UCD Conway Focus Spring 2014

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Issue 21,23 3 Spring 2014

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" Prestigious awards to Conway Researchers 1 ! The Sir Henry Wellcome postdoctoral % scheme aims to fellowship provide the

promising 5 6

most newly qualified researchers with a postdoctoral unique (67 -! ! opportunity to develop independent research ! careers. For8 ! the first time, the 5 this Wellcome Trust has awarded $

fellowship to an ' Irish early career !

7 researcher, Dr Colm Ryan.

1

9 4

: (9 4 :- Dr Ryan will work with Prof Walter Kolch, % ! 5 Systems Biology Ireland and Prof Alan 6

$

Ashworth, Institute of Cancer Research,

London to investigate how genetic changes impact on a targeted approach to cancer ! " treatment.

# $

in " % A major challenge cancer therapeutics is & " other to kill tumour cells without harming $

have

cells in the body. Cancer cells genetic that " % changes distinguish them from healthy

cells, and consequently may leave them ' (" ) "

vulnerable treatments. to targeted *+ , - A promising approach to $ developing .

" such targeted " treatments to identify

" " % is. genes

" whose function is only essential for survival cancer-associ in the presence of a specific % ated mutation. Such a phenomenon, where the function of gene A becomes essential

/" # only in the presence of a mutation in gene " -+ B, is called synthetic lethality. However, + % " little is understood about how additional +% "

genetic differences between individuals might impact on their use.

" lethality " impact on synthetic treatments,

" treat and investigating whether certain be more

genetic ments might robust to differences than others. " %

The 11th Luke’s Young . St " " Investigator " award was won by Irish Cancer Society research fellow, Dr Maria Prencipe at the Royal "

College Physicians of Ireland on January

% . of 29th 2014. *01., % ' " This prestigious award supported the

by Royal Academy of Medicine in Ireland and " St " Luke’s Radiation Oncology

Network, " work to Dublin went to Dr Prencipe for her " 01.% for castration find a new molecular target resistant prostate cancer (CRPC).

- 23 " " Dr Maria Prencipe colleagues and working with Fellow, Prof William Watson Conway " " recently identified the transcription factor $% 4 " named serum response factor as an (SRF) " important target in CRPC using and " genetic computational analyses. " "

%

$ "

head-on, clinicians and scientists need to mechanisms

% understand the underlying of resistance.

' (" " “Our study shows evidence of cross-talk "

" between receptor (AR) androgen " and SRF in advanced prostate cancer. At the core of / 5 " ' ' this cross-talk is a negative loop feedback between SRF and AR that were able to we

" demonstrate in vitro, clinical samples and " " in is % supported by a computational model�,

said Dr Prencipe. Prof Walter Kolch, Director & 6. both Maria

on said, “I congratulate Colm and (" " their achievements. It is fitting " " ! " recognition for their dedication to fundamental cancer research and " improving outcomes for patients with 5 " %7 advanced disease�. " " 8 + % + & 9 : 0 : : . . 1 1 + + : . : : ' (" ;% + ' % 23 3 / 22< ==*>,?@A >@

When prostate cancer is detected early in

0 "

patients, surgery and radiation

" " " " treatments are effective therapies. Patients $ " with locally advanced and metastatic prostate cancer are treated with androgen

ablation (hormone depletion or chemical " " castration) therapy. "

Despite an initial response, the majority of men progress to develop castration-resistant prostate cancer which, despite the emergence of new treatments, is challenging to treat. To meet this challenge

Dr Maria Prencipe

) /

Dr Ryan’s fellowship will focus on understanding how such genetic changes

Director’s Message

1

8 8

;

Welcome!

" " facilities In the last quarter, the dedicated for Systems Biology Ireland adjacent $ to Conway Institute became UCD " (" operational; new director of UCD " the

$ Charles Institute of Dermatology, Prof

% . Martin Steinhoff joined UCD from " B ' University of California San Francisco; and ' =3 the Institute hosted the first UCD Ireland ;- 23 ;- " A East cancer open house. " %

4 " C " < The UCD Ireland East cancer open house / " provided a unique opportunity for cancer " " " " survivors, patient advocacy groups and

clinicians from across the Ireland East " " network to sit at the laboratory bench and %

talk with researchers about the projects they are working on in the battle against 4 cancer. The dedication and passion of our

was -+ evident early career researchers clearly $

and, in turn, they were inspired by the " who individuals might ultimately benefit " " from this research.

Dr Colm Ryan " / 0 23 3%

0 developments " many These create " " and integrative interfaces for collaboration undoubtedly " strengthen impact and will the Institute’s priority of strategic

" + building a strong translational medicine programme. " "

Professor Walter Kolch "

% Director

B 4 : -+ + 0 "

<2:4 <7' ' ' 1 '0 / D;+-D E '0 /; 0+ D ; ; +&

+ 0 . 0

Institute hosts UCD Ireland East Cancer Open House 5 5

5 !survivors 7 9

5 Cancer and patient advocacy

4 groups met academics, clinicians and ' : scientists involved in cancer research in the first UCD Ireland East cancer7A ! open : $ ' house. 5 !

! The event provided a window to ' the 1 ! 9 myriad of stakeholders embroiled in the 7 1

battle against and5 5 the opportunity cancer to B00"$ personalise the contributions each are

making. It emphasised the requirement

. 0 . among for connectivity and engagement cancer B in all players in the battle against for % order to achieve improved outcomes .

"

patients. D; N B N in the " house Participants cancer open tours within the Conway and "

" Institute Systems Biology Ireland the evening on "

of Thursday, 23rd January were given insights

%

to the projects and technologies within . B .

the

research pipeline by postdoctoral

and researchers PhD graduates working at "

the coal-face of cancer research.

" " "

about

" “We spoke to participants how mathematical " %7 we use complex networks to model cancer systems with a view + developing new . to drugs and targeted + " said 6. Philip

. therapies�, Smyth, Education

with & Outreach Officer Systems Biology " " Ireland.

% .

John Crown, UCD Clinical Prof Newman

" Professor & consultant oncologist and Vincent’s University St Hospital spoke to participants about the future of drug % . " treatments as " therapies both 10 become personalised and targeted. " %7

Clinicians and academic partners met the . )

B for following day to discuss the potential

advancing the "

" scientific programme of " " East cancer research within the Ireland Hospital network; a catchment population

# " of 1.75 million people. B G

*0' ,

There were tours on topics such as ‘How do cancer cells low oxygen?’, ‘How .

" survive cancers change during treatment’ (" ! " "

and ‘Cancer cells cycling’. D; O B %

This critical mass of clinicians and "

researchers within this network provides # % huge opportunities for enriched basic / collaboration A 333 and 0 research crucially

will greatly enhance interactions with pharmaceutical 0' % and +" "

the medical device industries.

+ B . 64 + " " % "

" 23 3 " "

-

During the economic crisis, Institute grant funding fell by more than 40% but Conway Fellows have managed to reverse this trend by increasingly securing non-exchequer and industry funding.

With 11 European partners in 6 countries from public research organisations and industry, FIBRO-TARGETS aims to target cardiac fibrosis for heart failure treatment. More than 6.5 million people suffer from heart failure in Europe.

Prof Boris Kholodenko is a partner on the A EU FP7-KBBE project entitled Synthetic Cellular Signalling Circuits (SynSignal) 1 ! 9 7 that aims to deliver synthetic biology toolbox a and finished products designed 5 custom % for present and future industrial major @ > ,

applications cellular signalling. 5 5 of

Specifically, the focus will be on clarifying " " involved the mechanisms in myocardial interstitial that contribute to fibrosis heart failure and likely to become are

% therapeutic targets for this disease.

" % . " " 00 " " (" " " "

" %

Walter

" Kolch,

said, % Prof Director “As a0 0' you often become scientist, engrossed

" " painstaking " "

in the complexities and % -+ + " detail. of the experimental process, losing sight 0'

of the wider perspective. " open $ This cancer house event provides a unique to connect opportunity with and be inspired by the people I hope will %

ultimately benefit from our fundamental

64 programmes.� " " 0' research " $ % . UCD

Ireland East cancer open house was " organised by Conway Fellow, Dr Amanda in the UCD McCann along with colleagues Translational Oncology research group

7 $ B and UCD Research. . % 6 " Medicine $ B " 7% 0 " " 00 " B D; N " $ $ * / 5, " " % Conway Fellow, Dr Darran O’Connor speaking with participants touring laboratory facilities during the UCD Ireland East cancer open house.

Continued funding successes

Conway Fellows continue to secure national funding under programmes such as the Food Institutional Research Measure (FIRM) by the Dept of Agriculture, Food & the Marine. Prof Helen Roche and Dr Fiona McGillicuddy and colleagues in Teagasc (Dr Aidan Moloney) and the UCD Institute of Food & Health (Dr Frank Anne

Nugent) &0F Monaghan, Dr received through this scheme funding % B to examine if a novel acid (CLA) found fatty in beef has beneficial effects with " " respect diet-induced diabetes and to % 6 " cardiovascular health. ("

' &0F "

5 $

Cellular signalling systems are crucially &0F for

range important a broad of critical health and disease areas and high value " industrial applications. 0 %

+ C " SynSignal will dramatically 0 impact on of drug discovery the 3 accessibility %

technologies, particularly for cancer and diabetes, and " " for enabling technologies create the *D.GB, to next generation of flavours, fragrances, and nutritional 0 % . ingredients.

Dr Chris Watson (UCD Conway), Dr Mark

" $ Ledwidge (SMMS), and Prof Ken McDonald %

(SVUH), have been awarded EU FP7 " for funding the FIBRO-TARGETS research " project. " "

&

"

Walter is Prof Kolch part of another "

recently funded EU " FP7 collaborative project " % . research focused on cardiovascular

Systems Biology B" " disease. to Identify Molecular Targets for Vascular " Disease Treatment (sysVASC) to identify $ aims the causative events in cardiovascular " diseases in order to predict novel % therapeutic targets.

#" "

" " " 7 %

. " " 1 " 0 - + " %

$

D.GB consortium includes The sysVASC 17 (" and, % partners from 10 countries for the first time a large research 4 in (" consortium, uses modern, medical systematic " " approaches that can contribute to early "

and individual diagnosis " and treatment through the use of new biomarkers from $ % blood and urine. . " " " "

? / &0F % B" / (" +% % " F 23 3 >CC >A

(l-r): Dr Aidan Moloney, Teagasc; Minister for Agriculture, Food & the Marine, Mr Simon Coveney TD; Professor Helen Roche, UCD Conway Institute and Minister of State at the Department of Agriculture, Food and the Marine, Mr Tom Hayes TD.

Imprinting hypoxic signature to help resolve inflammation The Taylor group in collaboration with colleagues in the University of Colorado, Denver including lead author and Conway alumnus, Dr Eric Campbell have recently shown how immune cells can shape the microenvironment of an inflamed tissue to effect disease $ ' progression.

"

;- 1BK A A 9 A

Neutrophils or polymorphonuclear â‚Ź"E+!+00 leukocytes (PMNs) are a specific type 5 7 of immune cell with vital role to play < a F in host defence. They move to regions ' (7 F of injury or infection to detect and kill

5 19. invading microbes. These actions involve 5 $ energy demanding processes that consume significant amounts of oxygen. * % : % ", " " "

This study investigated how neutrophils contribute to inflammation in diseases such as Crohn’s disease and ulcerative colitis. The research team were able to show that activated neutrophils are capable of depleting local oxygen to such an extent that epithelia in close proximity sense this and trigger genetic changes *+: , to promote tissue " survival. " +: % .

"

Conway Fellow, Prof " Cormac Taylor 2Asaid, “Initial carried out in UCD , Conway studies * > " @ " Institute demonstrated that immune cells A " # " " when stimulated, consume significant % amounts of oxygen. Using microarray analysis, team uncovered a set of . -+ the + "

hypoxia-responsive genes regulated % + % G by cross-talk between neutrophils and / " " "

epithelial cells in the mucosal tissue. This study, led by Prof Sean Colgan at the University of Colorado, Denver, suggests that neutrophils initiate a hypoxic microenvironment that prompts surrounding mucosal tissue to take corrective action to restore the balance +: of gas levels even after the neutrophils have been cleared away. These findings

may provide insight into new therapeutic % . " approaches inflammatory disease. to

" " " Reference Transmigrating Neutrophils Shape the Mucosal Microenvironment through Localized Depletion Oxygen to Influence Resolution of Inflammation. +: % ; Campbell EL et al. Immunity 2014 Jan 16;40(1):66-77. % I" % B " %

Personalising in idiopathic pulmonary fibrosis 5 ;$ treatment " Researchers led by Conway Fellow, Prof Seamas Donnelly have identified G 55 8 a potential rapidly

= ! biomarker of progressive idiopathic pulmonary =

$ ! fibrosis (IPF) and pinpointed

8 ! a defective molecular function as a 5 potential therapeutic ! target.

5 5 = IPF is a fatal progressive 5 $interstitial

pneumonia that leads to the breakdown of normal lung architecture and the loss G of lung function / + as a result. G 0 "

' E . *G0' ., In humans, the innate immuneB " system is + 1 B " responsible for recognising tissue injury

and infection. Toll-like $ receptor("

3 (TLR3) is an

innate immune system &BD+ receptor

involved in this process of identifying " " %

pathogens and defending against them.

5 The Donnelly group investigated " " whether a particular defect %genetic / in the " TLR3 gene disrupt the

might

% 4

" " "

normal inflammatory response in IPF and accelerate the progression of the disease.

" " % This specific genetic variation in one of + component " &BD+of the DNA building blocks "

$ the TLR3 gene is named L412F single- (" % 0 (SNP). nucleotide polymorphism " "

# G0' . with The UCD team in collaboration internationally colleagues examined the of defective TLR3 function impact 4

in the lung and the progression of $ IPF on " using fibroblasts with lung " from patients " (" and without L412F SNP and % . TLR3 " " in a laboratory disease model. "

Q

5 ;$ ?!! % % ?=3=3! 5 ;$

! B % 5 ;$ ? " " &BD+ 5 G F% / B% + B " /% " " B 23 3 @ *C, 23 KP23C

%

Commenting on the results, Dr Gordon . G0' . postdoctoral

Cooke, senior research 5 ;$ on ;- + ' fellow and an author this publication said, “This study identifies the TLR3 L412F polymorphism a potential marker of " " &BD+as rapidly progressive disease defective and $ TLR3 represents potential % function . $ a therapeutic in IPF.� target " "

‘Molecular fossil’ identified in fungi All but a few eukaryotes die without oxygen, and they respond dynamically to changes in the level of oxygen available to them. One example of ancient oxygen-requiring biochemical pathway in eukaryotes is the < 1 biosynthesis of sterols, H F producing cholesterol in animals and ergosterol

8 in fungi.

Reference The Toll-like Receptor 3 L412F Polymorphism and Disease ;- + ' " " Progression in Idiopathic Pulmonary Fibrosis. Dwyer DN " " ;- > 1 et al. American Journal of Respiratory & Critical Care B 188; %12,B " Medicine. 1442-1450. December 15,

2013.

. "

The Butler group used comparative genomic analysis to investigate the timing of the evolutionary switch from one regulatory mechanism to another; from SREBPs to Upc2. They found that one yeast species, Yarrowia " lipolytica is unique it contains both SREBP and

" as % Upc2 genes.

Masson-trichrome staining of lung sections from TLR3/- mice shows increased collagen deposition

G0' . / + G 5 ;$

forms, which is important for virulence.

Conway Fellow, Prof Geraldine Butler

5 5

C The mechanism regulating the sterol

between 5 $ pathway is widely conserved

animals fungi and centres on a G 2%Aand protein family % of transcription activators "

. named the sterol regulatory element

binding proteins (SREBPs), which form part of a sterol-sensing complex.

" " " However, in one group of fungi; the % Saccharomycotina, control of the sterol

pathway been taken over by an - has "

unrelated protein, Upc2. regulatory "

" "

:

"

Using biochemical genetic and "

analysis,

the group showed Upc2 is the

that main regulator of the hypoxic response Y. % 0 in

lipolytica, and " regulates the levels of sterols in the membrane, while SREBP

" " appears to be a ‘molecular fossil’ that has

" % lost its role as a sterol regulator. .

The SREBP gene retains some in the "

8 role hypoxic response of Y. lipolytica however,

and is required maximal "for % 0 growth $ when oxygen Derivatives of levels are low.

" SREBPs are also required the growth " $ for of several yeast species as % filamentous

says, “We found that the evolutionary switch from SREBP to Upc2 was a twostep in which Upc2 appeared + process : in an ancestor of Saccharomycotina, 6'

" and subsequently lost its sterol SREBP " regulatory function while retaining an " ancient role in filamentation.

findings " "

" The are exciting from an 7% evolutionary perspective but also have . " " tremendous potential for clinical use if 1 " 0 & they can be applied to the development of' % more effective anti-fungal therapies�. ? Reference Zinc finger transcription factors displaced SREBP B

" proteins as the major sterol during Saccharomycotina regulators

evolution. Maguire SL et al. PLoS Genetics. doi/ % 9 8 + pgen.1004076 G 4 % )+ ' : % / E / *23 3,

Targeting monocyte function to reverse atherosclerosis to adhere to the developing plaque. in the regulation of monocyte adhesion, + ;$ polarisation, and migration.

The Belton group recently published findings describing a novel mechanism through which a dietary fatty acid alters monocyte function inducing : 5

= ! regression of pre-established 5 7 > ? atherosclerosis. @ 5

Atherosclerosis, the underlying of 8 5 cause A heart and 75 stroke, is a complex B/ disease B. B0,0$ progressive involving multiple 9 ! disease 9 5 8 5 genetic and environmental factors.

5 : 55

One contributing factor to the 5 development of atherosclerotic plaque is the continual ( :- recruitment 7 > ? $of circulating pro-inflammatory monocytes to the damaged blood vessel and their subsequent migration through the activated endothelial where they rapidly differentiate into macrophages.

The Belton group have previously shown in a murine model of atherosclerosis that conjugated linoleic acid (CLA), alters . B " monocyte/macrophage function causing regression of the disease.

"

"

"

Dr Orina are trying " Belton said, �We to define the mechanisms through which % 0 " + CLA mediates its atheroprotective 1 B 1 85 effect so as to identify novel pathways " reverse that limitF or ultimately " " " atherosclerosis.

In % this study, we have been able to clearly demonstrate that CLA targets integrin gene expression so as to suppress the ability of monocytes to adhere to endothelial cells. We also show that CLA modulates monocytes toward an anti-inflammatory phenoype resulting in impaired monocyte migration.�

Reference Conjugated Linoleic Acid Targets b2 Integrin Expression to Suppress Monocyte Adhesion. de Gaetano, M;/ Dempsey

" / E et al. The Journal of Immunology, 2013, 191:: 4326–4336. " G" / %

+ G" ' E - $ $ " F ) " " " %

1 " " # "

The recruitment of monocytes is a highly orchestrated process. Transmembrane proteins called integrins play a central : 5 5 role in this by mediating rolling and

8

adhesion of leukocytes that causes them :5 B0,0 C

! 5 : ( :-D 9 9 $

The data presented the Belton group " by " describe novel functional role for CLA " " a

Confocal microscopy of human peripheral blood monocytes treated with CLA isomers, vehicle (VC), control lipids (OA) and positive control (TROG). CLA inhibits migratory response of HPBMCs

%

Ministerial launch of Systems Biology Ireland B Minister

On December 5th 2013, Research " SeĂĄn for and Innovation, the dedicated " " Sherlock TD launched

% . " research facility for Systems Biology (SBI) and % . Ireland highlighted its $ in potential for breakthroughs

personalised medicine.

" "

% Minister Sherlock said, “This magnificent new facility is a major step that will + 1 + & enable SBI to " lead " in the advancement of personalised medicine on a global J. K " L5C:MJ. K scale, and in a key area prioritised for investment under Horizon 2020.�

. " J. K " " Combining the power of computers and + modern to understand diseases %biology & such as cancer, develops diagnostics SBI

and therapies that are tailored to the % individual patient. Finding the right drug

for the right patient a major problem is " " and SBI aim to double the number of patients J. K " that cancer drugs work for by 2020. " "

% “To really take advantage of the. new drugs available " " becoming for* targeted therapies, , "

we urgently need the telescopic sights that allow

"

us to take each patient’s will " %

cancer into the crosshairs individually. SBI is developing these sights� says Prof Walter Kolch, SBI Director.

+ 23 3 Systems ' Biology ' Prof Walter Kolch (Director, Ireland), Sherlock *'' ,< B E B % for Research and Sean TD (Minister of State Innovation) Hugh Brady (President UCD) Prof Boris Kholodenko (Associate Director, Systems Biology Ireland)

D " + E " "

Welcoming new Conway Fellow Following his successful application, " +

" Dr Rodrigues, UCD School of Brian " Physics has been awarded / 23 3% . Conway

" " fellowship. His research is focused on " and functional biological materials advanced scanning probe microscopy H + " of based characterisation techniques biological materials.

demonstrates " the NUI, Galway possibilities force " microscopy $ of atomic (AFM). Dr and PhD Rodrigues candidate Liam Collins B

utilised very high-aspect ratio probes to navigate complex architecture of the microscopic algae (diatoms) show % 1 " and B that nano-scale " / . architectural 8 features of the frustule remained after chemical modification.

A recent Nature Communications article in collaboration with Prof Abhay Pandit at

“Atomic force microscopy is a versatile tool applicable to many of the Conway research

4

1

* % 8 I" % , to themes, and I look forward developing collaborations 5 8with fellow productive * % researchers 8I" % , in years + to Conway the come�, said Dr Rodrigues. , "

* % I" % "

" %

Reference Thiol-functionalization of the living diatom- tailoring the chemistry of the frustule during synthesis. Lang,Y et al. Nature Communications 2013: 4, 3683..

! " # $% & $ '# ()*+* ,- .,/ /.0/ 1# ()*+* ,- .,/ /.0, 2# $ $ 3

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