Elaine QuinnCommunications & Education Officer

UCD Conway Institute of Biomolecular & Biomedical ResearchUniversity College Dublin

Belfield, Dublin 4Ireland

E: elaine.quinn@ucd.ie T: (+353-1) 716 6706F: (+353-1) 716 6701

W: www.ucd.ie/conwayFunded through the Programme for Research in Third Level Institutions, administered by the HEA.

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UCD CONWAY INSTITUTE OF BIOMOLECULAR & BIOMEDICAL RESEARCH

Launch of Systems Biology Ireland Announced

Systems Biology Ireland, the newScience Foundation Ireland-fundedCentre for Science, Engineering andTechnology (CSET) was launched by theMinister for Science, Technology andInnovation, Conor Lenihan T.D. onSeptember 15th 2009.Systems Biology Ireland is led by UCDand supported by researchers in NUI,Galway. The new centre will receivee14.8 million from SFI and a furthercombined contribution of almost e4.7million by the various industry partners- Ark Therapeutics, Hewlett Packard,Servier, Agilent Technologies, SiemensIreland and Protagen AG. Commenting on the announcement,Minister Lenihan said “(This)investment establishing SystemsBiology Ireland is clear evidence of theGovernment’s ongoing commitment tofurther enhancing Ireland’s scientificbase to aid our economic recovery.” Systems biology is a powerful new wayto use the strength of computers andmathematics to understand biology.This research centre will try to unravelthe complexities of cells through the useof models that predict biologicalbehaviours. The research beingundertaken will enable quicker andbetter treatments of a range of medicalconditions, including various cancersand should allow for better therapies tobe delivered more effectively topatients.Professor Walter Kolch has relocated to

Ireland from the Beatson Institute,Scotland to lead the SBI programme. Heis joined by Conway Fellows, ProfessorsBoris Kholodenko (deputy director),DesHiggins and Cormac Taylor. They willwork with co-principal investigators,Professors Tim O’Brien and Frank Barry,the respective director and scientificdirector of the Regenerative MedicineInstitute (REMEDI) based in NUI,Galway.Outlining the potential of systemsbiology to speed up research and helptarget therapies to particular patienttypes, Professor Kolch said: “We will usesystems biology to improve ourunderstanding of cell mechanisms, cellcommunication networks with theultimate aim of regulating cell activity.Our work will help speed up theexperimentation process, therebyreducing by years the time it takes todevelop a new drug therapy. We willalso work on pin-pointing the efficacy ofdrug therapies on different patienttypes so that doctors can better identifythose who will respond best toparticular treatments.” Welcoming the announcement,Professor Des Fitzgerald, UCD ConwayDirector said: “SBI is a majordevelopment within the UCD ConwayInstitute, which has always had a strongfocus on biomedical research, supportedby proteomics and bioinformatics. SBIwill train a new type of scientist withdeep knowledge across the disciplines

of biology, medical sciences,mathematics and computation.”Commenting on the investment byindustry, Dr Laurent Perret, Présidentdu Comité Scientifique du Groupe deRecherches Servier said: “SBI providesa further opportunity for Servier toengage in leading-edge research inIreland and for us to work together toaddress unmet medical needs using anextraordinarily powerful technology”.

Minister for Science, Technology and Innovation,Mr Conor Lenihan TD pictured with ProfessorFrank Gannon, Director General of ScienceFoundation Ireland (left), and Professor WalterKolch, Director, Systems Biology Ireland (right)at the announcement of Systems Biology Ireland

Welcome! As we enter the last quarterof 2009, UCD Conway’s involvement inthe overall university PRTLI5submission process continues with sitevisits into mid-November. Enablingworks are now complete for theproposed Charles Institute and thenewly launched Systems Biology Ireland(SBI), which form part of the capitalprogramme. We are involved in severalnational access facilities including high-throughput screening and transgenics

and are proposing a radiopharmaceuticalresearch & services programme. SeveralConway Fellows are involved in thevarious stands including PhDprogrammes involving MMI and SBI(strand 2) and emerging areas such asnanoremedies (strand 3).

Over the coming months, as part of theTCD-UCD Innovation Alliance, we willestablish Conway Innovations to providelocal support to facilitate the innovation

process, develop strong links to ourindustry partners and assist graduatetraining through the innovationacademy.

Regards

Professor Des FitzgeraldDirector

Director’s Message

Conway Fellow, Professor Dolores Cahilland Professor Kenneth Dawson, UCDhave been awarded funding from ScienceFoundation Ireland to secure thepurchase of a protein expression factoryfor use in their research and incollaboration with other research groupslocally, nationally and internationally.

The equipment facilities a highthroughput process starting with PCRamplification of genetic source material,construction of expression vectors,transformation and expression ofpurified proteins or vectors. In additionto the four 96-well plates that allowprocessing of large quantities of geneticmaterial, the protein expression factoryprovides faster and more accurateprocessing as well as software andtechnical support.

A virtual experiment planning process isfacilitated using web based software. Aresearcher who wishes to proceed to

executing this experiment can then useJobManager software to instruct therobotics and calculate the consumablerequirements.

One of the initial planned projects incollaboration with Conway Fellow,Professor Pauline Rudd of the NationalInstitute for Bioprocessing Research &Training (NIBRT) will look at theimportance of glycosylation in theprocess of cell recognition within theimmune system. The expression factorywill assist in changing about 90glycosylation sites on a T-cell receptorand put these mutants in vectorconstructs for further investigationwithin human cells.

Supplied by NextGenSciences andsupported by eXeTech, this proteinexpression factory is the only instrumentof its kind in Ireland. Currently in testingphase, it is hoped that the machine willbe fully operational in November 2009.

Researchers interested in using theinstrument should contact Dr AlejandroMerino (alejandro.merino@ucd.ie) orvisit www.cbni.eu/Technology.

Ireland’s First Protein Expression Factory Installed in UCD Conway

Dr Rosemary Clyne and postdoctoralfellow Dr Julia Grassl have been invitedto edit of a special issue of the journalProteomics (www.proteomics-journal.com) that will be published inOctober. The issue is a compilation of 22original peer-reviewed research andreview articles in the area of yeastproteomics. Included in the special issueare review articles from UCD Conway

Fellows, Drs Gerard Cagney and MatthiasWilm. Julia's work on optimising samplepreparation methods, which was done incollaboration with Conway Fellow, Prof.Mike Dunn's group and Denator AB(Sweden), was accepted for publicationin the special issue. This work has alsobeen presented as a poster at the 8thHUPO World Congress 2009 in Toronto.Rosemary presented this and other work

at the 2nd Irish Proteomics Workshopheld during September in UCD ConwayInstitute. Other presentations from thegroup include a talk by PhD student,Catherine Daly and best poster prize forPhD student Maria Iacovella at the IrishFungal Meeting 2009 (UCD ConwayInstitute).

Guest Editors on ‘Proteomics’

The Guide to ‘Pain-free Biochemistry’

Based on a lifetime’s experience ofhelping students with the concepts ofbiochemistry, Prof. Paul Engel’s newbook, Pain-free Biochemistry will bepublished this Autumn. Departing fromthe usual textbook pattern of lengthychapters, Engel covers short topics inbite-size chunks written in an informal

style. There is an extensive glossaryoffering simple explanations and a longsection of appendices for those whowant a little more depth to the topic.The book avoids unnecessarycomplexity, introducing long names andcomplicated structures only where theyare essential to understanding. Although

the ‘pain’ the book was designed toalleviate was that of student nurses,physiotherapists and radiographers, thebook might well prove helpful for awider audience and perhaps even theodd committed biochemist!

NextGenSciences expression factory

UCD_Conway_Oct 15/10/2009 08:36 Page 1

Honouring a Research Career Dedicated to Memory Storage Mechanisms

Dr Niamh O’Sullivan was awarded theUCD Conway Festival of Research &Innovation gold medal, sponsored byRoche, for her preliminary research toidentify epigenetic mechanisms, whichmay contribute to disease characteristicsseen in schizophrenia.

A postdoctoral researcher in the AppliedNeurotherapeutics Research Group, DrO’Sullivan was shortlisted from over 100Conway scientists to present this originalresearch at the 9th annual UCD ConwayFestival of Research & Innovation onSeptember 17th.

It is well established that multiple geneticand environmental factors contribute toschizophrenia. Dr O’Sullivan and hercolleagues believe that these factors mayinteract at critical periods in earlydevelopment to create a defectiveepigenetic state within certain brainstructures. The knock-on effect ofdisrupting the functionality andconnectivity of nerve cells within the brainmay result in the onset of the symptomsassociated with schizophrenia.

Niamh O’Sullivan outlined how she hasbegun to identify functional regulatory

elements that control gene activation indifferent cell types, at different stages ofdevelopment using a next-generation genesequencing platform. Ultimately, she hopesthat by revealing the sequence ofmolecular events responsible for theemergence of schizophrenia-likebehaviour, scientists will then be able toidentify new therapeutic targets for thedisease.

Drs Sam Maher (PI: Prof. David Brayden)and Sara Hayden (PI: Dr Emma Teeling)were placed second and third in thecompetition for their respectivepreliminary research on improving drugpermeability across the gastrointestinaltract and understanding the relationshipbetween odours and the genes that governour sense of smell.

The judging committees involved in theoral and moderated poster sessions wereunanimous in their praise for the quality ofresearch presented during the course ofthe 9th annual Festival. KristinaGegenbauer, Sarah Kandil, David Mageeand Brendan Dolan received prizes fordelivering concise overviews of their workduring the moderated themed postersessions.

Delegates at the conference heard keynotelectures from Professor Kingston Mills, TCDand Conway Fellow, Professor GeraldineButler. The event was sponsored byBioSciences, Servier Laboratories Ireland& Roche.

Epigenetic Mechanisms in Schizophrenia wins Festival Medal

Pictured (L-R) Dr Niamh O’Sullivan, Dr Keith Murphy,Professor Des Fitzgerald, Ms Jenny Pearson, Rocherepresentative.

Joint winner of the Nobel Prize inPhysiology or Medicine in 2000,Professor Eric Kandel delivered theplenary lecture of the 9th annual UCDConway Festival of Research &Innovation after receiving a Ulyssesmedal in recognition of his research onthe mechanism of memory formationfrom Dr Hugh Brady, the President ofUCD.

“Professor Kandel’s story is one of alifetime dedicated to investigating themechanism of memory formation; alifetime of research achievements in hisquest, as he once said himself, tounderstand the brain - one cell at a time,”said Dr Hugh Brady who presented theaward in front of a capacity crowd. “Thisaward is in recognition of his outstandingcontribution to neurobiology, aninspirational story to set our resolve asscientists and researchers.”

Born in Vienna on November 7, 1929,Kandel immigrated to America before thestart of World War II. He believes that itwas the traumatic events of his last year inVienna living under Nazi rule that

triggered his specific later interest in themechanisms of memory.

His lecture entitled: The long and short oflong-term memory, outlined his scientificwork and discoveries, which culminated inthe 2000 Nobel Prize in Physiology orMedicine (jointly awarded to ArvidCarlsson and Paul Greengard).

The three Nobel Laureates madepioneering discoveries concerning onetype of signal transduction between nervecells in the brain, known as slow synaptictransmission. The discoveries have beencrucial to the understanding of the normalfunction of the brain and how disturbancesin this signal transduction can give rise toneurological and psychiatric diseases.

Kandel found that the brain mustchemically alter proteins to generateshort-term memories and mustadditionally make particular kinds ofproteins in order to transform short-termmemories into long-term memories - thebrain's way of filing important documentsaway, for potential future use. He was alsoamong the first to detail the critical role

played by serotonin in transmittingelectrical messages between nerve cells.When serotonin is lacking, it can lead todepression, bipolar disorder andschizophrenia.

Today, Eric Kandel's research group at theCentre for Neurobiology and Behaviour inColumbia University are studying selectedexamples of several major forms ofmemory storage.

Professor Eric Kandel, UCD Ulysses medal recipientand plenary speaker at the 9th annual UCD ConwayFestival of Research & Innovation

Innovation Success for Kinsella Group

Researchers led by Conway Fellow, Prof.Therese Kinsella successfully filed a PCTpatent in August 2009 covering a seriesof modified promoter sequences thatare suitable for recombinant proteinexpression in wide range of cells ofhuman origin, including stem cells. Theresearch findings underpinning thisinvention centres on the humanthromboxane A2 receptor and have beenrecently published in the Journal ofLipid Research, Journal of Molecular &Cellular Medicine (in press) and theJournal of Molecular Biology (in press).

Thromboxane plays an important role inhaemostasis and signals through the alphaand beta isoforms of the thromboxane A2

receptor (TP) in humans. Both areencoded by a single gene but regulated bytwo distinct promoters, Prm1 and Prm3.Dr Anne-Marie Gannon carried out muchof the group’s recent work that centres ondescribing the factors regulating Prm1and how this impacts on the expression of

TPalpha. The key transcription factors identifiedinclude the housekeeping Sp1 andinducible Egr1, a factor often seen to beup-regulated after an adversecardiovascular event. Of particular note,and possibly reflecting the importance ofthe receptor within the vasculature, is theidentification of NF-E2 as a key factorinvolved in its expression, and thereforethe thromboxane receptor joins an elitegroup of genes, primarily associated withhaematopoietic stem cells, established asbeing regulated by NF-E2. The data alsoestablishes Wilms’ tumour suppressorprotein (WT1) as a critical repressor ofthe promoter. Given the importance ofthromboxane receptor expression andfunction in both the vasculature and thekidney, this may explain, at least in-part,some of the renal dysfunction seen in thechildhood cancer Wilms’ tumourassociated with genetic defects in WT1. Additionally, Prof. Kinsella has recentlybeen awarded an Enterprise Ireland

Technology Development Grant also basedon her research on the humanthromboxane A2 receptor. In collaborationwith Conway Fellow, Prof. Pat Guiry(CSCB) and Dr Helen Reid, the team hopeto develop novel thromoboxane receptorantagonists geared to the anti-thrombotics area.

Ref: Regulation of the human thromboxane A2 receptor

gene by Sp1, Egr1, NF-E2, GATA-1, and Ets-1 in

megakaryocytes. Gannon AM, Kinsella BT.J. Lipid Res.

2008 Dec;49 (12):2590-604.

The Wilms' Tumor Suppressor Protein WT1 acts as a key

Transcriptional Repressor of the Human Thromboxane A

Receptor Gene in Megakaryocytes. Gannon AM, Kinsella

BT.J Cell Mol Med. 2008 Nov 22

Regulated Expression of the alpha Isoform of the Human

Thromboxane A(2) Receptor during Megakaryocyte

Differentiation: A Coordinated Role for WT1, Egr1, and

Sp1.Gannon AM, Turner EC, Reid HM, Kinsella BT. J Mol

Biol. 2009 Sep 8. [Epub ahead of print]

New Insights to the Metabolic Control of Insulin Secretion

The results of a recent study by Conwayresearchers and collaborators in theUniversity of Geneva and University ofUlster have identified Arala1 (aspartate-glutamate carrier 1 AGC1), a malate-aspartate NADH shuttle member, as akey metabolic control site in insulinsecreting cells. The work washighlighted when published recently bythe journal Clinical Science.

In pancreatic beta-cells, nutrientmetabolism and insulin secretion aretightly coupled. The NADH shuttle systemis primarily made up of the malate-aspartate and glycerol-3-phosphateshuttles. The former is thought to play animportant role in the amplification ofinsulin secretion. The research group led by Conway Fellow,

Professor Philip Newsholme hypothesisedthat overexpression of Aralar 1, a calciumsensitive isoform of the aspartate-glutamate exchanger and integralcomponent of this shuttle, would affectcellular nutrient metabolism and insulinsecretion. Dr Katrin Bender looked at the effects ofamino acid and glucose metabolism in aclonal beta-cell line BRIN-BD11, derivedfrom rat islet cells and RINm5F cellsthrough electrofusion. She found Aralar1overexpression increased glucose- andamino-acid stimulated insulin secretion,cellular glucose metabolism, L-alanine andL-glutamine consumption, cellular ATPand glutamate concentrations, andstimulated glutamate release. However,cellular triacylglycerol and glycogencontents were decreased as was lactate

production.Significantly, Dr Bender showed that theaddition of glucose and alanine caused thegreatest increase in insulin secretion incomparison with any other nutrientcombination in Aralar-1 over expressingcells. Dr Katrin Bender completed this researchas part of her doctoral thesis supervisedby Prof. Newsholme. It was fundedthrough the Health Research Board.

Ref: Overexpression of the malate–aspartate NADH

shuttle member Aralar1 in the clonal beta-cell line

BRIN-BD11 enhances amino-acid-stimulated insulin

secretion and cell metabolism. Katrin Bender, Pierre

Maechler, Neville H. McClenaghan, Peter R. Flatt and

Philip Newsholme. Clinical Science (2009) 117, 321–330

doi:10.1042/CS20090126

Conway Fellow, Dr Albert Smolenski andhis group have identified new proteinsinvolved in the secretion of plateletgranules. The research outlining theirdiscovery that synaptotagmin-likeprotein 1 (Slp1) and the GTPase-activating protein Rap1GAP2 controldense granule release was recentlypublished in Blood, the leading journal inhaematology research.

Platelets have an important role in thepathogenesis of atherosclerosis,myocardial infarction and stroke. Theycirculate in the blood stream and bind toinjured vessel walls providing a seal thatprevents bleeding. At sites ofatherosclerotic damage, platelets canadhere and aggregate leading to occlusionof the vessel followed by irreversibledamage to the tissue supplied by theartery. Platelet activation involves the release of

storage granules containing manybioactive molecules that reinforce plateletfunctions. Platelets contain three differentgranule types but the mechanismscontrolling their secretion are not wellunderstood. The Smolenski group wereable to show that Slp1 strongly inhibitswhereas Rap1GAP2 enhances densegranule release. The effect of Rap1GAP2requires binding to Slp1 and the groupidentified a new protein motif thatmediates the interaction between the twoproteins. The discovery of synaptotagmin-likeprotein 1 and Rap1GAP2 might pave theway for the development of more efficientand specific antiplatelet therapies.Currently, antiplatelet therapy usingmolecules like aspirin or the ADP receptorblocker, clopidogrel is limited by side-effects such as an increased risk ofbleeding.The work originated in earlier studies by

the group that led to the identification ofRap1GAP2 as the only GTPase-activatingprotein of Rap1 in platelets. This proteinregulates cell adhesion and plateletaggregation. The group characterisedRap1GAP2 as a phosphorylated substrateof cyclic nucleotide-dependent proteinkinases. The cyclic nucleotide signallingnetwork is a built-in inhibitory system inplatelets that regulates most aspects ofplatelet function. The unexpected findingof Rap1GAP2’s role in granule secretionsuggests that both aggregation andgranule release might be closelycoordinated. A SFI principal investigatorprogramme grant funded the work.

Ref: Synaptotagmin-like protein 1 interacts with the

GTPase-activating protein Rap1GAP2 and regulates

dense granule secretion in platelets (2009)Neumüller,

O., Hoffmeister, M., Babica, J., Prelle, C., Gegenbauer, K.

and Smolenski, A.P. Blood 114: 1396-1404.

Controlling the Release of Platelet Granules

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