A possible therapeutic avenue in Cystic Fibrosis

Cystic fibrosis (CF) is an inherited chronic disease that primarily affects the lungs and digestive system. CF is caused by mutations in the Cystic Fibrosis Transmembrane Regulator (CFTR) gene, a chloride channel responsible for helping conduct chloride and other ions across epithelial membranes. The loss of a functional CFTR channel disrupts ionic homeostasis resulting in mucus production that clogs the lungs and pancreas and results in a vicious cycle of chronic infection and inflammation as the disease progresses.

There are almost 2,000 different variants in the CFTR gene and 70 % of CF patients contain a mutation at position 508, which results in the loss of Phe508 and disruption of the folding pathway of CFTR. ΔF508 CFTR is a trafficking mutant that is retained in the endoplasmic reticulum (ER) and unable to reach the plasma membrane. Efforts to enhance exit of ΔF508 CFTR from the ER and improve its trafficking are of utmost importance for the development of treatment strategies. Clinically, progress has been made in recent years identifying therapeutics that target CFTR dysfunction in patients with specific mutations. However, small molecules that directly target the most common misfolded CFTR mutant, ΔF508, and improve its intracellular trafficking in vitro, have shown modest effects We performed a study aimed to identify new therapeutic targets that will help address the unmet clinical need for CF patients homozygous for  the ΔF508 mutation.We aimed to understand the protein interactions regulating CFTR transport using mass spectrometry-based proteomics. Using mass spectrometry based protein interaction profiling and global bioinformatics analysis we revealed mammalian target of rapamycin (mTOR) signalling components to be associated with ∆F508 CFTR.  Our results showed upregulated mTOR activity in ΔF508 CF bronchial epithelial cells. In addition to a well described role in several cancer subtypes, excessive activation of the mTOR pathway has been reported to be involved in age-related misfolding diseases. There are a range of inhibitors that target the PI3K/Akt/mTOR pathway and after screening a selection of inhibitors, we identified 6 different inhibitors that demonstrated an increase in CFTR stability and expression. Mechanistically, we discovered the most effective inhibitor, MK-2206 exerted a rescue effect by restoring autophagy in ΔF508 CF cells. These findings highlight this pathway as a possible therapeutic avenue worth further exploration in Cystic Fibrosis.

Judith Coppinger and her team: Mark Ward and Zivile Useckaite

We aimed to understand the protein interactions regulating CFTR transport using mass spectrometry-based proteomics. Using mass spectrometry based protein interaction profiling and global bioinformatics analysis we revealed mammalian target of rapamycin (mTOR) signalling components to be associated with ∆F508 CFTR.  Our results showed upregulated mTOR activity in ΔF508 CF bronchial epithelial cells. In addition to a well-described role in several cancer subtypes, excessive activation of the mTOR pathway has been reported to be involved in age-related misfolding diseases. There are a range of inhibitors that target the PI3K/Akt/mTOR pathway and after screening a selection of inhibitors, we identified 6 different inhibitors that demonstrated an increase in CFTR stability and expression. Mechanistically, we discovered the most effective inhibitor, MK-2206 exerted a rescue effect by restoring autophagy in ΔF508 CF cells. These findings highlight this pathway as a possible therapeutic avenue worth further exploration in Cystic Fibrosis.

This study was a collaboration between several groups at University College Dublin, Cystic Fibrosis Unit, St Vincent’s Hospital, Royal College of Surgeons in Ireland, Beaumont Hospital and the University of Mainz, Germany. Ongoing work in this area is taking place at the National Children’s Research Centre. Further details can be found here in a recent publication on this work.

The 13th World Congress of Biological Psychiatry

In keeping with the strategic objective of further increasing our international profile in the research domain, Professor John Waddington (Emeritus, MCT) has recently returned from the World Congress of Biological Psychiatry, Copenhagen, where he was invited to organise, Chair and speak in a symposium on ‘Psychosis is disrespectful to diagnostic boundaries: Nosological and pathobiological implications of psychoses beyond the schizophrenia spectrum’. He was also invited to Co-Chair and speak in a second symposium on ‘Beyond unitary models of psychosis: Confronting complex aetiology and dimensionality’. This reinforces the high standing in which our investigators are held in the international scientific community. 

Irish Centre for Vascular Biology Achievements

Bayer announced awards of $2 Million in Hemophilia Research and Patient-care Grants to 16 People at The International Society on Thrombosis and Haemostasis 2017, held in Berlin in July.

Congratulations to Dr. Roger Preston, Irish Centre for Vascular Biology[ICVB], (MCT) who was awarded a prestigious Special Project Award (€200,000) from the Bayer Haemophilia Award Programme to develop novel pro-hemostatic agents for the enhanced treatment of patients with haemophilia.

There was a strong representation from MCT at the ISTH Congress including Professor Dermot Kenny, Professor James O’Donnell, Dr. Roger Preston and their respective teams, and Dr. Dermot Cox, President, SSC* 2018. [*SSC:The Scientific and Standardization Committee].

Orla Willis Fox, Phd student with Dr. Roger Preston (ICVB/MCT), was awarded an ISTH Young Investigator Award for submitting one of the highest ranked abstracts. Her abstract title was ‘Inhibition of Activated Protein C Aspartyl Beta-hydroxylation Restricts Anticoagulant Function but Enhances Cytoprotective Signaling Activity’.

Professor James O’Donnell, ICVB/MCT presented an invited state-of-the-art lecture on his landmark studies on VWF and Cerebral Malaria,Dr. Michelle Lavin, ICVB/MCT on LOVIC [The Low Von Willebrand factor Ireland Cohort (LoVIC)] study, Dr. Sonia Agulia, ICVB/MCT on The Role of Sialylation in low VWF levels andSoracha Ward, ICVB/MCT gave a presentation on VWF Clearance.

Professor James O’Donnell at the International Society on Thrombosis and Haemostasis Congress, Berlin

Additionally, there was significant interest among the attendees in the ISTH SSC 2018 Annual Meeting which will be held in Dublin 2018;  Dr. Dermot Cox, President, SSC 2018 anticipates a record attendance of 3,000 delegates for the Dublin meeting. Olwen Foley , (MCT) managed the Irish stand.

ICVB/MCT

Orphan Drug Status for ALM201 for Ovarian Cancer

Over the last 10 years, Prof Tracy Robson has collaborated closely with Almac Discovery on the development of the therapeutic peptide, ALM201, based on her initial research into the anti-angiogenic properties of FKBPL.  ALM201 is part of the active anti-angiogenic domain of FKBPL and is a potent inhibitor of angiogenesis both in vitro and in vivo.  The technology was patented by Professor Robson and licensed to Almac Discovery.  Following collaborative pre-clinical work showing robust efficacy, this ‘first-in-class’ FKBPL-based antiangiogenic peptide has entered phase I/II clinical trials in the ovarian setting (EudraCT No: 2014-001175-31). Whilst the trial is ongoing, we have received exciting news that the U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation to the drug candidate ALM201 in the treatment of ovarian cancer. The FDA Office grants orphan drug designation to encourage the development of drugs for the prevention, or treatment of a medical condition affecting fewer than 200,000 people in the US and grants market exclusivity for a seven-year period if the sponsor complies with certain FDA specifications. Receiving Orphan Drug Designation for ovarian cancer underlines the fact that ALM201 may address a significant unmet medical need for this important disease.

Tracy Robson

Inflammasomes – key molecules in inflammation and novel targets for the treatment of inflammatory diseases

MCT Research Talks – 19th June 2017

Dr Rebecca Coll is a Research-Industry Fellow at the University of Queensland, studying innate immunity and novel anti-inflammatory drugs. Rebecca received her PhD in Immunology in 2013 under the supervision of Professor Luke O’Neill at Trinity College Dublin and moved to Associate Professor Kate Schroder’s group at the Institute for Molecular Bioscience in UQ in 2014. Over the last five years, her research has focused on inflammasomes – protein complexes at the heart of inflammation and disease – and how these complexes can be targeted therapeutically to prevent damaging inflammation.

Dr. Rebecca Coll

Rebecca led the biological characterisation of MCC950, a small molecule inhibitor of the NLRP3 inflammasome and an exciting prospect as a new therapy for treating patients with NLRP3-mediated diseases. In 2016, Rebecca received the Research Australia Discovery Award for her work on MCC950.

 

Claire McCoy

 

Congratulations to Dr.Dunne and Dr.Nolan

Dr.Dunne and Dr.Nolan from MCT together with other 40 candidates graduated at the RCSI’s 2017 June Conferring ceremony which took place in the College Hall of 123 St. Stephen’s Green. 

Congratulations and well done!

 

Imagine playing Marco Polo on the big football pitch?

Do you remember playing Marco Polo and trying to acoustically locate and tag the players? Imagine playing Marco Polo on the big football pitch when each player has their eyes closed and trying to locate a football. You would probably visualise the pitch in your head and try to create a virtual reality.
What if none of the players ever saw the pitch? Football? How could it be possible to play? Is it possible at all? I have never thought of that until recently. But, there are enthusiasts around who make the difference for blind people and let them enjoy football and the game. We are lucky to know one of them! It is our John O’Brien.

John has started the football coaching journey recently. He and Stephen Bolger (of our security team at Bilfinger) have been coaching the Irish National Blind Football team and are enrolled on the FAI (Football Association of Ireland) Coach Education Pathway. Under Stephen and John’s guidance, along with their fellow coaches, Ireland put in some great performances in the tournament and finished in sixth place – a great achievement for their first international tournament.

Adapted from the news by the RCSI Communication Department

Head of the MCT Department, Prof Tracy Robson says “It seems that as well as skilfully managing our MCT laboratories, John clearly has other hidden talents. It’s amazing that John is giving up his free time to coach the Irish National Football Team; a wonderful outreach activity. We are all very proud of you John…..”

You do not need to be millennials to create the world where everyone has a sense of purpose.

Come and ask John how he does it and what is next!

Olga Piskareva

Extending international collaboration: ‘the future is East’

 

While RCSI is an institution with a long-standing international perspective on education in the health sciences, it has as a strategic goal the further extension of its international activities, particularly in relation to research collaborations. RCSI is doing so through several mechanisms, which include Science Foundation Ireland International Strategic Collaboration Awards (ISCAs), namely ISCA-Brazil, ISCA-China and ISCA-Japan, awards from the Japan Society for the Promotion of Science (JSPS), the EU Erasmus+ programme, and via joint programmes with individual institutions. Over the past several years, I’ve been pleased to contribute to these developments and continue to do so in my new role as Professor Emeritus.

In October-November 2016, I spent three weeks in Japan under a JSPS Invitation Fellowship. From a base at Hoshi Pharmaceutical University, Tokyo, I also visited and gave seminars at Nihon University at its Tokyo and Matsudo campuses, Nagoya University, and Takeda Pharmaceutical Company, Fujisawa. Even after many previous visits to Japan, it’s difficult to describe the enduring professional and personal pleasures of interacting and fostering collaborations with Japanese academics/scientists and enjoying their beautiful country and so hospitable a culture and society. In addition to ongoing research collaborations with Prof. Hiroko Ikeda and her colleagues, this summer will see the second exchange of RCSI and Hoshi University students to participate in the International Research Summer School, directed in RCSI by Dr. Sarah O’Neill (MCT), whereby up to four students from each Institution travel to the other to undertake a 2-month research project. Additionally, later this year Dr. Sudipto Das (MCT) will travel to Hoshi University under a JSPS Postdoctoral Fellowship to further extend collaborative research studies. We hope that such interactions will grow over the years to come.

In February-March 2017, I spent three weeks in China under a joint appointment as a Professor of Pharmacology in the College of Pharmaceutical Sciences at Soochow University, approximately 100 km west of Shanghai. China is a country that is now pursuing a ‘twin-track’ approach of “… internal restructuring of its economy combined with exposure to global trade winds and investment”. While this presents some similarities but many fascinating contrasts with academe in both Japan and Ireland, interacting and fostering collaborations with Chinese academics/scientists also brings many professional and personal pleasures. While there, I gave three undergraduate lectures on mental health, met with postgraduate students and postdoctoral researchers, and facilitated the visits of Prof. Tracy Robson & Dr. Darran O’Connor (MCT), Prof. Jochen Prehn (Physiology & Medical Physics) and Prof. Brian Kirby (School of Pharmacy) to Soochow University and the subsequent reciprocal visits of Profs. Xinliang Mao and Xinchen Teng to RCSI. In addition to ongoing research collaborations with Prof. Xuechu Zhen, this summer will see the third exchange of RCSI and Soochow University students to participate in the International Research Summer School, whereby, as with Hoshi University, up to four students from each Institution travel to the other to undertake a 2-month research project. Dr. Darren Griffith (Pharmaceutical & Medicinal Chemistry) will be the next RCSI colleague to visit Soochow University and we hope that such interactions, like those with Hoshi University, will grow over the years to come.

At the Monument to the laboratory mouse, a sculpture in front of the Institute of Cytology and Genetics of the Russian Academy of Sciences, to commemorate the use of mice in genetic research to understand mechanisms of disease and develop new drugs

It is difficult to think of a greater contrast than my recent visit, April 2017 under Erasmus+ funding, to Novosibirsk State University and the Institute of Physiology and Fundamental Medicine. Novosibirsk is Russia’s third-largest city and is located in Siberia, approximately 2,800 km east of Moscow. The University and Research Institutes are located in Akademgorodok [Akadem = academic, gorod = town, ok = small, hence Akademgorodok = small academic town], the purpose-built educational and scientific centre of Siberia constructed in the late 1950s approximately 30 km south of the city of Novosibirsk. In April, there was still some snow on the ground and the nearby Ob river was still frozen and will remain so until the end of May. During my stay there, the weather ranged from one blizzard and one (in their terms) ‘regular’ fall of snow through to warm, sunny periods with a temperature of 20C; Prof. Marc Devocelle (Pharmaceutical & Medicinal Chemistry) and I were reluctant to travel to Novosibirsk until April, to avoid the harsh Siberian winter, a meteorological objective that was only partially successful. This academic centre has both original and new buildings, with good teaching and research facilities. Under the kind offices of Profs. Vladimir Pustylnyaki and Michele Debrenne, Novosibirsk State University, I gave three undergraduate lectures on the neuroscience of mental health, and under the auspices of Dr. Tatiana Lipina, Institute of Physiology and Fundamental Medicine gave a postgraduate seminar.

During a research seminar at the Institute of Physiology and Fundamental Medicine

Meetings with them and several other colleagues explored the potential for future research collaborations. After what we regarded as a good meeting, one colleague reached into a cupboard for a bottle of vodka and poured us each a generous measure; he hoped this would induce ’emotional warmth’ commensurate with what he regarded as the positivity of the meeting. After this had been imbibed, he then poured a second generous measure of vodka, to reinforce these positive sentiments. Clearly, RCSI needs to reconsider its policies in this regard with a view to appropriately realigning its practices to these new international standards. As I write this in the second week of May, Prof. Konstantin Volcho, Dr. Ekaterina Semenova and Dr. Artyom Rogachev are currently making reciprocal visits to RCSI under Erasmus+ funding and we hope that such interactions, like those with Hoshi and Soochow Universities, will grow over the years to come.

To paraphrase: ‘The future is bright, the future is East’.

John Waddington   

Dr Annie Curtis wins L’Oréal-UNESCO Fellowship For Women in Science

Our congratulations to Dr Annie Curtis with L’Oréal-UNESCO Fellowship For Women in Science Award! Well done!

She was awarded a prestigious L’Oréal-UNESCO For Women in Science 2017 Fellowship at a ceremony held at the Royal Society in London on May 5th.

She was one of five winners of these fellowships and the only Irish winner this year. The fellowship will support her research into understanding the precise mechanisms by which the body clock restrains inflammation from a key immune cell called the macrophage.

Professor Tracy Robson said: “This is a fantastic achievement and I am proud to congratulate Dr Annie Curtis on this highly competitive award for which there were nearly 300 applicants. It is a great testament to her research within the recently established Immuno-Clock Lab. Annie will be an excellent ambassador for Women in Science and this award reflects the world-class research ongoing at RCSI. Indeed the only Irish winners of these For Women in Science fellowships now reside within this institution.”

Recipients of L’Oréal-UNESCO For Women in Science 2017 Fellowship. Courtesy of RCSI Communications Department

The recipients of L’Oréal-UNESCO For Women in Science 2017 Fellowship:

  • Dr Annie Curtis, Royal College of Surgeons in Ireland, the human body clock and inflammation
  • Dr Radha Boya, University of Manchester, Nanoscience
  • Dr Manju Kurian, UCL Great Ormond Street, Neurology
  • Dr Bethan Psaila, University of Oxford, Haematology
  • Dr Priya Subramanian, University of Leeds, Mathematics

RCSI Communications Department

 

Teasing out the mechanisms of biofilm formation for the treatment of S. aureus infections on indwelling devices: the role of the surface protein SdrC

Antibiotic resistance has become a great challenge in the healthcare setting. In particular antibiotic resistant strains of Staphylococcus aureus pose further challenges. Methicillin resistant S. aureus (MRSA) is widespread in healthcare facilities and in the wider community and multi-drug resistant strains have been identified. S. aureus is normally present on the surface of the skin where it causes no harm. However, it can easily colonize open wounds causing infection. Systemic infections can result from these wound infections leading to severe problems such as sepsis and infective endocarditis. Infection after surgical implantation of devices, such as joint replacements, can result in the formation of biofilms coating the devices that are difficult to treat. Biofilms are an accumulation of bacteria on a surface which often persist as most antibiotics do not easily penetrate them. In biofilms, bacteria interact directly with the foreign surface, with host proteins coating the surface and can also accumulate through interactions directly with each other.

Thus, there are multiple mechanisms involved in biofilm formation. It is important to fully understand all the mechanisms of biofilm formation in order to be able to disrupt their formation and persistence. In our recent paper, we have characterized the direct binding interaction (cell-cell adhesion) through the S. aureus surface protein, serine-aspartate repeat protein C (SdrC). Our study also reveals the mechanism of interaction between SdrC and inert surfaces. Furthermore, we have demonstrated how a small peptide can be used to block these interactions preventing biofilm formation suggesting a possible approach that could be used to treat SdrC dependent S. aureus biofilms. This study is the result of a multi-disciplinary collaboration across research institutes in Ireland and Belgium with Dr. Brennan (RCSI) contributing to the molecular modelling, Prof. Joan Geoghegan, Prof. Timothy Foster and Leanne Hayes (Trinity College Dublin) leading the molecular biology and microbiological functional studies and researchers from University Catholique de Louvain characterizing the interactions quantitatively using atomic force microscopy.

Marian Brennan

More details can be found in “Molecular interactions and inhibition of the staphylococcal biofilm-forming protein SdrC”.