Fighting cancer with biodegradable plasticUCD researchers led by Conway Fellow, Dr Kevin O’Connor have created an improved anti-cancer agent using small molecules derived from a biodegradable plastic, PHA. Their findings are published in the April issue of Biomaterials.

PHA or polyhydoxyalkanoate is a biodegradable plastic produced by particular bacteria, such as Pseudomonasputida commonly found in Irish soil. PHA is intensively studied as a substitute for non-degradable plastic packaging. However, this is the first example globally of a biodegradable plastic monomer being used as a cancer therapeutic.

The structure of PHA can be broken down into simpler component building blocks or monomers called (R)-3-hydroxyalkanoic acid one of which is called (R)-3-hydroxyde-canoic acid or R10 for short.

The research team created a new molecular structure in the laboratory by chemically linking R10 to a hybrid of two naturally occurring peptides with anti-cancer activity named P18.

They then investigated the impact of this new synthetic molecule (R10P18) on a variety of cancer cell types. ‘We found that these new synthetic molecules were able to drive cancer cells to self-destruction or ap-optosis much more effectively than the P18 peptide would do if acting alone’, explained Dr Kevin O’Connor from UCD School of Biomolecular & Biomedical Science.

We detected better uptake of the new

molecules by cancer cells with programmed cell death beginning within two hours of entry 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 will ultimately behave.

In the case of the R10P18 molecule, the enhanced anti-cancer activity displayed is due to the presence and position of the hydroxyl (OH) component. The structure promises flexibility for further chemical or biological manipulation in the future.

A crucial part of translating laboratory research on potential drug candidates is to investigate the behaviour of these novel compounds with other commercially available chemotherapeutics. Clinicians often favour a treatment regimen that uses a combination of drugs rather than a single compound. Acting together, drugs can be more effective and the desired response is achieved with a lower dosage.

The new R10P18 molecules act synergistically with chemotherapeutics 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 Conway Fellows, Professor William Gallagher (UCD School of Biomolecular & Biomedical Science) and Dr Annette Byrne

(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 Centre for Synthesis & Chemical Biology. It was funded through UCD Ad Astra scholarship, the Higher Education Authority PRTLI4 programme, and Science Foundation Ireland. UCD Conway imaging and flow cytometry core technologies were used during the course of the research.

Director’s MessageWelcome!

Congratulations to Professors Mark Crowe, Pat Guiry and Cormac Taylor who have been announced as newly elected members of the Royal Irish Academy. Each has made significant contributions to scholarly research as demonstrated by their published research. This public recognition of their academic excellence is the highest academic honour in Ireland.

I am delighted to welcome four new Conway Fellows; Dr Andrew Philips, Dr Fiona McGillicuddy, Professor Carel Le Roux and Professor Ron Pinhasi. I have no doubt that they will forge successful collaborations with other Institute members and contribute fully to the continued success of the Institute.

The Institute will celebrate a decade of discovery and innovation in September

2013 as we mark the anniversary of the building opening its doors to researchers from across the UCD campus and affiliate 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).

Professor Walter Kolch Director

Issu

e 19

, Sum

mer

201

3

Reference:

O’Connor S, et al. The anti-cancer activity of a cationic anti-microbial peptide derived from monomers of polyhydroxyalkanoate. Biomaterials (2013) http://dx.doi.org/10.1016/j.biomaterials.2012.12.032

UCD researchers led by Conway Fellow, Professor David Brayden in UCD School of Veterinary Medicine have successfully reduced inflammation in the swollen arthritic knees of a murine model using a novel nanoparticle.

The team used an anti-inflammatory molecule complexed in a nanoparticle of hyaluronic acid to overcome the body’s normal clearing processes.

In addition to reducing inflammation after a localised injection of this new nanoparticle preparation, the team

identified the inflammatory receptor target for the components of the particle and demonstrated its reduction.

“By using these molecules in a ‘nano’ format, we were able to successfully target the site of inflammation and retain them there to reduce swelling. The effect compared favourably to treatment with steroids”, said Prof Brayden. “This may provide a new type of long-acting, ‘nano’ therapy for human or animals suffering with inflammatory arthritis in the future”.

This condition has a huge social impact for the aging Western population with the World Health Organisation (WHO)

reporting 10% of men and 18% of women aged over 60 have symptomatic osteoarthritis (OA). The WHO estimates that 80% of those have limitations in movement and 25% cannot perform major daily activities.

Reducing experimental inflammatory arthritis

ReferencesAn intra-articular salmon calcitonin-based nanocomplex reduces experimental inflammatory arthritis. Ryan SM, McMorrow J, Umerska A, Patel HB, Kornerup KN, Tajber L, Murphy EP, Perretti M, Corrigan OI, Brayden DJ. Journal of Controlled Release (2013) 167: 120-129 Feb 4.

through β1-integrin-induced cytoskeletal pathways.

MMI medal for UCD StudentTrudy McGarry won the 2013 Molecular Medicine Ireland (MMI) medal for her oral presentation of rheumatoid arthritis research.

Currently a student on the MMI Clinical & Translational Research Scholars Programme (CTRSP), Trudy carried out her research project in conjunction with Conway Fellow, Professor Douglas Veale, St. Vincent’s University Hospital and UCD School of Medicine & Medical Science.

Her study focuses on the signalling pathways involved in joint destruction seen in rheumatoid arthritis. Rheumatoid arthritis (RA) is a chronic, progressive autoimmune disease, characterised by

synovial proliferation and destruction of cartilage and bone.

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

Toll-like receptor, TLR2 has been implicated in the pathogenesis of joint destruction in RA but the mechanisms involved have yet to be elucidated.

In presenting the results of her study, Trudy McGarry explained how TLR2-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

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, seven pupils visited UCD Conway Institute to hear first-hand about the working lives of Conway researchers.

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

educational route to this role.

The pupils got a little closer to experiencing life ‘at the bench’ with a tour of the Institute that took in the nuclear magnetic resonance (NMR) facility where PhD student Jennifer Cleary (Malthouse group) spoke about working up close to 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.

Experiencing life at the bench

(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

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 MitoTracker® Green stains mitochondria. Regions of yellow indicate where the red stained peptide co-locates with the green stained mitochondria in overlaid images.

€

Inflammation is an important response in the body but chronic or uncontrolled inflammation can also cause trouble in conditions including rheumatoid arthritis, inflammatory bowel disease and sepsis.

A new study involving UCD researchers has discovered a signal that appears to trigger inflammation when the threat of a bacterial infection looms, and the experiments have also been able to block the signal in model systems, pointing to possible new approaches to treating inflammatory diseases.

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

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

“When you go to high altitude, this factor gets expressed in cells and that helps to increase the number of red blood cells in your blood, so you can adapt to the lower oxygen,” explains Conway 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 experience an activation of this HIF pathway,” says Prof Taylor. “And our 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 Eoin Cummins helped to work out that in macrophages sensing a bacterial threat,

A new ‘on’ signal for inflammationthe build-up of succinate seems to ‘tell’ HIF-1a to switch on an inflammatory gene.

“In this case, HIF drives a gene called interleukin-1, a potent pro-inflammatory gene, and that will contribute to the inflammatory process.”

The new study makes an important link between energy burning processes in the immune system and an ‘on’ signal for inflammation. The research also showed that a drug usually used for epilepsy was able to tone down this succinate/HIf-1a pathway in a model of sepsis, and this could point to new approaches to intervening when inflammation is running out of control.

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

Primitive forms of complex human processes identified The evolution of multicellularity marks one of the most profound evolutionary developments contributing to the appearance of human and animal life on the planet. However, with relatively little known about this seminal event, a number of international genome research efforts have focused on identifying 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 already present in unicellular organisms.

The Science Foundation Ireland (SFI) funded study led by Conway Fellow, Professor Brendan Loftus, UCD School of Medicine & Medical Science sequenced the genome of a unicellular amoeba (Acanthamoeba castellanii).

The researchers found within the genome an intact signalling facility (tyrosine kinase signalling) long associated with multicelluar organisms and thought to have arisen much later in evolution. Tyrosine kinase signalling is a core means of intercellular communication and coordination. Its appearance in unicellular organisms indicates the necessity for a sophisticated level of interaction with one’s neighbours even as a unicellular organism.

The study also demonstrated that pathogen recognition receptors, a key element of the innate immune system of humans used to recognise and engulf pathogens, were already in use as part of a primitive form of self-defence in amoebae.

As many human pathogens evolve their virulence outside of human hosts through interactions in their environments, these findings inform how certain pathogens have evolved to evade or manipulate the innate immune system.ReferenceGenome of Acanthamoeba castellanii highlights extensive lateral gene transfer and early evolution of tyrosine kinase signalling. Clarke M, Lohan A et al. Genome Biology 2013, 14:R11 doi: 10.1186/gb-2013-14-2-r11

Setting standards for protein localisationIn order to understand how cells work, scientists first need to establish where every single protein in the cell resides. In the largest study of its kind to date, the two most widely used microscopy-based methods that can be applied to this task have been compared.

The international collaboration led by Conway Fellow, Professor Jeremy Simpson, UCD School of Biology & Environmental Science and Professor Emma Lundberg, KTH-Stockholm looked at more than 500 proteins using antibody-based localisation and fluorescent protein tagging methods.

Their findings show that by following a defined set of rules, both antibody-based and fluorescent-tagging methods are highly complementary to each other, and show a high degree of correlation for the determination of protein localisation in cells.

The study also provides a significant and experimentally validated data set of protein localisation in mammalian cells,

which in itself is a valuable resource for the scientific community.

According to Professor Simpson, “The debate of whether antibodies or fluorescent protein tagging is the most reliable method to determine protein localisation has been going on for more than 15 years.

In addition to determining the localisation of more than 500 proteins, half of which had no previous localisation annotation, this study has allowed us to address a key experimental issue.”

This work is expected to set the standard methodology for ultimately determining the localisation of the entire human proteome.

ReferenceImmunofluorescence and fluorescent-protein tagging show high correlation for protein localization in mammalian cells. Stadler C, Rexhepaj E, Singan VR, Murphy RF, Pepperkok R, Uhlén M, Simpson JC, Lundberg E. Nature Methods (2013) Feb 24 doi: 10.1038/nmeth.2377. [Epub ahead of print].

Identifying key regulators of kidney injuryMicro-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.

They have described for the first time how the miRNA family, let-7 miRNA, plays a key role in regulating kidney injury by targeting key fibrosis pathways in human kidney epithelial cells.

The team investigated the miRNA responses in human kidney tubule epithelial cells cultured under fibrotic conditions that mimic diabetic kidney disease and in the 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 of Nephrology.

The extent of let-7c miRNA expression seems to impact on the integrity of epithelial cells as the study found less let-7c miRNA expression in injured epithelial cells than in healthy cells.

‘The next step for us now is to 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 in experimental models of disease. These studies will further enhance our understanding of the role of miRNA in diabetic kidney disease as both biomarkers and potential novel therapeutic targets.’ReferenceEoin P Brennan, Karen A Nolan, Emma Borgeson, Oisin S Gough, Caitriona M Mc Evoy, Neil G Docherty, Debra F Higgins, Madeline Murphy, Denise M Sadlier, Syed Tasadaque Ali-Shah, Patrick J Guiry, David A Savage, 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)

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 localisations between the two methods, and red nodes indicating conflicting localisations between the two methods.

Welcoming new Conway FellowsDr Fiona McGillicuddy is interested in the impact of obesity and inflammation on HDL function and cardiovascular health. A key goal of this research is to establish the effects of the obesigenic environment on the capacity of macrophages to mediate cholesterol efflux to HDL particles. The effects of obesity on reverse cholesterol transport will be assessed in vivo by monitoring 3H-cholesterol movement from macrophages onto HDL particles and measuring uptake into liver, bile and elimination in the faeces. The obese phenotype will subsequently be manipulated by diet or anti-inflammatory regimens to improve metabolic health but maintain equivalent obesity and the effects on macrophage-faeces reverse cholesterol transport will be monitored.

Dr Andrew Phillips focuses on researching the development of sustainable catalytic processes utilising natural products; energy related catalysis, especially in the area of hydrogen storage from ammonia boranes; pioneering new multifunctional anticancer compounds with enhanced selectivity and inhibitor delivery; development of silver antibiotic drugs with biofilm inhibitor behaviour and activity against MRSA bacteria.

Professor Ron Pinhasi envisages synergies with Conway Fellows specifically in the area of research concerned with the health of past populations and the evolution of

Dr Fiona McGillicuddy, Wellcome Trust Research Career Development Fellow, UCD Conway Institute

Dr Andrew Phillips, Stokes Lecturer, UCD School of Chemistry & Chemical Science

Professor Ron Pinhasi, Associate Professor, UCD School of Archaeology

pathogens and disease using ancient DNA studies of pathogens. He is also interested in areas such as human evolution, variation, demographic history 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 in the mechanisms by which Roux-en-Y gastric bypass reverses diabetic kidney disease. His research is primarily concerned with the increased mortality and morbidity associated with obesity and its related diseases. A better mechanistic understanding of how the ‘gut talks to the brain’ will allow safer and more effective treatments to be used in future. To this end, the role of gut hormones, bile acids and changes in food preference are areas of interest to him.

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

€

Inflammation is an important response in the body but chronic or uncontrolled inflammation can also cause trouble in conditions including rheumatoid arthritis, inflammatory bowel disease and sepsis.

A new study involving UCD researchers has discovered a signal that appears to trigger inflammation when the threat of a bacterial infection looms, and the experiments have also been able to block the signal in model systems, pointing to possible new approaches to treating inflammatory diseases.

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

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

“When you go to high altitude, this factor gets expressed in cells and that helps to increase the number of red blood cells in your blood, so you can adapt to the lower oxygen,” explains Conway 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 experience an activation of this HIF pathway,” says Prof Taylor. “And our 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 Eoin Cummins helped to work out that in macrophages sensing a bacterial threat,

A new ‘on’ signal for inflammationthe build-up of succinate seems to ‘tell’ HIF-1a to switch on an inflammatory gene.

“In this case, HIF drives a gene called interleukin-1, a potent pro-inflammatory gene, and that will contribute to the inflammatory process.”

The new study makes an important link between energy burning processes in the immune system and an ‘on’ signal for inflammation. The research also showed that a drug usually used for epilepsy was able to tone down this succinate/HIf-1a pathway in a model of sepsis, and this could point to new approaches to intervening when inflammation is running out of control.

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

Primitive forms of complex human processes identified The evolution of multicellularity marks one of the most profound evolutionary developments contributing to the appearance of human and animal life on the planet. However, with relatively little known about this seminal event, a number of international genome research efforts have focused on identifying 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 already present in unicellular organisms.

The Science Foundation Ireland (SFI) funded study led by Conway Fellow, Professor Brendan Loftus, UCD School of Medicine & Medical Science sequenced the genome of a unicellular amoeba (Acanthamoeba castellanii).

The researchers found within the genome an intact signalling facility (tyrosine kinase signalling) long associated with multicelluar organisms and thought to have arisen much later in evolution. Tyrosine kinase signalling is a core means of intercellular communication and coordination. Its appearance in unicellular organisms indicates the necessity for a sophisticated level of interaction with one’s neighbours even as a unicellular organism.

The study also demonstrated that pathogen recognition receptors, a key element of the innate immune system of humans used to recognise and engulf pathogens, were already in use as part of a primitive form of self-defence in amoebae.

As many human pathogens evolve their virulence outside of human hosts through interactions in their environments, these findings inform how certain pathogens have evolved to evade or manipulate the innate immune system.ReferenceGenome of Acanthamoeba castellanii highlights extensive lateral gene transfer and early evolution of tyrosine kinase signalling. Clarke M, Lohan A et al. Genome Biology 2013, 14:R11 doi: 10.1186/gb-2013-14-2-r11

Setting standards for protein localisationIn order to understand how cells work, scientists first need to establish where every single protein in the cell resides. In the largest study of its kind to date, the two most widely used microscopy-based methods that can be applied to this task have been compared.

The international collaboration led by Conway Fellow, Professor Jeremy Simpson, UCD School of Biology & Environmental Science and Professor Emma Lundberg, KTH-Stockholm looked at more than 500 proteins using antibody-based localisation and fluorescent protein tagging methods.

Their findings show that by following a defined set of rules, both antibody-based and fluorescent-tagging methods are highly complementary to each other, and show a high degree of correlation for the determination of protein localisation in cells.

The study also provides a significant and experimentally validated data set of protein localisation in mammalian cells,

which in itself is a valuable resource for the scientific community.

According to Professor Simpson, “The debate of whether antibodies or fluorescent protein tagging is the most reliable method to determine protein localisation has been going on for more than 15 years.

In addition to determining the localisation of more than 500 proteins, half of which had no previous localisation annotation, this study has allowed us to address a key experimental issue.”

This work is expected to set the standard methodology for ultimately determining the localisation of the entire human proteome.

ReferenceImmunofluorescence and fluorescent-protein tagging show high correlation for protein localization in mammalian cells. Stadler C, Rexhepaj E, Singan VR, Murphy RF, Pepperkok R, Uhlén M, Simpson JC, Lundberg E. Nature Methods (2013) Feb 24 doi: 10.1038/nmeth.2377. [Epub ahead of print].

Identifying key regulators of kidney injuryMicro-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.

They have described for the first time how the miRNA family, let-7 miRNA, plays a key role in regulating kidney injury by targeting key fibrosis pathways in human kidney epithelial cells.

The team investigated the miRNA responses in human kidney tubule epithelial cells cultured under fibrotic conditions that mimic diabetic kidney disease and in the 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 of Nephrology.

The extent of let-7c miRNA expression seems to impact on the integrity of epithelial cells as the study found less let-7c miRNA expression in injured epithelial cells than in healthy cells.

‘The next step for us now is to 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 in experimental models of disease. These studies will further enhance our understanding of the role of miRNA in diabetic kidney disease as both biomarkers and potential novel therapeutic targets.’ReferenceEoin P Brennan, Karen A Nolan, Emma Borgeson, Oisin S Gough, Caitriona M Mc Evoy, Neil G Docherty, Debra F Higgins, Madeline Murphy, Denise M Sadlier, Syed Tasadaque Ali-Shah, Patrick J Guiry, David A Savage, 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)

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 localisations between the two methods, and red nodes indicating conflicting localisations between the two methods.

Welcoming new Conway FellowsDr Fiona McGillicuddy is interested in the impact of obesity and inflammation on HDL function and cardiovascular health. A key goal of this research is to establish the effects of the obesigenic environment on the capacity of macrophages to mediate cholesterol efflux to HDL particles. The effects of obesity on reverse cholesterol transport will be assessed in vivo by monitoring 3H-cholesterol movement from macrophages onto HDL particles and measuring uptake into liver, bile and elimination in the faeces. The obese phenotype will subsequently be manipulated by diet or anti-inflammatory regimens to improve metabolic health but maintain equivalent obesity and the effects on macrophage-faeces reverse cholesterol transport will be monitored.

Dr Andrew Phillips focuses on researching the development of sustainable catalytic processes utilising natural products; energy related catalysis, especially in the area of hydrogen storage from ammonia boranes; pioneering new multifunctional anticancer compounds with enhanced selectivity and inhibitor delivery; development of silver antibiotic drugs with biofilm inhibitor behaviour and activity against MRSA bacteria.

Professor Ron Pinhasi envisages synergies with Conway Fellows specifically in the area of research concerned with the health of past populations and the evolution of

Dr Fiona McGillicuddy, Wellcome Trust Research Career Development Fellow, UCD Conway Institute

Dr Andrew Phillips, Stokes Lecturer, UCD School of Chemistry & Chemical Science

Professor Ron Pinhasi, Associate Professor, UCD School of Archaeology

pathogens and disease using ancient DNA studies of pathogens. He is also interested in areas such as human evolution, variation, demographic history 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 in the mechanisms by which Roux-en-Y gastric bypass reverses diabetic kidney disease. His research is primarily concerned with the increased mortality and morbidity associated with obesity and its related diseases. A better mechanistic understanding of how the ‘gut talks to the brain’ will allow safer and more effective treatments to be used in future. To this end, the role of gut hormones, bile acids and changes in food preference are areas of interest to him.

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

Fighting cancer with biodegradable plasticUCD researchers led by Conway Fellow, Dr Kevin O’Connor have created an improved anti-cancer agent using small molecules derived from a biodegradable plastic, PHA. Their findings are published in the April issue of Biomaterials.

PHA or polyhydoxyalkanoate is a biodegradable plastic produced by particular bacteria, such as Pseudomonasputida commonly found in Irish soil. PHA is intensively studied as a substitute for non-degradable plastic packaging. However, this is the first example globally of a biodegradable plastic monomer being used as a cancer therapeutic.

The structure of PHA can be broken down into simpler component building blocks or monomers called (R)-3-hydroxyalkanoic acid one of which is called (R)-3-hydroxyde-canoic acid or R10 for short.

The research team created a new molecular structure in the laboratory by chemically linking R10 to a hybrid of two naturally occurring peptides with anti-cancer activity named P18.

They then investigated the impact of this new synthetic molecule (R10P18) on a variety of cancer cell types. ‘We found that these new synthetic molecules were able to drive cancer cells to self-destruction or ap-optosis much more effectively than the P18 peptide would do if acting alone’, explained Dr Kevin O’Connor from UCD School of Biomolecular & Biomedical Science.

We detected better uptake of the new

molecules by cancer cells with programmed cell death beginning within two hours of entry 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 will ultimately behave.

In the case of the R10P18 molecule, the enhanced anti-cancer activity displayed is due to the presence and position of the hydroxyl (OH) component. The structure promises flexibility for further chemical or biological manipulation in the future.

A crucial part of translating laboratory research on potential drug candidates is to investigate the behaviour of these novel compounds with other commercially available chemotherapeutics. Clinicians often favour a treatment regimen that uses a combination of drugs rather than a single compound. Acting together, drugs can be more effective and the desired response is achieved with a lower dosage.

The new R10P18 molecules act synergistically with chemotherapeutics 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 Conway Fellows, Professor William Gallagher (UCD School of Biomolecular & Biomedical Science) and Dr Annette Byrne

(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 Centre for Synthesis & Chemical Biology. It was funded through UCD Ad Astra scholarship, the Higher Education Authority PRTLI4 programme, and Science Foundation Ireland. UCD Conway imaging and flow cytometry core technologies were used during the course of the research.

Director’s MessageWelcome!

Congratulations to Professors Mark Crowe, Pat Guiry and Cormac Taylor who have been announced as newly elected members of the Royal Irish Academy. Each has made significant contributions to scholarly research as demonstrated by their published research. This public recognition of their academic excellence is the highest academic honour in Ireland.

I am delighted to welcome four new Conway Fellows; Dr Andrew Philips, Dr Fiona McGillicuddy, Professor Carel Le Roux and Professor Ron Pinhasi. I have no doubt that they will forge successful collaborations with other Institute members and contribute fully to the continued success of the Institute.

The Institute will celebrate a decade of discovery and innovation in September

2013 as we mark the anniversary of the building opening its doors to researchers from across the UCD campus and affiliate 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).

Professor Walter Kolch Director

Issu

e 19

, Sum

mer

201

3

Reference:

O’Connor S, et al. The anti-cancer activity of a cationic anti-microbial peptide derived from monomers of polyhydroxyalkanoate. Biomaterials (2013) http://dx.doi.org/10.1016/j.biomaterials.2012.12.032

UCD researchers led by Conway Fellow, Professor David Brayden in UCD School of Veterinary Medicine have successfully reduced inflammation in the swollen arthritic knees of a murine model using a novel nanoparticle.

The team used an anti-inflammatory molecule complexed in a nanoparticle of hyaluronic acid to overcome the body’s normal clearing processes.

In addition to reducing inflammation after a localised injection of this new nanoparticle preparation, the team

identified the inflammatory receptor target for the components of the particle and demonstrated its reduction.

“By using these molecules in a ‘nano’ format, we were able to successfully target the site of inflammation and retain them there to reduce swelling. The effect compared favourably to treatment with steroids”, said Prof Brayden. “This may provide a new type of long-acting, ‘nano’ therapy for human or animals suffering with inflammatory arthritis in the future”.

This condition has a huge social impact for the aging Western population with the World Health Organisation (WHO)

reporting 10% of men and 18% of women aged over 60 have symptomatic osteoarthritis (OA). The WHO estimates that 80% of those have limitations in movement and 25% cannot perform major daily activities.

Reducing experimental inflammatory arthritis

ReferencesAn intra-articular salmon calcitonin-based nanocomplex reduces experimental inflammatory arthritis. Ryan SM, McMorrow J, Umerska A, Patel HB, Kornerup KN, Tajber L, Murphy EP, Perretti M, Corrigan OI, Brayden DJ. Journal of Controlled Release (2013) 167: 120-129 Feb 4.

through β1-integrin-induced cytoskeletal pathways.

MMI medal for UCD StudentTrudy McGarry won the 2013 Molecular Medicine Ireland (MMI) medal for her oral presentation of rheumatoid arthritis research.

Currently a student on the MMI Clinical & Translational Research Scholars Programme (CTRSP), Trudy carried out her research project in conjunction with Conway Fellow, Professor Douglas Veale, St. Vincent’s University Hospital and UCD School of Medicine & Medical Science.

Her study focuses on the signalling pathways involved in joint destruction seen in rheumatoid arthritis. Rheumatoid arthritis (RA) is a chronic, progressive autoimmune disease, characterised by

synovial proliferation and destruction of cartilage and bone.

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

Toll-like receptor, TLR2 has been implicated in the pathogenesis of joint destruction in RA but the mechanisms involved have yet to be elucidated.

In presenting the results of her study, Trudy McGarry explained how TLR2-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

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, seven pupils visited UCD Conway Institute to hear first-hand about the working lives of Conway researchers.

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

educational route to this role.

The pupils got a little closer to experiencing life ‘at the bench’ with a tour of the Institute that took in the nuclear magnetic resonance (NMR) facility where PhD student Jennifer Cleary (Malthouse group) spoke about working up close to 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.

Experiencing life at the bench

(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

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 MitoTracker® Green stains mitochondria. Regions of yellow indicate where the red stained peptide co-locates with the green stained mitochondria in overlaid images.