherland and Pr<strong>of</strong> Jillian Kril<br />
Discipl<strong>in</strong>e <strong>of</strong> Pathology
Alcohol-related bra<strong>in</strong> damage<br />
and neurogenesis<br />
Sutherland et al. Submitted to Exp Neurol<br />
Fluorescent<br />
microscopy<br />
ARBD and Hepatic Encephalopathy<br />
Human bra<strong>in</strong> transcriptome<br />
2
Dementia<br />
Alzheimer's disease Frontotemporal dementia<br />
Sutherland and Kril. Ch 16, Neuroscience: Deal<strong>in</strong>g with Frontiers<br />
Masters CL, Kril JJ et al. Pathology 2011;43:93-102.<br />
Neuroglob<strong>in</strong>, PI3K/Akt<br />
signal<strong>in</strong>g and Alzheimer's<br />
disease<br />
3
2013 Honours Year Project:<br />
<strong>Cell</strong>-<strong>cell</strong> <strong><strong>in</strong>teractions</strong> <strong>in</strong> <strong>tumour</strong> <strong>progression</strong><br />
Dermatology Research Labs, Blackburn Bldg<br />
Pr<strong>in</strong>cipal supervisor: Assoc. Pr<strong>of</strong>. Guy Lyons<br />
guy.lyons@sydney.edu.au<br />
Associate supervisors: Dr Cathy Payne<br />
Dr Vani Raviraj<br />
Pr<strong>of</strong>. Gary Halliday
<strong>Cell</strong>-<strong>cell</strong> <strong><strong>in</strong>teractions</strong> <strong>in</strong> <strong>tumour</strong> <strong>progression</strong><br />
• Mutations cause two basic properties <strong>of</strong> cancer:<br />
• Uncontrolled proliferation<br />
• Spread from the site <strong>of</strong> orig<strong>in</strong><br />
• Tumours <strong>of</strong>ten conta<strong>in</strong> <strong>cell</strong>s that have different mutations<br />
i.e. they are dist<strong>in</strong>ct clones<br />
• This genetic diversity provides the opportunity for<br />
<strong><strong>in</strong>teractions</strong> to occur between clones<br />
• Clonal <strong><strong>in</strong>teractions</strong> might make <strong>tumour</strong>s more malignant<br />
BUT DO THEY?<br />
Aim: Create clones with dist<strong>in</strong>ct oncogenes and<br />
test their malignant behaviour alone and together
<strong>Cell</strong>-<strong>cell</strong> <strong><strong>in</strong>teractions</strong> <strong>in</strong> <strong>tumour</strong> <strong>progression</strong><br />
Techniques used:<br />
1. Genetic eng<strong>in</strong>eer<strong>in</strong>g<br />
2. Genetic modification <strong>of</strong> cultured mammalian <strong>cell</strong>s<br />
3. Analysis <strong>of</strong> gene expression immunologically<br />
4. Fluorescence microscopy<br />
5. Small animal handl<strong>in</strong>g and bioimag<strong>in</strong>g
Eng<strong>in</strong>eer gene expression vectors<br />
Use molecular biological methods to make plasmid and viral<br />
vectors suitable for express<strong>in</strong>g genes <strong>in</strong> mammalian <strong>cell</strong>s
Make genetically modified human <strong>cell</strong> l<strong>in</strong>es<br />
Transfect the start<strong>in</strong>g non-malignant clone<br />
with candidate oncogenes<br />
Gene 1<br />
+<br />
RFP<br />
Clone 1 Clone 2<br />
Clones 1 and 2<br />
together<br />
Proliferation * Motility * Invasion * Tumour Growth
Live <strong>cell</strong> imag<strong>in</strong>g microscopy to measure<br />
<strong>cell</strong> motility
Live animal imag<strong>in</strong>g to measure<br />
<strong>tumour</strong> growth<br />
Paul Sou
2013 Honours Year Project:<br />
<strong>Cell</strong>-<strong>cell</strong> <strong><strong>in</strong>teractions</strong> <strong>in</strong> <strong>tumour</strong> <strong>progression</strong><br />
Dermatology Research Labs, Blackburn Bldg<br />
Pr<strong>in</strong>cipal supervisor: Assoc. Pr<strong>of</strong>. Guy Lyons<br />
guy.lyons@sydney.edu.au<br />
Associate supervisors: Dr Cathy Payne<br />
Dr Vani Raviraj<br />
Pr<strong>of</strong>. Gary Halliday
Redef<strong>in</strong><strong>in</strong>g the role <strong>of</strong> monocytes/macrophages <strong>in</strong> vascular disease<br />
Are all macrophages <strong>in</strong> the plaque bad?<br />
Th<strong>in</strong> cap<br />
(mac MMPs)<br />
large<br />
necrotic core<br />
(mac foam <strong>cell</strong>s)<br />
the<br />
Heather Medbury, Vascular Biology Research Centre,<br />
Surgery, Westmead Hospital, Westmead<br />
Heart attack<br />
stroke
Classical activation M1 Alternatively activated M2( a, b, c...)<br />
CD86<br />
CD64 CD163<br />
Plaque <strong>in</strong>stability?<br />
M1:CD86 M2:CD163<br />
CD206 (MR)<br />
Athero‐protective?<br />
Macrophage marker, procollagen I, co‐expression mac marker & procollagen I, nuclei
Redef<strong>in</strong><strong>in</strong>g monocyte/macrophage role by address<strong>in</strong>g:<br />
SMC<br />
1. Site <strong>of</strong> transformation: (blood or plaque)<br />
MMP’s<br />
4. Fate <strong>of</strong> the <strong>cell</strong>:<br />
Proliferation, death, migration<br />
3. Function<br />
‐Foam <strong>cell</strong><br />
‐MMPs<br />
‐Collagen<br />
production<br />
2. Pathway <strong>of</strong> differentiation (<strong>in</strong>clud<strong>in</strong>g plasticity)<br />
EC
Dr Hilda Pickett<br />
hpickett@cmri.org.au<br />
Cancer Research Unit<br />
http://www.cmri.org.au
Telomere biology group<br />
Cancer <strong>cell</strong>s become<br />
immortal by activat<strong>in</strong>g<br />
the enzyme telomerase<br />
to replenish telomere<br />
loss dur<strong>in</strong>g <strong>cell</strong> division
Telomere ma<strong>in</strong>tenance mechanisms <strong>in</strong> cancer<br />
Projects available:<br />
1. Molecular changes associated with the alternative lengthen<strong>in</strong>g <strong>of</strong><br />
telomeres (ALT) mechanism <strong>of</strong> telomere ma<strong>in</strong>tenance<br />
2. <strong>The</strong> role <strong>of</strong> telomere rapid deletion <strong>in</strong> <strong>cell</strong> proliferation<br />
3. Functional analysis <strong>of</strong> s<strong>in</strong>gle nucleotide polymorphisms with<strong>in</strong> the TERT<br />
locus<br />
4. <strong>The</strong> role <strong>of</strong> non-cod<strong>in</strong>g RNAs <strong>in</strong> telomere ma<strong>in</strong>tenance mechanisms<br />
hpickett@cmri.org.au
Def<strong>in</strong><strong>in</strong>g the antigen presentation capacity <strong>of</strong> bra<strong>in</strong> endothelial <strong>cell</strong>s<br />
Primary supervisor: Dr Julie Wheway (julie.wheway@sydney.edu.au)<br />
Co‐supervisor: Pr<strong>of</strong> Georges Grau (georges.grau@sydney.edu.au)<br />
Techniques used will <strong>in</strong>clude <strong>cell</strong> culture, tripartite co‐culture assays, flow cytometry and fluorescence<br />
microscopy.<br />
pRBC<br />
“Pr<strong>of</strong>essional”<br />
APC<br />
Bra<strong>in</strong> endothelial <strong>cell</strong>s<br />
Immature<br />
T <strong>cell</strong><br />
?<br />
Activated<br />
T <strong>cell</strong>
Exam<strong>in</strong><strong>in</strong>g an immunomodulatory role for endothelial microparticles<br />
Primary supervisor: Dr Julie Wheway (julie.wheway@sydney.edu.au)<br />
Co‐supervisor: Pr<strong>of</strong> Georges Grau (georges.grau@sydney.edu.au)<br />
Techniques used will <strong>in</strong>clude <strong>cell</strong> culture, flow cytometry and fluorescence microscopy and western<br />
blott<strong>in</strong>g.<br />
pRBC<br />
Inflammation<br />
Bra<strong>in</strong> endothelial <strong>cell</strong>s<br />
Membrane surface<br />
shedd<strong>in</strong>g<br />
eMPs<br />
?<br />
Immature<br />
T <strong>cell</strong><br />
Activated<br />
T <strong>cell</strong>
Nature Genetics <strong>Cell</strong><br />
American Journal <strong>of</strong> Human Genetics<br />
Human Molecular Genetics<br />
Sports Illustrated 2010<br />
A gene for speed: the<br />
role <strong>of</strong> α-act<strong>in</strong><strong>in</strong>-3 <strong>in</strong> the<br />
regulation <strong>of</strong> skeletal<br />
muscle mass<br />
Supervisors: Pr<strong>of</strong>essor Kathryn<br />
North, Dr Kate Qu<strong>in</strong>lan and Dr<br />
Peter Houwel<strong>in</strong>g
WT KO<br />
kate.qu<strong>in</strong>lan@sydney.edu.au<br />
~ 1 billion people
Located <strong>in</strong> Westmead Millennium Institute<br />
Currently have 3 grants<br />
Supported by the Storr Trust<br />
Westmead pulls <strong>in</strong> 1/3 <strong>of</strong> NHMRC fund<strong>in</strong>g go<strong>in</strong>g to USYD<br />
My group is 10: 1 Postdoc, 4 PhD students, 4 RAs, 1 TA.<br />
Have 20 knock‐out mouse l<strong>in</strong>es available<br />
Look<strong>in</strong>g for students to do Honours and then a PhD<br />
New Build<strong>in</strong>g <strong>in</strong> March 2014
Does liver talk to fat??<br />
Eg:<br />
Adiponect<strong>in</strong><br />
TNF, IL6<br />
FABP4<br />
?????? BA<br />
Metabolic Studies us<strong>in</strong>g TGR5, FXR & Adiponect<strong>in</strong> KO mice
Does diet promote adipocytok<strong>in</strong>e changes?
Skills learned<br />
1. <strong>Cell</strong> based models<br />
2. Mouse based models.<br />
3. Biochemistry, histology.<br />
4. Human cohorts.<br />
lionel.hebbard@sydney.edu.au<br />
Phone: 02 9845 9132
Most common <strong>in</strong>herited<br />
disease present<strong>in</strong>g <strong>in</strong><br />
neurogenetics cl<strong>in</strong>ics<br />
Cl<strong>in</strong>ically and genetically heterogeneous<br />
disorder affect<strong>in</strong>g both the motor and<br />
sensory neurons <strong>of</strong> peripheral nervous<br />
system<br />
CHARCOT MARIE<br />
TOOTH DISEASE (CMT)<br />
50 Genes known to cause CMT<br />
<strong>The</strong> biological problem is the<br />
‘dy<strong>in</strong>g back’ <strong>of</strong> the nerve or<br />
axonal degeneration
Family Studies & L<strong>in</strong>kage Analysis<br />
Utilis<strong>in</strong>g Exome SequenceData<br />
Bio<strong>in</strong>formatics<br />
IDENTIFYING<br />
NEW GENES<br />
CAUSING<br />
MOTOR<br />
AND SENSORY<br />
NEURON DEATH<br />
International Track record<br />
State-<strong>of</strong>-the-art technology for<br />
variant validation<br />
High Resolution<br />
Melt (HRM)<br />
Well resourced lab – staff & students
Westmead Millennium Institute<br />
Dr Mark Douglas<br />
Hepatitis C Virus<br />
Pathogenesis Group<br />
for Medical Research
Hepatitis C Virus (HCV)<br />
› 3% <strong>of</strong> the world’s population (1% <strong>in</strong> Australia) is <strong>in</strong>fected with HCV<br />
› It is now the ma<strong>in</strong> cause <strong>of</strong> liver failure, liver transplant and liver cancer <strong>in</strong><br />
Australia, USA and UK<br />
› HCV causes more deaths than HIV <strong>in</strong> Australia and USA<br />
› It is now curable but current treatments are toxic and <strong>of</strong>ten fail, so new<br />
treatments are needed<br />
2
Metabolic Complications <strong>of</strong> Hepatitis C<br />
HCV <strong>in</strong>teracts with Host Lipid Metabolism<br />
› Steatosis (fatty liver) – HCV Genotype 3<br />
- Lipids essential for HCV replication<br />
- Virus circulates <strong>in</strong> serum with lipoprote<strong>in</strong>s<br />
- Block lipid synthesis <strong>in</strong>hibits HCV replication<br />
› Insul<strong>in</strong> resistance (diabetes) – Genotype 1<br />
- Faster <strong>progression</strong> to liver fibrosis,<br />
cirrhosis and liver cancer<br />
- Predicts non-response to antiviral treatment (<strong>in</strong>terferon,<br />
ribavir<strong>in</strong>)<br />
› Mechanisms are poorly understood<br />
3
PROJECT 1<br />
Treat<strong>in</strong>g hepatitis C virus with cannab<strong>in</strong>oid antagonists<br />
› Endocannab<strong>in</strong>oids are hormones related to cannabis that control lipid<br />
metabolism<br />
› CB1 is the ma<strong>in</strong> endocannab<strong>in</strong>oid receptor <strong>in</strong> the liver<br />
› CB1 expression is <strong>in</strong>creased <strong>in</strong> the livers <strong>of</strong> people with chronic hepatitis C<br />
- This likely contributes to steatosis and encourages virus replication<br />
› Drugs that block CB1 (CB1 antagonists) can <strong>in</strong>hibit HCV replication <strong>in</strong> <strong>cell</strong><br />
culture models.<br />
› This project explores the mechanism <strong>of</strong> this effect, and will hopefully lead<br />
to trials <strong>of</strong> CB1 antagonists <strong>in</strong> patients with Hepatitis C<br />
4
PROJECT 2<br />
Revers<strong>in</strong>g IFN refractor<strong>in</strong>ess to improve HCV treatment<br />
› <strong>The</strong> ma<strong>in</strong> treatment for HCV is <strong>in</strong>terferon (IFN) alpha<br />
- Over 50% <strong>of</strong> patients with HCV genotype 1 fail current IFN treatment<br />
› Patients who respond poorly to IFN have evidence <strong>of</strong> IFN pre-activation <strong>in</strong><br />
their liver, which <strong>in</strong>duces IFN refractor<strong>in</strong>ess and poor response to IFN<br />
› We have discovered novel prote<strong>in</strong>s that <strong>in</strong>hibit IFN signall<strong>in</strong>g <strong>in</strong> patients<br />
with hepatitis C <strong>in</strong>fection<br />
› We have shown that PPAR alpha agonists (anti-cholesterol drugs) can<br />
partially reverse IFN refractor<strong>in</strong>ess <strong>in</strong> HCV <strong>cell</strong> culture models<br />
› This project will explore the mechanisms <strong>of</strong> this effect, and will hopefully<br />
lead to trials <strong>of</strong> these drugs <strong>in</strong> patients with chronic Hepatitis C<br />
5
› Contac Mark Douglas<br />
› Mark.douglas@sydney.edu.au<br />
› Tel: 9845-7705<br />
6
Change<br />
Sensitive Resistance<br />
Supervisor:<br />
Dr. Patric J. Jansson<br />
Cancer <strong>The</strong>rapeutics and Target<strong>in</strong>g Group,<br />
Iron Metabolism and Chelation Program<br />
Problem<br />
Project: How to overcome MDR?
Supervisor: Paul K. Witt<strong>in</strong>g (Pathology)<br />
E-mail: pwitt<strong>in</strong>g@med.usyd.edu.au<br />
Phone: 9767-9103<br />
Discipl<strong>in</strong>e <strong>of</strong> Pathology<br />
<strong>University</strong> <strong>of</strong> <strong>Sydney</strong><br />
1
Redox Biology Lab<br />
• Research team comprises 1 PTE Postdoctoral<br />
Fellow, five Postgraduate students (3 x PhD and 2 x<br />
MPhil), one PTE Research assistant, and facility for<br />
a maximum <strong>of</strong> two Honours students (2013)<br />
Technical expertise<br />
• Field <strong>of</strong> redox biology coupled with monitor<strong>in</strong>g <strong>of</strong><br />
oxidative stress <strong>in</strong> develop<strong>in</strong>g vascular disease<br />
2
Animal study<br />
Research Projects<br />
• Title: Post translational changes to key cardiac prote<strong>in</strong>s <strong>in</strong> the<br />
hearts <strong>of</strong> diabetic rats after experimental heart attack<br />
<strong>Cell</strong>-based studies<br />
• Title: Achiev<strong>in</strong>g neuro-protection by <strong>in</strong>creas<strong>in</strong>g neuronal <strong>cell</strong><br />
content <strong>of</strong> neuroglob<strong>in</strong>.<br />
• Title: Snore-like vibrations stimulate a pro-<strong>in</strong>flammatory and<br />
prothrombotic state <strong>in</strong> endothelial <strong>cell</strong>s<br />
3
Model <strong>of</strong> experimental AMI <strong>in</strong> rats<br />
<strong>The</strong> left anterior descend<strong>in</strong>g<br />
(LAD) coronary artery is ligated<br />
to simulate AMI<br />
Blood flow is <strong>in</strong>hibited to this<br />
region <strong>of</strong> the myocardium for 30<br />
m<strong>in</strong> (ischemia).<br />
Release <strong>of</strong> the suture simulates<br />
tissue reperfusion.<br />
4
<strong>University</strong> <strong>of</strong> <strong>Sydney</strong><br />
Outcomes <strong>of</strong> sleep<br />
studies <strong>in</strong> <strong>in</strong>fants:<br />
Obstructive Sleep Apnea<br />
(OSA) & CPAP use.<br />
Dr Rita Machaalani & Pr<strong>of</strong> Karen Waters<br />
SIDS & Sleep Apnea Laboratory<br />
Side effect <strong>of</strong> OSA<br />
=daytime sleep<strong>in</strong>ess<br />
Treatment= (cont<strong>in</strong>uous positive<br />
airways pressure (CPAP) mach<strong>in</strong>e
Project title: Phospho‐regulation <strong>of</strong> centrosome prote<strong>in</strong>s <strong>in</strong> cancer <strong>cell</strong>s<br />
Supervisors: Dr Rose Boutros<br />
Dr Megan Chircop<br />
Laboratory: <strong>Cell</strong> Cycle Unit<br />
<strong>The</strong> Children’s Medical Research Institute<br />
Westmead<br />
<strong>The</strong> centrosome<br />
Structural prote<strong>in</strong>s: ‐, ‐, ‐tubul<strong>in</strong>s, Centr<strong>in</strong>s, Pericentr<strong>in</strong>, N<strong>in</strong>e<strong>in</strong>, Nucleophosm<strong>in</strong>, CP110,...<br />
Regulatory Prote<strong>in</strong>s: CDKs, Cdc25, PLK, Nek2, PP2A, 14‐3‐3, dyne<strong>in</strong>, dynact<strong>in</strong>, Mps1, ...
<strong>The</strong> Project<br />
A study <strong>in</strong> S. Cerevisiae revealed that the majority <strong>of</strong> yeast centrosome prote<strong>in</strong>s are<br />
phosphorylated at some stage dur<strong>in</strong>g <strong>cell</strong> division Keck et al. Science 332:1557, 2011<br />
Hypothesis: Phosphorylation <strong>of</strong> centrosome prote<strong>in</strong>s is important for normal<br />
centrosome function and <strong>cell</strong> division <strong>in</strong> human <strong>cell</strong>s.<br />
Misregulation <strong>of</strong> these can contribute to cancer.<br />
Aims: Investigate the role <strong>of</strong> prote<strong>in</strong> phosphorylation <strong>in</strong> regulat<strong>in</strong>g centrosome<br />
function <strong>in</strong> cancer<br />
‐ mutate phosphorylation sites by site‐directed mutagenesis<br />
‐ <strong>in</strong>troduce phosphorylation mutants <strong>in</strong>to <strong>cell</strong>s and screen for<br />
phenotypes us<strong>in</strong>g immun<strong>of</strong>luorescence microscopy
E‐cadher<strong>in</strong><br />
B‐caten<strong>in</strong><br />
Decipher<strong>in</strong>g the function <strong>of</strong> NDRG1<br />
Primary Tumour<br />
A number <strong>of</strong> molecular changes<br />
occur <strong>in</strong> the <strong>cell</strong> <strong>in</strong>clud<strong>in</strong>g:<br />
‐E‐cadher<strong>in</strong> is reduced<br />
‐B‐caten<strong>in</strong> is reduced<br />
<strong>The</strong>se molecules are crucial for<br />
<strong>cell</strong> adhesion and motility.<br />
E‐cadher<strong>in</strong><br />
B‐caten<strong>in</strong><br />
NDRG1<br />
Change <strong>in</strong> Morphology to<br />
become more <strong>in</strong>vasive<br />
NDRG1 can REVERSE this!<br />
Control NDRG1<br />
Control NDRG1<br />
NDRG1 restores the expression<br />
<strong>of</strong> crucial molecules that<br />
promote <strong>cell</strong> adhesion and<br />
<strong>in</strong>hibit <strong>cell</strong> motility.<br />
Cancer Metastasis<br />
HOW DOES<br />
NDRG1 DO<br />
THIS???<br />
Perhaps YOU will be<br />
able to f<strong>in</strong>d out!!!<br />
Contact:<br />
Dr. Zakl<strong>in</strong>a Kovacevic<br />
zakl<strong>in</strong>a.kovacevic@sydney.edu.au
2013 Honours Projects <strong>in</strong><br />
Cardiovascular & Hormonal Research Laboratory<br />
Susie Mihailidou - anastasia.mihailidou@sydney.edu.au<br />
Level 13,<br />
Koll<strong>in</strong>g Institute <strong>of</strong> Medical Research,<br />
Royal North Shore Hospital<br />
Honours student<br />
PhD student<br />
Medical student – Elective term<br />
2 Research Fellows<br />
Royal North<br />
Shore Hospital
Occlud<strong>in</strong>g branch <strong>of</strong> LAD<br />
2013 Honours Projects <strong>in</strong><br />
Cardiovascular & Hormonal Research Laboratory<br />
Susie Mihailidou - anastasia.mihailidou@sydney.edu.au<br />
Experimentally simulate a heart attack<br />
Reperfusion Injury<br />
Free radicals<br />
Stress-response<br />
Apoptosis<br />
Autophagy<br />
Non-ischemic areas<br />
Cardiac damage<br />
Royal North<br />
Shore Hospital<br />
Infarct<br />
area<br />
At- risk but viable
For 2013:<br />
• Regulation <strong>of</strong> aldosterone/m<strong>in</strong>eralocorticoid receptors <strong>in</strong> the heart<br />
• Glucagon-Like Peptide-1 agonists, reperfusion <strong>in</strong>jury and type 2 diabetes<br />
• Hyperglycemia Removes the Gender Gap Dur<strong>in</strong>g Experimental Myocardial<br />
Infarction<br />
2013 Honours Projects <strong>in</strong><br />
Cardiovascular & Hormonal Research Laboratory<br />
Susie Mihailidou - anastasia.mihailidou@sydney.edu.au<br />
Royal North<br />
Shore Hospital