Conway Focus Issue 19 Summer 2013

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Issue 19,23 3 Summer 2013

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plastic " Fighting cancer with biodegradable UCD researchers led1 ! by Conway Fellow, % have created Dr Kevin O’Connor an

5 agent 6

using small improved anti-cancer a biodegradable molecules derived from (67 -! !

plastic, PHA. Their findings are published in ! 8 ! the April issue of Biomaterials.

5 $ ' is a PHA or polyhydoxyalkanoate !

7 biodegradable plastic produced by 1

9 particular bacteria, such as Pseudomonas 4

: (9 4 :- putida commonly found in Irish soil. PHA is % ! 5 intensively studied as a substitute for non6

$

degradable plastic packaging. However, this

is the first example globally of a

plastic being used biodegradable monomer therapeutic. ! " as a cancer # $

of " broken %down The structure PHA can be & component " or into simpler building blocks $ called (R)-3-hydroxyalkanoic monomers " % acid one of which is called (R)-3-hydroxyde-

canoic acid for short. ' (" ) or R10 " *+ , The research team created a new molecular

- structure in the laboratory by chemically .

" $ linking R10 hybrid. of two naturally

" " " to a %

peptides " occurring with anti-cancer activity named P18. % They then investigated the impact of this

/" # new synthetic molecule (R10P18) on a " -+ variety of cancer types. ‘We found + % cell

" that these new synthetic molecules were able to +% "

drive cancer cells to self-destruction or apoptosis much more effectively than the P18 peptide would do if acting alone’, explained Dr Kevin O’Connor from UCD School of Biomolecular & Biomedical Science.

" by cancer cells

" molecules with

" beginning within programmed cell death entry two hours of to

the cell’. In the design " of new molecules, the precise location of

% every component part is critical as this will

dictate how the structure ultimately . " " will " behave. " In the. case of the R10P18 molecule,

% the enhanced activity displayed *01., anti-cancer

is due % to the' presence and position of the " hydroxyl (OH) The structure component. promises flexibility for " further

chemical or biological in the future. " manipulation " 01.% laboratory A crucial " part of translating

research on potential drug candidates is to

- 23 investigate the behaviour of these novel " " compounds with other commercially available chemotherapeutics. " Clinicians

" often favour treatment regimen that uses $% 4 a " a combination of drugs rather single than " a compound. Acting together, " drugs can be more effective and the desired "

response is " achieved with a lower dosage.

% 0 "

The new R10P18 molecules act

" " " with chemotherapeutics " synergistically $ " such as cisplatin to allow biological activity in the nanomolar concentration range.

According to Dr O’Connor, “The next step " " in our research is to test this putative therapeutic in " an in-vivo setting so that we

can establish drug toxicity levels and anti-tumour efficacy�.

) / The collaborative project also involved

detected better We uptake

of the new

1

8 8

;

Conway Fellows, Professor William Gallagher (UCD School of Biomolecular & 4 " C and

Byrne Biomedical Science) Dr Annette

" < / " " " " four new " I am delighted to welcome

Fellows; Dr Philips, Conway Andrew Dr " " Le Fiona

McGillicuddy, Professor Carel % Roux and Professor Ron Pinhasi. I have

Director’s Message " " Welcome! $ Congratulations to Professors Mark " (" Crowe, Pat Guiry and Cormac Taylor who "

$ have been announced as newly elected

% . members of the Royal Irish Academy. " B ' Each has made significant contributions ' =3 to scholarly research as demonstrated ; 23 ;-research. public " A by their published This " % recognition of their academic excellence is

the highest academic honour in Ireland.

no doubt that they will forge successful

4 Institute collaborations with other and

members contribute fully to-+ the $

continued success of the Institute. " " The Institute will " celebrate a decade of

discovery and innovation in September

$ "

(Royal College of Surgeons in Ireland and % UCD School of Biomolecular & Biomedical Science), as well as researchers in Trinity ' (" College Dublin, Royal College of Surgeons " in Ireland and the Synthesis & "

Centre for " Chemical It was funded Biology. " through UCD Ad5 " Astra scholarship, the Higher / ' ' Education Authority PRTLI4 and

programme, Science Foundation Ireland. UCD Conway " imaging and " flow cytometry core " technologies were used during the course of % the research. & 6.

(" " Reference:

" " ! "

O’Connor S, et al. The anti-cancer activity of derived a cationic anti-microbial peptide from "

monomers of polyhydroxyalkanoate. Biomaterials (2013) http://dx.doi.org/10.1016/j.biomaterials.20 5 " %7 12.12.032

" " 8 + % + & 9 : 0 : : . . 1 1 + + : . : : ' (" ;% + ' % 23 3 / 22< ==*>,?@A >@

Uptake and localisation of biotinylated peptides

in HeLa cells. Cells were cultured in the presence of biotinylated-P18L. Cells are treated with two dyes separately: Streptavidin Texas Red binds to the Biotinylated peptide and MitoTrackerÂŽ Green stains mitochondria. Regions of yellow indicate where the red stained peptide co-locates with the green stained mitochondria in overlaid images.

" / 0 23 3% 0 " " " 2013 as we mark the anniversary of the " building opening to + researchers its doors " from across the UCD and affiliate campus hospitals. We hope to welcome back many " of the alumni to a special commemorative " event as part of the 2013 UCD Conway "

%

Festival of Research & Innovation (11-12 September 2013). B 4 :

-+ + Professor Walter Kolch0 " Director

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

+ 0 . 0

Welcoming new Conway Fellows

5 5 5 ! 7 9

5 Dr Fiona McGillicuddy is interested in 4 the impact of obesity and inflammation ' : on HDL function and cardiovascular : $ ' this health. A key goal of research 7A ! is to

5 ! establish the effects of the obesigenic

! of

environment on the capacity 1 !to9 ' macrophages mediate cholesterol 7 1

efflux to HDL particles. The effects of 5 5 obesity on reverse cholesterol transport willB00"$ be assessed in vivo by monitoring 3H-

cholesterol from macrophages . 0 . movement onto HDL particles and measuring B uptake into liver, bile and elimination % in the faeces. The obese phenotype will .

" or subsequently be manipulated by diet D; N B N anti-inflammatory regimens to improve health " equivalent metabolic but maintain " and " obesity the effects on macrophage "

will faeces reverse cholesterol transport

% be monitored. . B . Dr Andrew Phillips focuses on researching the development of " sustainable catalytic processes utilising energy related *0' , catalysis,

natural products; in storage especially the area of hydrogen .

" boranes; from ammonia pioneering new (" ! " "

multifunctional anticancer compounds D; O and B % with enhanced selectivity inhibitor

delivery; development of silver antibiotic

+ B . and drugs

with biofilm inhibitor behaviour 64 against + " activity MRSA bacteria. " % "

" Professor Ron Pinhasi envisages

23 3 Fellows " synergies with Conway " specifically in the area of research

concerned with the health of past populations and the evolution of

" " " " pathogens and disease using ancient " %7

DNA studies of pathogens. He is also interested areas such as human + in .

evolution, demographic history + " variation, 6. . and microeveoluion; the Middle-Upper

Palaeolithic transition in the Caucasus; " " palaeogenetics: population history,

% . selection, phylogeography; variability in human growth and development in past

" populations. % . " Professor Carel le Roux is interested 10 " in the mechanisms by which Roux bypass "

en-Y gastric reverses diabetic disease.

%7 kidney His research is primarily

concerned with the increased mortality . ) B and morbidity associated

"

" with obesity and its related diseases. A better " " mechanistic understanding of how the

‘gut talks to

the brain’ will # " allow safer more 5 B

and effective treatments to be G To this role used in future. end, the of gut

bile hormones, acids and changes " in food # % preference are areas of interest to him. / A 333 0 0' % +" "

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

" %

" % 0 0'

" " " "

% . -+ + " 0' " $ % 64 " " 0' Dr Andrew Phillips, Stokes Lecturer,

" of & UCD School Chemistry Chemical Science

$ % . "

7 $ B . % 6 " $ B " 7% 0 " " 00 " B D; N " Professor Ron Pinhasi, Associate $ Professor, UCD School of " $ * / 5, Archaeology " %

-

Dr Fiona McGillicuddy, Wellcome

Professor Carel le Roux, Professor of Experimental Pathology, UCD Conway Institute & UCD School of Medicine and Medical Science

Trust Research Career Development Fellow, UCD Conway Institute

' signal &0F " A new ‘on’ for inflammation Inflammation an important A is response in the body but chronic or uncontrolled 1 ! 9 7 inflammation can also cause trouble in conditions including rheumatoid 5 % arthritis, inflammatory bowel disease @ > , and sepsis. 5 5 5 $ A new study involving UCD researchers

has discovered a signal that appears to &0F

trigger inflammation when the " threat of a bacterial infection looms, and the 0 % experiments have also been able to block + C systems, pointing

" the signal in model

0 to possible new approaches to treating 3 diseases. % inflammatory " "

The published*D.GB, in Nature and led by study, Trinity Dublin, found that in the College 0 % . presence of a potential bacterial threat, macrophages change how they burn $ energy. This " switch in burning eventually build-up % leads to the of succinate in cells, turn triggers chain " and this in a of biochemical events that encourage " inflammation. " "

One link in "that hypoxia-induced " chain is factor 1a (HIF-1a), best known for its role in helping the body adapt to conditions of % low oxygen. &

"

“When go to high this factor you altitude,

gets expressed in cells and that " " helps to increase number. of red cells the " % blood in your blood, so you can adapt B" " to the lower explains Conway oxygen,� " Fellow, Professor Cormac Taylor from UCD School $ of Medicine & Medical Science. " %

But that’s not the only place that HIF-1a has a job to do. “At time of $ stress including inflammation you also D.GB experience an activation HIF ("

of this % pathway,� says (" Prof Taylor. our 4 “And previous work has looked at this in models " " of inflammatory bowel disease.�

"

" In the new study, led by TCD’s Prof Luke $ O’Neill, Prof Taylor and Research % Fellow

Dr Cummins helped to work out that . Eoin

"

" in macrophages sensing bacterial " threat, a "

the build-up succinate seems ‘tell’ &0F of

to HIF-1a to switch on an inflammatory % B gene.

" " “In this case, HIF drives a gene called % 6 " interleukin-1, a potent pro-inflammatory (" gene, and that will contribute to the

#" process.� "

inflammatory " " new

" 7 The study makes an important link %

between energy processes in the . burning " " immune system and an ‘on’ signal for 1 " 0 - + inflammation. The research also showed " % that a drug usually used for epilepsy was able to tone down this succinate/HIf1a pathway in a model of sepsis, and this could point to new approaches to intervening when inflammation is ? running out of / control. &0F % B" / (" +% % " F 23 3 >CC >A

Reference Succinate is an inflammatory signal that induces IL-1β through HIF-1Îą. G. M. Tannahill et al.Nature 496,238– 242(11 April 2013)doi:10.1038/nature11986

Identifying key regulators of kidney injury Micro-RNAs (miRNAs) are a recently discovered class of RNA molecules that regulate how genes are expressed. UCD researchers led by Conway Fellow, Professor Catherine Godson are studying the role of miRNAs in diabetic kidney disease.

"

;- 1BK $ '

A A 9 A how They have described for the first time the miRNA family, miRNA, a key let-7 â‚Ź"E+!+00 plays role kidney injury by targeting 5 in

regulating 7 key fibrosis pathways human kidney < in F epithelial cells. ' (7 F 5 19. The team investigated the miRNA 5 $

responses in human kidney tubule epithelial cells cultured under fibrotic conditions that * % : % ", mimic kidney disease and in the " diabetic " "

presence of anti-inflammatory mediator lipoxin A4 to suppress fibrosis.

‘Promoting the resolution of inflammation makes for an interesting therapeutic approach that could reduce the risk of developing diabetic kidney disease. We believe that the lipoxins involved in regulating this process may be acting through miRNA mechanisms’, said Dr *+: , Eoin Brennan, first author of the published article in the Journal of +: the American " " Society Nephrology. of % . " "

2A

The extent let-7c miRNA expression * >of" @ " , seems impact on Ato " the integrity # of " " epithelial cells as the study found less let % 7c miRNA expression in injured epithelial cells than+ in healthy . -+ cells. " % + % G

‘The next for us now is to / step "

" " determine if let-7 miRNAs can actually play a role as biomarkers of diabetic kidney disease and

we will do this by measuring expression in both urine and kidney biopsies of patients,’ said Professor Catherine Godson from UCD School of Medicine & Medical Science. ‘We will also investigate the therapeutic potential of let-7c delivery to the kidney models in experimental of disease. +: our These studies will further enhance

of

understanding of the role miRNA in % " diabetic kidney disease as . both biomarkers and potential novel therapeutic

targets.’

" " " Reference Emma Borgeson, Eoin P Brennan, Karen A Nolan, Oisin S

Gough, Caitriona M Mc Evoy, G Docherty, Debra Neil F Higgins, Madeline Murphy, % Denise Sadlier, Syed +: ; M Tasadaque Ali-Shah, Patrick J Guiry, David A Savage, % I" % B Alexander P. Maxwell, Finian Martin, the GENIE " % Consortium, Catherine Godson. Lipoxins attenuate renal fibrosis by induction of let-7c and suppression of TGFβR1. Journal of the American Society of Nephrology, 2013 (24(4):627-637)

5 ;$ " Setting standards for protein localisation G 55 8 In order to understand how cells work,

= ! where scientists first need to establish =

$in ! every single protein the cell resides.

8 of ! In the largest study its kind to date, 5 the two most widely used microscopy ! based methods that can be applied to 5 compared. = this task5 have been

5 $

The international collaboration led

G by Conway Fellow, Professor Jeremy / + G 0 " Simpson, UCD School of Biology & ' Science and E .

*G0' ., Environmental Professor + 1 B B " " Emma Lundberg, KTH-Stockholm 500

looked at more than proteins $ ("

using antibody-based localisation and fluorescent tagging methods. protein &BD+

" " %

Their findings show that by following a

5

antibody-based defined set of rules, both " " and fluorescent-tagging methods are % / other, and highly complementary to each

for the show " a high degree of correlation

% 4

determination of protein localisation in cells.

The study provides a significant also " " and experimentally validated data set " of

protein localisation in mammalian cells,

" which in itself is " % a valuable resource for the scientific community. + " &BD+

" $

According to Professor (" % 0 Simpson, “The debate of whether antibodies or " " fluorescent protein is the most

# tagging G0' . reliable method to determine protein localisation has been going on for more 4 than 15 years.

" $ " the " (" In addition to determining localisation % . 500 " " of more than proteins, half of which no localisation " annotation, had previous study has % this allowed us to address a key

;- + ' " " " " ;- > 1 B % B "

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

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

experimental issue.� . G0' . 5 ;$ ;- + '

This work is expected to set the standard methodology for ultimately determining " " &BD+of the localisation the entire human $ proteome.

% . $ " Reference " Immunofluorescence and fluorescent-protein

tagging show high correlation for protein localization C, Rexhepaj in mammalian cells. Stadler E, Singan

VR, Murphy RF, Pepperkok R, UhlĂŠn M, Simpson JC, . " Lundberg E. Nature Methods (2013) Feb 24 doi: 10.1038/ nmeth.2377. [Epub ahead of print].

Experimentally-determined subcellular localisation of almost 500 human proteins. The localisations of proteins were determined using both immunofluorescence and GFP-tagging, with each protein being assigned to a localisation class (CY, cytoplasm; CSK, cytoskeleton; ER, endoplasmic reticulum; GO, Golgi apparatus; MI, mitochondria; NU, nucleus; PM, plasma membrane; VE, vesicle). Each node represents a protein, with dark green nodes indicating identical localisations recorded between the two methods, light green nodes indicating similar G0' . / + and red G localisations between the two methods, nodes conflicting 5 ;$ indicating localisations between the two methods.

Primitive complex human processes identified Q forms of

The evolution of multicellularity marks one of the most profound < 1 evolutionary developments H F contributing to the

appearance

8 of human and on the planet. 5 animal life 5

However, relatively known with C little about this seminal event, a number

5 $ of international genome research efforts have focused identifying G 2%A on a " timeline for % the emergence of key

. genome features that contributed to

multicellularity. The findings of new research now adds " " " to a growing body of data that the %

development of multicellular animals was, in many key respects, - " enabled

through a re-purposing of existing "

" facilities present unicellular already in " organisms.

The Science Foundation Ireland (SFI) funded study led by Conway Fellow, " Professor Brendan Loftus, UCD School of

" % Medicine & Medical Science sequenced : " amoeba the genome of a unicellular "

(Acanthamoeba castellanii).

% 0 found genome

The researchers within the " (tyrosine an intact signalling facility kinase long associated

" signalling) " with multicelluar and % thought organisms " to have arisen much later in evolution. . signalling Tyrosine kinase is a core " of 8 communication means intercellular Its

and coordination. appearance in unicellular indicates the organisms " % 0 $

necessity for a sophisticated of " level interaction with one’s neighbours even as " $ a unicellular organism. %

The study also demonstrated that + pathogen recognition receptors, : a key 6' element of the innate

" immune system humans used to recognise and of

" engulf were already in use as pathogens, " part of a primitive form of self-defence

in amoebae.

" "

" 7%

As human evolve . many pathogens " " their virulence outside of & human 1 " 0 hosts through interactions in their ' % environments, these findings inform how certain pathogens have evolved to evade or manipulate the innate immune ? system. B "

Reference

Genome of Acanthamoeba castellanii extensive % 9 8 highlights + lateral geneG transfer and early evolution of tyrosine kinase 4 % )+ ' signalling. Lohan E A et al. Genome Biology 2013, : % Clarke M,/ / *23 3, 14:R11 doi: 10.1186/gb-2013-14-2-r11

Reducing experimental inflammatory arthritis

+ ;$ identified the inflammatory receptor reporting 10% of men and 18% of

UCD researchers led by Conway Fellow, Professor David Brayden in UCD School of Veterinary : 5

= ! Medicine have successfully reduced inflammation in the swollen arthritic 5 7 > ? knees of a@ 5 murine model using a novel nanoparticle. 8 5 A

B/ B. B0,0$ 75 The team used an anti-inflammatory 9 ! 9 5 8 5 molecule complexed in a nanoparticle of hyaluronic acid to overcome the body’s 5 : 55

normal clearing processes. 5 In addition to reducing inflammation ( :7 > ? $

after a localised injection of this new nanoparticle preparation, the team

target for the components of the particle and demonstrated its reduction. . B

"

“By using these molecules a ‘nano’ in format, we were able to successfully

"

target site of and " retain the

" inflammation

them there to reduce The " swelling. effect compared treatment with % 0 favourably to " + steroids�, said Prof Brayden. “This may 1 B 1 85 provide a new type of long-acting, ‘nano’ " F therapy for human or animals suffering " inflammatory " in " with arthritis the future�. % This condition has a huge social impact

women aged over 60 have symptomatic osteoarthritis (OA). The WHO estimates that 80% of those have limitations

" / in/ movement 25% cannot perform " and G"

/ % : major daily activities. + G" ' E - $ $ " References F ) " An intra-articular salmon calcitonin-based nanocomplex " arthritis.

reduces experimental inflammatory Ryan SM, A, Kornerup KN, McMorrow J, Umerska Patel HB, Tajber L, Murphy EP, Perretti M, Corrigan OI, Brayden DJ. Journal of

" % Controlled Release (2013) 167: 120-129 Feb 4.

for the aging Western population with the World Health Organisation (WHO)

1 " " # " MMI medal for UCD Student Trudy McGarry won the 2013 Molecular : 5 5 Medicine Ireland (MMI) medal for 8 her presentation rheumatoid oral of arthritis research. :5 B0,0 C

! 5 : ( :-D Currently student on the MMI Clinical 9 a9 $

& Translational Research Scholars B Trudy

Programme (CTRSP), carried out research in " her project conjunction with Fellow, " " Veale, Conway Professor Douglas % . " St. Vincent’s University Hospital and UCD of Medicine %&. School Medical Science. $

Her study focuses on the signalling " " pathways involved in joint destruction

in % seen rheumatoid arthritis. Rheumatoid arthritis (RA) is a chronic, + 1 + progressive & autoimmune disease, characterised " " by J. K " L5C:MJ. K

synovial proliferation and destruction of " " cartilage and bone.

" " %

through β1-integrin-induced cytoskeletal pathways.

When integrin receptors are engaged, they cell migration/invasion . induce " J. K through attachment to the extracellular " matrix and downstream " activation of RhoGTPases. + % &

Toll-like TLR2 has receptor, been

implicated in the pathogenesis of joint % destruction in RA but the mechanisms have yet to be " " involved elucidated. J. K "

In presenting the results of her " study, " Trudy McGarry how . TLR2

explained % induced cell " " migrational and invasive * mechanisms are specifically , " mediated "

" %

(L-R) Dr Mark Watson, Programme Manager (Education & Training); Trudy McGarry, MMI CTRSP scholar; Dr Graham Love, CEO Molecular Medicine Ireland + 23 3 ' ' *'' ,< B E B %

Experiencing life at the bench

D " + E " "

As part of the 2013 UCD School of Veterinary Medicine transition year programme organised by Conway " + " Fellow, Professor David Brayden " during the week of February 18th, / 23 3% . seven pupils visited UCD Conway " " Institute hear first-hand to "

about the working lives of Conway researchers. H + "

They met PhD students Paul Lavin (McGee group), Sharon O’Neill (Knaus group) and Aoibheann McMorrow (Roche group) who each explained the type of research projects that they are involved with as well as their

4

1

educational route to this role.

The pupils got a little closer to " experiencing life ‘at with a " the $ bench’ tour of the Institute that took in the nuclear magnetic (NMR) B resonance

facility PhD student where Jennifer Cleary about (Malthouse % 1 " group) spoke B working up. close to 8 the large Bruker " / magnets. They heard about E. coli plasmids from Dr David O’Connell in the protein expression laboratory and Dr Gordon Cooke (Donnelly group) gave some insight to lung fibrosis research.

* % 8 I" % , 5 8 * % 8I" % , + * % I" % , "

" " %

(L-R)(Front row) Tadhg Lonergan, Alyce Grant, Kate Doherty, Anna Duggan, Nicola Armstrong, Isobel Digby, Prof David Brayden, Jayne Baird; (Back row) Sharon O’Neill, Paul Lavin, Dr David O’Connell

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

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