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

 

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”.

 

International Research and Education

Prof Tracy Robson (MCT), Prof Jochen Prehn (Physiology & Medical Physics) and Dr Darran O’Connor (MCT) have recently returned from 1 week at the College of Pharmaceutical Sciences, Soochow University, Suzhou, China where they participated in a workshop with faculty to explore research collaborations and future joint funding applications under the newly announced SFI-NSF Partnerships for International Research and Education. Supported by an Erasmus+ programme coordinated by Prof Marc Devocelle (Department of Pharmaceutical and Medicinal Chemistry), the workshop involved presentations from RCSI and Soochow investigators describing their work and discussion to identify areas of synergy. Afternoon lectures by RCSI faculty were opened to postgraduate and postdoctoral researchers from Soochow, leading to a vigorous and stimulating discussion and Prof Xinliang Mao from Soochow will visit RCSI next month to further strengthen future collaborative research opportunities. 

Left to Right: Prof Tracy Robson (MCT), Prof Jochen Prehn (Physiology & Medical Physics) and Dr Darran O’Connor (MCT)

At the invitation of the President of the British Pharmacological Society, Professor John Waddington (Emeritus, RCSI) has been elected to Fellowship of the Society; this is in recognition of his career contributions to research, education and service in the discipline of pharmacology, not just in Ireland but globally. He has recently returned from 3 weeks at the College of Pharmaceutical Sciences, Soochow University, China, under his joint appointment as a Professor of Pharmacology. While there, he continued collaborative research, gave undergraduate lectures and fostered further joint endeavours between RCSI and Soochow University, which is in the top 5% of Chinese research universities.   

Tracy Robson

MCT Awards at Research Day 2017

Dear all,

MCT was well represented in the award ceremony at the recent Research Day; our congratulations go to the following:

Dr Mark McCormack, for receiving prizes in the RCSI Author Citations Prizes in two categories – the 2011 Most Highly Cited RCSI Senior Authored Paper and the 2011-2015 Most Highly Cited RCSI Senior Authored Paper with International Collaboration – for his paper entitled “HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans” published in the New England Journal of Medicine.

Dr Cathy Wyse, as part of Dr Annie Curtis’s group, was presented a prize for the front cover illustration of the RCSI Research Day abstract book, for a striking image of glial cells at the junction between the brain and pituitary gland.

Tony McHale, PhD student at the School of Pharmacy, & MCT, and the Irish Centre for Vascular Biology, RCSI received the prize for the best postgraduate oral presentation, for his talk on the topic of “First in Class Potential Novel Drug for the Treatment of Sepsis Caused by Urinary Tract Infections”.

Medical student Jack Donohue [RSS student], was awarded the Dr Harry O’Flanagan Prize for Excellence in Undergraduate Research for the best undergraduate oral presentation for a project carried out as part of the RCSI Research Summer School entitled “Sanger Confirmation of Suspected Epilepsy-Related Pathogenic Variants Identified Through Next-Generation Sequencing”.

Very well done to all!

Tracy Robson

Diagnostic gene sequencing in adults with epilepsy and intellectual disability

MCT Research Talks – 20th February 2017

Sinead Heavin reports

Sinead Heavin, PhD Post-Doctoral Researcher

Epilepsy is a common neurological disorder that affects ~40,000 people in Ireland. There are many different types of seizures which are caused by uncontrolled electrical impulses in the brain. Anti-epileptic drugs control seizures for ~50% of people with epilepsy but up to ~30% of patients remain uncontrolled despite treatment with multiple drugs. Epilepsy is caused by a number of factors include stroke, trauma and infections. However, more recently we have learned that epilepsy can be caused by genetic mutations. Some epilepsies are heritable while others arise de-novo. Many patients with an intellectual disability (ID) also have epilepsy. Many of these patients lack a specific diagnosis due to limited testing and available investigations. We sequenced a cohort of 99 adult patients with epilepsy and ID on a custom gene panel of ~150 genes. A likely pathogenic variant was identified in 20 patients in 19 different genes, including SCN1A, DCX and DEPDC5, well-known epilepsy genes. Furthermore, we identified copy number variants in two patients which are likely causative. Further work is needed to investigate the phenotype-genotype correlations identified in this study and any potential treatment options that may arise.

Kay McKeon

8 February 2017

An informal, private reception was held in the College for Kay McKeon on Wednesday, 8th February, to mark her retirement and contribution to RCSI after 39 years.

Kay joined Clinical Pharmacology in 1978 and with Prof. Kevin O’Malley was responsible for commissioning the then ‘new’ laboratories. She continued to play a fundamental role in developing Clinical Pharmacology’s laboratories and building the department’s reputation through the 1980s and 1990s into RCSI’s premier research department.

She played a central role in assisting Kevin O’Malley’s successor, Prof. Des Fitzgerald, in securing RCSI’s first large HEA-PRTLI and SFI grants, working long hours with the intricate details and logistics for such applications.

During this period, Kay was seconded to oversee the development of the RCSI Centre for Human Proteomics, before returning to base and seeing in another period of change on the departure of Prof. Fitzgerald and formation of Molecular & Cellular Therapeutics (MCT) from the Departments of Biochemistry and Clinical Pharmacology under Profs. David Croke and John Waddington as HODs; she played a key role in the management of MCT as a member of it’s Executive.

At a more personal level, Kay was someone who carried out her responsibilities in a genuinely supportive and politically astute manner; many appreciated her sensitivity, in assisting all ‘new staff’ settle in and in maintained balance and stability in overseeing laboratories with up to 100 staff.

Yet in addition to this, Kay also found the time to contribute more broadly to RCSI, particularly its philanthropic activities, for example, the Old Folks Christmas Lunch for those living in the vicinity of the College and related activities; an all-too-rare rare combination of professionalism and altruism.

An important part of what Clinical Pharmacology and MCT has achieved serves as her legacy to the College, in making MCT what it is today and the entity that Prof. Tracy Robson has recently inherited.

Hebrews 6 (10 … 19): ‘For God would not be so unjust as to forget all that you did for love of his name, when you rendered service to his people, as you still do … It is like an anchor for our lives, an anchor safe and sure’.

Kay has been an ‘anchor safe and sure’ across four decades. We thank you, Kay, for everything you’ve done for Clinical Pharmacology, MCT, RCSI and the community at large and wish you well for the future.