Last Monday while in Amsterdam with my Mam and two sisters, a friend of mine sent a text to let me know that the 2017 Nobel Laureates in Physiology and Medicine were Hall, Rosbash and Young. They were awarded the Nobel for their work in identifying the key genes that create circadian or body clock rhythms in the fruit fly. My feet literally were stuck to the ground, it was thrilling to know that these gentlemen would get the recognition that they so deserve, but also what this will mean for the field of science that I am so passionate about. The body clock is the molecular timekeeping system that exists in practically every organism on the earth and in every cell in our body. Simply put, it allows the cell to tell what time of day it is. Why is that important? We live on a spinning planet and because of the earth’s rotation to the sun, all life on earth has been subjected to daily periods of light and heat, dark and cold. The body clock allows us to anticipate and respond to these 24-hour predictable environmental changes and synchronises our physiology to it. For example, the body clock increases cortisol levels in the body ahead of awakening, this helps us to become active once we wake. The body clock also increases expression of digestive enzymes in the intestinal tract during daylight hours (this is why curry chips at 3am is never a great idea!).
Back in the 80’s Hall, Rosbash and Young independently isolated a gene called Period, they showed how the gene encodes a protein PER that builds up in cells at night and degrades during the day. This daily rise and fall of PER essentially allow the cell to track time of day. How thrilling it must have been for them to observe this daily change in the mRNA levels of Period gene (Figure 1- black line), all that is changing along the x-axis is the time of day.
So what does this mean three decades later? We have made great strides in understanding how the molecular clock works. We now know that the clock keeps time by a series of transcriptional-translational feedback loops. We also know that the clock controls 40% of all coding genes within the body. The body clock controls all aspects of our physiology from metabolism to immunity.
Many diseases, such as osteoarthritis and cardiovascular disease, are highly time of day dependent. Moreover, it appears that disruption of our body clocks, caused by our non-stop 24/7 lifestyle and exposure to artificial light at all times of day, is partly responsible for the increase in chronic inflammatory diseases. Unfortunately, most cell culture systems are not synchronized with the time of day, and this, in my opinion, is one of the main reasons that many researchers unknowingly neglect this field. Finally, we are making great strides in attempting to time specific treatments to the right time of day, an area called chronotherapy. Therefore, it is my hope that this increased awareness of the body clock will bring more researchers into this fascinating field. If we don’t fully understand how our body clock controls physiology and disease we will certainly be left in the dark.
Annie Curtis is a Research Lecturer and runs the Immune Clock laboratory at MCT and is fascinated by all things body clock related.
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.
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.
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.
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.
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.
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!
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.
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.
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’.
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.”
The recipients of L’Oréal-UNESCO For Women in Science 2017 Fellowship:
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.
More details can be found in “Molecular interactions and inhibition of the staphylococcal biofilm-forming protein SdrC”.
Dear MCT folks,
Do you constantly doodle in the side margins of your notebook? Are you looking for something to release your creative talent?
Well look no further dearies,
We are looking to YOU to update our MCT Logo
What’s in it for me I hear you ask? A €100 voucher no less!