Conway Focus Issue 14 Summer 2011

Elaine QuinnCommunications & Education Officer

UCD Conway Institute of Biomolecular & Biomedical ResearchUniversity College Dublin

Belfield, Dublin 4Ireland

E: [email protected]: (+353-1) 716 6706F: (+353-1) 716 6701

W: www.ucd.ie/conway

Investing in Your Future

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Research by Conway Fellow, Dr OliverBlacque has revealed new informationabout a gene implicated in Joubertsyndrome and related cerebellar disorders(JSRDs), characterised by blindness, boneabnormalities, cystic kidneys,developmental delay and loss of muscletone and control. The findings of thisresearch, funded through a ScienceFoundation Ireland President of IrelandYoung Researcher Award (PIYRA) to OliverBlacque, were recently published in theJournal of Cell Biology.

One of seven genes associated with JSRDs,Arl13b codes for a protein already known toplay roles in the formation and/or functionof cilia, which are hair-like projectionsextending from the surface of the cell.However, the precise molecular details ofwhat exactly Arl13b is doing in cilia haveremained unclear.

Blacque’s team studied the gene in the ciliaof tiny worms (Caenorhabditis elegans)while collaborators in the University ofTokyo conducted parallel experiments incultured human cells. Together, theyconfirmed that Arl13b proteins uses lipidanchors to associate with the ciliarymembrane.

Much of the work on the project was carriedout by UCD doctoral candidate, SebihaCevik. She and her colleagues went on todemonstrate in C. elegans how disrupting

the function of worm Arl13b causes theciliary membrane to bulge and becomemisshapen as well as affecting the ability ofother proteins to properly distribute withinthe ciliary membrane.

They also found that a fully functionalArl13b protein is needed for the normalfunctioning of a protein transport system incilia. This intraflagellar transport system(IFT) makes contact with the ciliarymembrane. Based on these results, theyproposed a new working model for Arl13b,where it functions at the ciliary membraneto regulate important ciliary membraneproperties such as shape, transmembraneprotein distributions and IFT.

Up to only 20 years ago, many believedmost cilia to be redundant cellularorganelles that have fallen victim tomammalian evolution - a type of cellularappendix. We now know that these cellularantennae present on nearly all of our cellsand serve fundamental roles in manymotility and sensory functions, includingsignalling pathways critical to development.

It is now not surprising that defects incilium structure and function are associatedwith an ever expanding range of humandiseases and syndromes, collectively calledciliopathies, which have overlapping clinicalfeatures such as polycystic kidneys andlivers, retinal degeneration, boneabnormalities, hydrocephalus, as well as

complex traits including obesity, diabetes,mental retardation and even cancer.

Dr Oliver Blacque hopes that these findingswill ultimately lead to a greaterunderstanding not only of JSRDs, but alsoof closely related ciliopathies such asMeckel Gruber and Bardet-Biedl syndrome,as well as perhaps more commonphenotypes associated with ciliumdysfunction such as mental retardation andobesity.

He notes “That Arl13b associates with ciliarymembranes and is required for ciliumstructure/function in both worms andmammals demonstrates the remarkableevolutionary conservation of how this smallG-protein functions.”

ReferenceJoubert syndrome Arl13b functions at ciliarymembranes and stabilizes protein transport inCaenorhabditis elegans. Cevik S, Hori Y, Kaplan OI,Kida K, Toivenon T, Foley-Fisher C, Cottell D, Katada T,Kontani K, Blacque OE. J Cell Biol. 2010 Mar 22;188(6):953-69

May2010Issue10

I am delighted to welcome you to theConway Focus and look forward to workingwith you in the coming months!

As an institute with an increasinglyinterdisciplinary research focus andexpertise in specialist technology platforms,we are uniquely placed to participate in theeducation and training of the nextgeneration of research scientists. The newlylaunched PhD programme in Bioinformaticsand Systems Biology recently attracted 80EU and 120 non-EU applicants for up to 15studentships.

We introduced 4 new advanced coretechnology modules on a pilot basis thisacademic year; those covering principlesand practical aspects of imaging and appliedproteomics began in late March and will rununtil mid-June with a further two modules ingenomics and flow cytometry taking placeover week-long periods during the summermonths.

We hope to determine from this pilot ifdemand for training from within UCD as wellas from external academic centres andindustry will dictate stand-alone delivery ofthese advanced modules or inclusion within

larger programmes such as the new MSc inImaging commencing in September 2010.

I hope that a number of new initiatives,including the early-stage researcher forumdescribed in this issue, will not onlystrengthen the community of Conwayresearchers and forge new interdisciplinarylinks but will celebrate and heightenawareness of our research and innovationsuccesses.

Professor Walter KolchDirector, UCD Conway Institute

Director’s Message

Worm research reveals cilia disease gene function

UCD CONWAY INSTITUTE OF BIOMOLECULAR & BIOMEDICAL RESEARCH

Arl13b at ciliary membrane

Centre of Excellence hosts international workshop

As a European Centre of Excellence, theDepartment of Rheumatology in St Vincent’sUniversity Hospital was chosen to host aninternational two-day workshop on March26th & 27th 2010. Sponsored by RochePharma, the Participate workshop gavetwenty rheumatologists from centres inEurope and Australia the opportunity towitness the care of patients with rheumatoidarthritis (RA) at St Vincent’s.

The Participate programme focused onadvanced treatment regimens for RA in theclinic, including practical aspects of biologictherapy carried out in the accredited infusionsuite that provides optimal care for RApatients. In addition to lectures from ConwayFellows, Professors Oliver FitzGerald andDouglas Veale, delegates heard from clinicalnurse specialists about patient education,screening and monitoring of biologicaltherapies.

Addressing the international guests, Ms MaryDuff, Director of Nursing and Ms. KayConnolly, Assistant Director of Nursing for theBone & Joint Unit expressed their hope thatthe experience of the multidisciplinary teamfrom St Vincent’s would provide a template fordelegates to reproduce similar care andfacilities for the management of RA patients intheir respective countries.

Launch of Conway postdoctoral & graduate forum

A new fortnightly forum for Conway graduateand postdoctoral researchers will be launchedin May 2010. This initiative will give early-stage researchers the opportunity to talk aboutscience and issues that concern them in aninformal environment with refreshmentsprovided! Content for the forum will be

decided by the members but it is envisagedthat it will include a mix of technologyoverviews, informal and formal researchseminars, PhD viva rehearsals and careerdevelopment talks from within and beyondacademia. Forum committee members, PhDstudent Mr Thomas Schwarzl

([email protected] ) and postdoctoralresearchers, Dr David Gomez([email protected]) and Dr Craig Slattery([email protected] ) invite suggestions forthe forum schedule.

Frog peptide structure selected for journal cover

An image of the frog peptide structure centralto the work of a UCD Conway research teamwas selected as the front cover image for theApril 2010 edition of the scientific journal,Biochimica et Biophysica Acta (BBA);Proteins & Proteomics.

Peptides in the skin of many species of froghave anti-bacterial and anti-fungal propertiesas well as the ability to lyse or rupturemammalian cells. This innate immunityprotects it from attack. These properties offrog skin peptides are exciting from theprospect of being developed intotherapeutically valuable anti-infective and anti-cancer agents.

Conway Fellow, Dr Chandralal Hewage and histeam carried out molecular modelling of theXT-7 peptide and its analogue [G4K]XT-7 in a

variety of solutions in order to understand thestructural basis for the difference in biologicalactivity.

This particular XT-7 peptide, isolated from theskin of Silurana tropicalis, shows potential fordrug development as it has impressive activityagainst the growth of bacteria and Candidaalbicans. However, this potential as an anti-infective agent is restricted by its haemolyticactivity.

A change to the amino acid structure of theXT-7 peptide can create an analogue thatretains anti-infective properties but without thecomplicating haemolytic activity. The singleamino acid substitution (glycine replaced bylysine) improves the therapeutic potential ofthis naturally occurring peptide.

Cover of April 2010 edition of Biochimica et BiophysicaActa (BBA); Proteins & Proteomics.

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Irish biopharmaceutical developmentcompany, Sigmoid Pharma recently scoopedthe overall Innovation of the Year award atthe inaugural Irish Times All-IslandInnovation Awards. The life-science SME,founded by UCD pharmacology graduate, DrIvan Coulter, has actively collaborated withConway Fellow, Professor Cormac Taylorsince being granted a Science FoundationIreland industry research partnership awardin 2004.

The Irish Times award recognises the stellarinnovative performance of Sigmoid Pharma intheir application of research and development.The company has developed two new drugtechnologies, LEDDS™ and SmPill™, which notonly enhance the solubility and permeability ofthe drug but can deliver it to targeted locationsin the gastrointestinal tract, including thecolon.

The Sigmoid Pharma-Taylor collaboration isfacilitating the development of a newtherapeutic approach for the treatment ofinflammatory bowel disease (IBD) by bringingtogether the research methodology of theTaylor group with the proprietaryliquid/emulsion drug delivery system,LEDDS®, developed by Sigmoid Pharma.

Commenting on the award, Professor Taylorsaid, “We are delighted for Dr Coulter and histeam and indeed it reflects well on ourpartnership. A key driver of successfulscientific research in 2010 is meaningfulinteraction of academia with industry that

results in both academic outputs and theapplication of research toward clinical productdevelopment with indigenous companies.”

Commenting on the Taylor collaboration, DrCoulter said, “The collaboration with the Taylorlaboratory clearly demonstrates the potentialthat can be realised through focusedapplication of basic research. The developmentof a smart economy will depend on like-mindedcollaborative partners identifying opportunitiesand realising basic and applied researchsynergies. This collaboration, initiated througha SFI research supplement, highlights thepotential that innovative indigenous companiesworking with academia can realise.”

Taylor’s collaboration with Sigmoid Pharma hascertainly been successful by these metrics withthree co-authored publications to date in two ofthe highest ranking scientific journals in thefield, Gastroenterology and Proceeding of theNational Academy of Sciences, as well as thegeneration of proprietary innovative productsand the creation of high-skilled jobs.

More than 15,000 people in Ireland andmillions of people worldwide are living with thesymptoms IBD today. Current therapeuticoptions for this chronic debilitating disease arevery limited with surgery often being the onlyviable option. The Sigmoid product, currentlyin a phase II clinical study, uniquely enablesoral delivery of a powerful drug withoutcausing systemic side-effects.

Under normal conditions, the gastrointestinal

tract is lined with cells that block the contentsof the gut from leaking into the intestine. In anIBD patient, this barrier is broken and thecontents of the gut leak out into surroundingareas. The research team in UCD Conway useda model of IBD and, by applying a new class ofdrugs known as hydroxylase inhibitors, wereable to almost completely reverse thesymptoms of the disease.

“When we applied these new drugs to our IBDmodel, the gut was tricked into thinking that itwas being deprived of oxygen. This activatedprotective pathways, which in turn preventedthe death of the cells that line thegastrointestinal tract,” explained ProfessorTaylor. “Our pre-clinical trial data can nowinform the next phase Sigmoid Pharma productdevelopment pipeline”.

In addition to the product that is currently inphase II clinical studies, Sigmoid Pharma isdeveloping a LEDDS™-enabled formulation ofthe hydroxylase inhibitordimethyloxaloylglycine (DMOG) to bring abouteffective, safe and targeted delivery of thispotential therapeutic agent.

Conway collaborator scoops Irish Times Innovation Award

Conway researchers led by Dr. TaraMcMorrow and Professor Michael Ryan havesuccessfully secured €485,500 in funding aspart of an overall award to the SystemsBiology towards Novel Chronic KidneyDisease Diagnosis and Treatment (SysKid)consortium under the European Union FP7programme.

Syskid (www.SysKid.eu) was established tofurther our understanding of chronic kidney

disease (CKD) and improve patient treatment,with particular focus on CKD arising fromdiabetes and hypertension. The multi-disciplinary research consortium has 25partners (16 universities, 9 industry partners)from 15 countries and the project is due to runfor five years.

The UCD Conway team, including postdoctoralresearchers Dr. Craig Slattery and Dr. NataliaMartin, will utilise cell culture and animal

models to identify processes involved in earlyCKD progression and investigate novelstrategies for preventing and slowing theprogression of the disease. These studies willbe integrated with clinical and epidemiologicalstudies across the consortium using systemsbiology methodologies in order to develop newdiagnostic strategies and treatment options toprevent CKD development. [email protected] for details of a PhDposition currently available.

Success in EU FP7 call

Bioinformatic analysis of HIV progression studies

Meta-analysis by UCD researchers led byConway Fellow, Professor Denis Shields hasdetermined that there is no clear evidencethat particular defective viral sequences inthe HIV-1 nef gene or certain regions of theprotein play a significant role in diseaseprogression.

HIV-infected patients can be categorised onthe basis of the number of years it takes forthem to progress to AIDS. Some patientsmaintain stable CD4 lymphocyte counts anddo not go on to develop AIDS even after morethan 10 years of infection.

Scientists are curious as to why these long-term, non- progressor (LTNP) patients do notdevelop AIDS. This may reflect differences inthe host, viral genetics or environmentalfactors that could potentially be exploited forthe treatment of the disease.

Studies in model organisms have shown thatinfection with nef-deficient virus shows anattenuated course of infection and some

studies in humans have shown that nonprogression was associated with grossdeletions in the nef gene.

However, much of the research in the area todate has been based on observational or casestudies rather than rigorous, systematicscientific evaluation. This work by doctoralcandidate Ravindra Pushker set out todetermine in a substantially larger sample setif any association exists between diseaseprogression and particular amino aciddifferences or deletions within the nef gene.

On a per patient basis, there was no excess ofLTNP patients with one or more defective nefsequences when compared to progressors.While the high frequency of amino acidreplacement at particular residues is indicativeof rapid evolvement, permutation testingshowed that residues with more replacementsthan expected were not statistically significant.

The researchers conclude that current dataprovides no evidence that individual residues

of HIV nef are critical in determining the rateof disease progression. Professor DenisShields believes that searches for modifiers ofprogression rates should now focus on otherhost and viral factors. “Systematic evaluationof large quantities of data by bioinformaticscan be just as important in refutinghypotheses that are current in the literature, asit is in discovering unknown patterns”, he said.

This research was funded through ScienceFoundation Ireland and University CollegeDublin.

Reference:Meta-analysis to test the association of HIV-1 nef aminoacid differences and deletions with disease progression.Ravindra Pushker, Jean-Marc Jacquē, Denis C. Shields.Journal of Virology, Apr 2010 p3644-3653

GlycoExtractor advances glycan data manipulation

Glycomics needs the supporting frameworkof extensive, well-curated databases andflexible analytical tools. Currently, this fieldof study lacks the established,comprehensive and centralised datacollections, standards and informationreporting protocols that exist withingenomics and proteomics.

Researchers, Dr Natalia Artemenko and DrMatthew Campbell from the National Instituteof Bioprocessing Research & Training (NIBRT)led by Conway Fellow, Professor Pauline Ruddhave developed an open access, web-basedinterface that facilitates extraction, queryingand sharing of HPLC-glycan data generated inhigh throughput processes.

Glycosylation is the most common andstructurally diverse post-translationalmodification of proteins. More than half of allgene products have been shown to beglycosylated. With many specific glycans orglycoforms showing potential as cancerbiomarkers, there is an increasing need todevelop high throughput, highly sensitive androbust strategies that detail the glycome of

cells, tissues and fluids.

Commercial packages that support HPLCinstruments cannot facilitate the extraction oflarge quantities of data. In an effort to alleviatethis bottleneck within high-throughputglycomic projects, the NIBRT team havedeveloped a web-based tool that interfaceswith the Waters chromatography softwarepackage to improve and automate the exportof data to various file formats for subsequentanalysis. The modular architecture of the toolalso facilitates the manipulation of data fromother data management systems.

The NIBRT team are now working to integrateGlycoExtractor with the EUROCarbDBframework to provide a comprehensive high-throughput HPLC data analysis platform forthe storage and annotation of experimentaldata. The integration of next generationbioinformatic tools will further thedevelopment of unified approaches forhandling large scale glycomics data initiativeswith applications in biomarker discovery

This research was partially supported by

EUROCarbDB, a research infrastructure designstudy funded by the EU 6th FrameworkProgramme. Prospective users can access theGlycoExtractor tool onhttp://glycobase.nibrt.ie:8080/DemoGlycoExtractor/mainPage.ReferenceGlycoExtractor: A web-based interface for highthroughput processing of HPLC-Glycan dataNatalia V. Artemenko, Matthew P. Campbell, and PaulineM. Rudd Journal of Proteome Research, 2010, 9 (4), pp2037–2041

NIBRT researchers Dr Matthew Campbell and Dr NataliaArtemenko who developed GlycoExtractor

Zebrafish model gives insights into diabetic blindness

New research led by Conway Fellow DrBreandán Kennedy indicates that treatmentof diabetic blindness should look atprotecting the neurons responsible for colourvision in the eye and not just targeting theblood vessels as is currently the practice.

Nearly 2.5 million people worldwide are blinddue to diabetic retinopathy. This secondarycomplication of diabetes activates the growthof new leaky blood vessels in the eye and isresponsible for the death of photoreceptors,the neurons that send visual messages to ourbrain.

Until now, it was unclear if the changes tovessels and neurons occurred independently ofone other and which type of retinal neuron is

most likely to die as a result of the raisedglucose levels seen in diabetes.

Dr Kennedy and his team found that new bloodvessels and the neuronal cell death in diabeticretinopathy can arise independently of eachother. In addition, they identified that conephotoreceptor neurons, those involved incolour vision and used in daylight, are mostaffected by the high glucose levels.

The research team made their observationsusing a novel zebrafish model of diabetes,which resembles the early stages of diabeticretinopathy in humans. It is an excitingdevelopment for the group who now hope tofurther extend their research and establish amodel of late stage diabetic disease.

Commenting on the research, Dr Kennedysaid, “By establishing a robust model for earlyand late stage diabetic retinopathy, we wouldhope to better understand the progression ofthe disease and pave the way for identifyingnew drug targets for its successful treatment”.

The research was funded through ScienceFoundation Ireland and the Health ResearchBoard.

Reference:

Predominant cone photoreceptor dysfunction in ahyperglycaemic model of non-proliferative diabeticretinopathy. Yolanda Alvarez, Jenneth Chen, AlisonReynolds, Nore Waghorne, John J. O’Connor, BreandanKennedy. Disease Models & Mechanisms (2010)

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New avenue to tackle CJD and Alzheimer’s diseaseTwo antibodies that could help block the onset of Alzheimer’s disease in the brain have been identified in a collaborative research project involving scientists at the Medical Research Council Prion Unit at University College London, UCD Conway Institute and Trinity College Dublin.

The antibodies, ICSM-18 and ICSM-35, were already known to play a crucial role in preventing protein misfolding; the main cause of Creutzfeldt–Jakob disease (CJD), the human form of mad cow disease.

The study findings published in Nature Communications has shown in mice that these antibodies can block damaging effects on brain tissue caused by a toxic substance called amyloid beta. Cumulatively, amyloid beta becomes attached to the surface of nerve cells in the brain, stopping them from communicating effectively and causing memory loss. The results showed that the antibodies stopped the amyloid beta proteins from taking hold and damaging the brain.

The study also confirms findings from a 2009 paper by Yale researchers, which first indicated that prion proteins, which can

change their shape and cause CJD, may be involved in Alzheimer’s.

“With an ageing population and increasing numbers of families affected by Alzheimer’s disease, there is an urgent need for new drugs that can help to preserve brain function and prevent memory loss, the symptom which most characterises the devastating impact of Alzheimer’s,” said Professor John Collinge, Director of the MRC Prion Unit at University College London, who led the study.

“We’re thrilled that this discovery shows in mice that these two antibodies which we are developing to treat CJD may also have a role in treating more common forms of dementia like Alzheimer’s disease. If these antibody drugs prove to be safe in use to treat CJD, we will consider whether studies in Alzheimer’s disease should be carried out.”

“A unique aspect of this study is that we used amyloid beta extracted from human brain, the same material we believe is causing memory loss in patients with this devastating disease, and we identified two antibodies that could block this effect,” said Professor Dominic Walsh, Professor of Neurodegeneration at the UCD School of

Biomolecular and Biomedical Science, and the UCD Conway Institute who was co-corresponding author on the research.

“The use of these specific antibodies is particularly exciting since they have already undergone extensive pre-clinical testing for use in treating CJD. So, a lot of basic work has already been done and could fast-track these antibodies for use in humans. The next step is further validation in other disease models of Alzheimer’s and then safety trials in humans,” he added.

Clinical trials to see whether drugs based on these antibodies can mitigate the damage caused to the human brain as a treatment for patients with CJD are due to begin in 2012.

Director’s MessageWelcome!

With the recent launch of the National Institute for Bioprocessing Research and Training (NIBRT), we bid farewell to Professor Pauline Rudd and her team as they leave the Institute building for their new home across campus. Minister for Research & Innovation, Seán Sherlock TD officially opened the new 6,500sq metre facility that will support the biopharmaceutical industry in Ireland

by educating and training highly skilled staff and conducting ground-breaking research in collaboration with industry. We look forward to maintaining close links with Pauline and rest of the NIBRT team through the many research collaborations established with other Conway Fellows.

The co-localisation of all imaging facilities to the lower ground floor of the Institute is now entering the final stage of completion. We anticipate that all electron microscopy

equipment will be successfully transferred into the building over the summer months. I am confident that the consolidation of this core technology platform will have a positive impact on service delivery for our researchers.

Professor Walter Kolch Director

The first detailed research study of protein expression changes within the hippocampus in schizophrenia and bipolar disorder has not only shown striking overlap of changes between disorders but localised altered expression to specific subregions in this part of the brain.

The findings by a research collaboration involving the Royal College of Surgeons in Ireland (RCSI), Beaumont Hospital and UCD Conway Proteome Research Centre were published in the May issue of Archives in General Psychiatry, the highest ranking journal in the field.

Abnormalities in the hippocampus are among the most consistent findings in schizophrenia research and are also implicated in bipolar disorder. Using mass spectrometry, the research team identified 152 proteins, with 61 of these

being differentially expressed in both disorders. These proteins are implicated in a range of different processes including cytoskeletal and metabolic functions.

Subsequent validation work carried out by the researchers confirmed changes in the cytoskeletal protein, septin11 and proteins involved in the membrane trafficking process of clathrin-mediated endocytosis in both disorders. The hippocampus is subdivided into specific regions; cornu ammonis (CA) regions 1 through 4 and the dentate gyrus. These subregions differ anatomically, functionally and in their vulnerability to neurological disorders. The most prominent protein changes seen were in regions CA2 and CA3.

‘These results give us greater insight into the nature and extent of region-specific

protein changes in psychotic disorders and may provide valuable information about the underlying molecular mechanisms in these illnesses,’ said Dr Melanie Föcking.

The proteomics research was conducted in collaboration with Conway Fellow, Professor Michael Dunn while Professor David Cotter led the research in RCSI and Beaumont Hospital. The work was funded by the Wellcome Trust, NARSAD and the Stanley Medical Research Institute.

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Dr Patricia McGowan was awarded joint first prize from the TIDA / SFI ‘Get Started’ Technology Venture Programme organised by Science Foundation Ireland (SFI) and the Irish Technology Leadership Group (ITLG). She will participate in a week-long visit hosted by the ITLG to meet members of the venture community and leading technology companies in Silicon Valley, California.

A senior postdoctoral researcher, Dr McGowan works in the breast cancer research group, led by Conway Fellow,

Professor Joe Duffy in the Education & Research Centre, St Vincent’s University Hospital. Her winning elevator pitch focused on an innovative product targeted at the treatment of triple negative breast cancer that may have potential in the clinical setting.

SFI is working in partnership with Enterprise Ireland on the Technology Innovation Development Award (TIDA) to realise a greater economic impact from the state investment in oriented basic research by teaching business skills to university researchers and scientists.

Pitching to ‘Get Started’

( L-R) Dr. Roisin Cheshire, Scientific Programme Manager, Science Foundation Ireland; Dr. Patricia McGowan (joint prize winner); Cian Hughes, Head of Operations, Irish Technology Leadership Group



















































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Conway Fellow, Dr Patricia Maguire recently hosted a visit by Team SAP Ireland, a group of six transition year secondary school students and their teacher, Mr Declan Askin from St Gerard’s College, Castlebar.

This exceptional group of students are gaining national and international acclaim for their robotics and biomedical engineering applications. They received a British Science Association CREST award and represented Ireland in the First Lego League (FLL) World Finals in St Louis,

Missouri, USA at the end of April 2011 where they won third place overall and the most inspirational team award.

Team SAP Ireland is currently working with SAP to develop a smart phone application, iCollapse. Using the accelerometer in the mobile phone, the application tracks the user’s movements and detects a collapse. This sets off an alarm encouraging a passer-by to remove the user’s phone and call the listed help contact(s). It also instructs the passer-by on how best to help the individual recover.

Bright futures ahead for Team SAP Ireland

Reference:

Interaction between prion protein and toxic amyloid β assemblies can be therapeutically targeted at multiple sites. Darragh B. Freir, Andrew J. Nicoll, Igor Klyubin, Silvia Panico, Jessica M. Mc Donald, Emmanuel Risse, Emmanuel A. Asante, Mark A. Farrow, Richard B. Sessions, Helen R. Saibil, Anthony R. Clarke, Michael J. Rowan, Dominic M. Walsh & John Collinge. Nature Communications Jun 7 2011 doi:10.1038/ncomms1341

Reference:

Common Proteomic Changes in the Hippocampus in Schizophrenia and Bipolar Disorder and Particular Evidence for Involvement of Cornu Ammonis Regions 2 and 3. Melanie Föcking, Patrick Dicker, Jane A. English, K. Oliver Schubert, Michael J. Dunn, David R. Cotter. Arch Gen Psychiatry. 2011;68(5):477-488

(L-R) Team SAP Ireland members Oisin Kyne, Mr Declan Askin (teacher) & Adrian Murphy pictured in Clarity during a visit to UCD.



















































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New prostate cancer biomarkers move closer to clinical use Irish biopharmaceutical developmentcompany, Sigmoid Pharma recently scoopedthe overall Innovation of the Year award atthe inaugural Irish Times All-IslandInnovation Awards. The life-science SME,founded by UCD pharmacology graduate, DrIvan Coulter, has actively collaborated withConway Fellow, Professor Cormac Taylorsince being granted a Science FoundationIreland industry research partnership awardin 2004.


















































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Conway Fellow, Professor William Watson and Professor John Fitzpatrick, UCD School of Medicine and Medical Science and Mater Misericordiae University Hospital recently received a translational research award for the validation of a panel of serum biomarkers to inform surgical intervention for prostate cancer.

One of four research projects to be funded under the joint Health Research Board and Science Foundation Ireland initiative, this proposal ultimately aims to develop a clinically-applicable predictive tool to identify the grade and stage of prostate cancer and inform the clinician and patient of the most appropriate treatment strategy.

The proposal is based on recently published and preliminary data by the UCD prostate cancer group and will involve independent external validation of the panel of proteins by international collaborators in Austria and Australia prior to any commercial development taking place.

Dr Sheng-Fei Oon (MD research student) published reviews in Nature Reviews Urology and the BJU International that systematically identified, for the

first time, all the areas of greatest unmet need for biomarkers in prostate cancer and has directed the focus of international biomarker research efforts to these areas maximising clinical utility.

Taking this as a guide, Mr Yue Fan (PhD student on the UCD Bioinformatics and Systems Biology PhD programme) used a proteomics approach and novel bioinformatics analysis to identify lists of potential candidate protein biomarkers. These findings, published in the Journal of Proteome Research, will help stratify prostate cancer patients into their appropriate treatment groups.

“There are many hundreds of biomarkers for prostate cancer but only one in clinical use because the others have either not succeeded in the validation phase or were not deemed useful at the bedside” stated Professor William Watson who leads the group and the Irish Prostate Cancer Research Consortium. “We have taken the approach of firstly identifying the relevant clinical questions and then designing appropriate discovery and validation efforts with a clearly defined comparison population using carefully calibrated and standardised collection, storage and processing protocols.”

This multi-faceted, but unified approach is placing Irish-based prostate cancer research in the forefront of many international prostate cancer research interests.

Pictured at the HRB-SFI Translational Research Award announcement (L-R); Minister for Research and Innovation, Mr Sean Sherlock T.D; Professor William Watson; Minister for Health, Dr James Reilly T.D.



















































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Protecting against adipose tissue inflammation in obesityequivalent immune cell recruitment.

‘It would be an over-simplification of the process to say that IL-1 has a direct linear effect on the majority of adipose tissue inflammation,’ said Professor Helen Roche. ‘We surmise that crosstalk between adipose derived cytokines is the most likely scenario whereby adipose tissue inflammation is amplified.

However, the contribution of IL-1 is critical to the medley of pro-inflammatory, insulin-desensitising signals relevant to obesity-induced insulin resistance. As such, these findings expand our current understanding of the paracrine effect associated with the lack of IL-1R1 in adipose tissue’.



















































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c-Myc impacts alternate splicing of key signalling factorsNew research shows that the proto-oncogenic factor, c-Myc directly affects the alternate splicing machinery of key signalling components in an effort to coordinate cell processes such as growth, proliferation, differentiation and apoptosis. The findings of the international collaboration led by Professor Walter Kolch, Director, Systems Biology Ireland & UCD Conway Institute were published recently in the journal, Cancer Research.

Occurring in more than ninety percent of genes, alternate splicing is a way of regulating protein expression and activity. It describes how a common strand of genetic information is cut or spliced to produce different mature RNA strands. These splice products or truncated proteins introduce diversity into cells even to the extent of producing antagonistic functions.

The research team report that protooncogenic factor, c-Myc directly

controls the genetic expression of the splice factor, hnRNP H. Expression of hnRNP H is necessary to ensure that a-raf mRNA is spliced in such a way as to form a full length A-Raf protein. This protein can then inhibit apoptosis by binding to MST2 kinase, which is seen typically in human colon and head and neck cancers.

They also describe a novel splice product or truncated protein called A-RafSHORT that occurs when low levels of c-Myc result in reduced expression of the hnRNPH splice factor in normal cells and tissues. It appears that A-RafSHORT acts like a tumour suppressor protein by safeguarding against oncogenic transformation.

As A-RafSHORT fails to bind MST2 kinase, it cannot regulate MST2 mediated apoptosis. However, it does bind and block activated Ras and consequently suppresses the Ras-ERK signalling pathway that is commonly activated in cancer.

‘These results suggest that a concerted response of c-Myc, hnRNP H and A-Raf expression is part of a physiological programme defining how cells respond to different growth conditions. We were also able to demonstrate that c-Myc is coordinating this response,’ said Professor Walter Kolch.

Cancer Research UK and Science Foundation Ireland supported this research that also involved researchers from the Beatson Institute for Cancer Research, Glasgow; University of Sheffield, UK; Garvan Institute of Medical Research, Australia; Ludwig-Maximilians University, Germany.

Reference c-Myc regulates RNA splicing of the A-Raf kinase and its activation of the ERK pathway. Jens Rauch, Kim Moran-Jones, Valerie Albrecht, Thomas Schwarzl, Keith Hunter, Olivier Gires & Walter Kolch. Cancer Res( E-Pub) April 21, 2011. doi:10.1158/0008-5472



















































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ISAC Scholar award

Dr Alfonso Blanco has received the 2011 ISAC Scholar award from the International Society for Advancement of Cytometry. The 5-year ISAC scholarship programme is designed to enhance the scientific and leadership potential of emerging leaders in this specialist field. It provides valuable training and mentoring opportunities for awardees.

Dr Blanco established the UCD Conway flow cytometry core facility in 2004. He is the founder member and president of the Irish Cytometry Society and a founder member of the European Cytometry Network. He designs and implements various cytometry education and training programmes and organises national and international cytometry meetings and conferences such as

the 11th European Clinical Cytometry meeting, scheduled for the Convention Centre Dublin during September 2011.

Obesity is a growing pandemic that imposes substantial health & economic burdens globally. Leading to metabolic complications such as insulin resistance and type II diabetes, obesity has significant ramifications for patients, families and communities.

Even our bodies recognise the threat imposed by obesity as they mount a pathological immune response to the condition. Scientists believe that interrogating the biochemical pathways underlying this immune response may give insight into therapeutic options.

UCD researchers led by Conway Fellow, Professor Helen Roche are contributing to this effort and their recent findings have been published in the highest impact journal in this scientific field, Diabetes.

In obesity, cells of the immune system (macrophages & T-cells) respond to a high fat diet by entering adipose tissue and releasing proinflammatory cytokines ( IL-1, IL-6, TNF-alpha). This creates a chronic state of inflammation that is

further enhanced locally with secretion of pro-inflammatory cytokines from the expanding adipose tissue mass itself. This leads to both adipocyte specific and systemic insulin resistance.

The Science Foundation Ireland – funded Roche group have shown that inflammatory signals transmitted via the proinflammatory cytokine, interleukin-1 receptor (IL-1R1) play a key role in adipose tissue inflammation during obesity.

IL-1 must be converted to an active form by NLRP3-capase-1 inflammasome complex. The active form of IL-1 then binds downstream to its receptor IL-1R1 in order to control the inflammatory signals that mediate adipose inflammation in obesity.

The UCD team focused on downstream consequences of IL-1RI receptor signalling in this pathway using murine models. They evaluated macrophage recruitment, cytokine secretions and adipocyte insulin sensitivity. They found that a lack of IL-1RI protects against high fat diet induced insulin resistance and reduces local adipose tissue inflammation despite the

Reference :Lack of Interleukin-1 Receptor I (IL-1RI) Protects Mice From High-Fat Diet–Induced Adipose Tissue Inflammation Coincident With Improved Glucose Homeostasis. Fiona C. McGillicuddy,Karen A. Harford, Clare M. Reynolds, Elizabeth Oliver, Mandy Claessens, Kingston H.G. Mills and Helen M. Roche. Diabetes doi:10.2337/db10-1278 June 2011.

Lipoxins attenuate renal fibrosis While inflammation is an integral part of the body’s natural immune response, it can become part of a greater problem if it runs past its course. Unresolved inflammation can lead to the development of fibrosis and organ failure with limited therapeutic options available to patients.

UCD researchers led by Conway Fellow, Professor Catherine Godson believe tackling unresolved inflammation may be a viable therapeutic option in renal fibrosis and chronic renal disease including diabetic nephropathy.

In a recent edition of Faseb Journal, the team describe the impact on a model of early renal fibrosis of lipoxin (LXA4), and its synthetic counterpart benzo-lipoxin, developed by Professor Pat Guiry, Conway Fellow & Director of the Centre for Synthesis & Chemical Biology. While the anti-inflammatory effects of these lipid mediators have previously been described, the anti- fibrotic effects found by the researchers are novel.

Lipoxins stimulate the resolution of inflammation through a number

of converging processes involving macrophage activation and the clearance of dead cells or efferocytosis.

Explaining the novel anti-fibrotic effects seen, PhD student Emma Börgeson says, ‘Fibrotic scar tissue forms when collagen is deposited at the site of inflammation. We found that benzo-lipoxin significantly reduced the amount of collagen laid down in our model and that collagen gene expression was reduced by both the natural and synthetic lipoxin.

Both LXA4 and benzo-LXA4 also caused a trend towards reducing renal cell death and we think this may reflect the fact that the inflammatory milieu is being pushed to resolution by lipoxin inhibiting the production of pro-inflammatory cytokines.’

Professor Catherine Godson believes that, ‘Lipoxins may represent a potentially useful therapeutic strategy in renal fibrosis. We would hope to further investigate if lipoxin and its analogues, as well as other lipid mediators, can accelerate recovery in progressive forms of early renal fibrosis.’

This collaborative research project also involved Dr Neil Docherty, Trinity College and Dr Roel Goldschmeding, University Medical Centre, Utrecht. It was supported by Science Foundation Ireland, Health Research Board, Enterprise Ireland, the Irish Government’s Programme for Research in Third Level Institutions as well as an IRCSET Embark postgraduate research scholarship to Emma Börgeson..



















































Reference:



Reference Lipoxin A4 and benzo-lipoxin A4 attenuate experimental renal fibrosis. E Börgeson, N.G Docherty, M Murphy, K Rodgers, A Ryan, T O’Sullivan,P Guiry, R Goldschmeding, D. F. Higgins, C Godson. Faseb J. (E-pub) May 31, 2011, doi: 10.1096/fj.11-185017

Reference :Fan Y, Murphy TB, Byrne JC, Brennan L, Fitzpatrick JM, Watson RW. Applying random forests to identify biomarker panels in serum 2D-DIGE data for the detection and staging of prostate cancer. J Proteome Res. 2011 Mar 4;10(3):1361-73.

Oon SF, Pennington SR, Fitzpatrick JM, Watson RW. Biomarker research in prostate cancer-towards utility, not futility. Nat Rev Urol. 2011 Mar;8(3):131-8.

Oon SF, Watson RW, O’Leary JJ, Fitzpatrick JM. Epstein Criteria for prostate cancer. BJU Int. 2011 Feb 14. doi: 10.1111/j.1464-410X.2011.09979.x. [Epub ahead of print]

Conway Focus Issue 14 Summer 2011

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Transcript of Conway Focus Issue 14 Summer 2011