Are you ready for MCT Lab Safari?

Registration is closed and all places on the MCT Lab Safari have now been filled.
We can’t wait to meet our potential future scientists tomorrow at 5pm! The lab coats are ready and the MCT labs have never looked so clean. We have prepared some great experiments and demonstrations to showcase our ongoing research. Everyone will have an opportunity to explore our labs and perform some hands-on science activities.

MCT Lab Safari Programme:

4.50pm:    Arrival and registration – Front Hall SSG
5pm:          Welcome and brief introductions
5.05pm:   Meet a leading scientist and hear her career journey
5.15pm:    Visit our research laboratories in small groups safari style
6.30pm:   Q&A with refreshments
7pm:          Close

 We are looking forward to seeing you all tomorrow!

TUESDAY, 14th NOVEMBER, 2017 5PM – 6.30PM
RCSI, ST STEPHENS GREEN, DUBLIN 2

Prof Luke O’Neill delivered the inaugural lecture at the RCSI Research Seminar Series

Prof Luke O’Neill delivered the inaugural lecture at the RCSI Research Seminar Series yesterday. Luke O’Neill is the professor of Biochemistry and Immunology at Trinity College Dublin. Luke is a world-renowned scientist known for his contributions to the field of Immunology, more specifically Toll-like receptors, innate immune signaling, cytokines and most recently Immunometabolism. He is one of Ireland’s most influential scientists having published >300 publications and is in the top 1% of the world’s most cited scientists in Immunology. He is the recipient of many prestigious awards including the Boyle Medal for Scientific Excellence and last year was elected a Fellow of the Royal Society.

Luke told us many exciting stories. The first highlighted how the inflammasome sensor NLRP3 is critical for the production of the pro-inflammatory cytokine IL-1. A cytokine essential for our fight against infection, but is elevated and extremely damaging in many diseases including Rheumatoid arthritis, colitis, Parkinson’s, Alzheimer’s, diabetes and hypertension. Luke’s team discovered a small molecule inhibitor against NLRP3 that has shown efficacy in 32 models of disease, as astounding effect never observed before. The inhibitor is now entering clinical trials and could excitingly pave the way as a radical treatment for many diseases.

The second story introduced the concept of Immunometabolism, a phenomenon where immune cells utilize metabolic pathways to generate inflammatory mediators. In response to infection, immune cells such as macrophages increase the production of glycolysis whilst at the same time cause a block in Kreb’s cycle. This block leads to the accumulation of intermediates such as succinate. Importantly, Luke has shown that succinate is critical for the production of IL-1 via the transcription factor HIF-1alpha. Inhibition of succinate ablates IL-1 production in response to infection, as well as in a number of disease models tested. Luke highlights that the manipulation of energy pathways could very likely provide an alternative mechanism for therapy in inflammatory disorders.

It was a real pleasure to hear Luke speak at RCSI. To learn more about the above stories, check out the following publications:

Lab Safari

EVER WONDERED WHAT THOSE PEOPLE IN WHITE LAB COATS ACTUALLY DO?

COULD YOU BE ONE?

Join us for an opportunity to see exactly what
happens in a research laboratory. The Department
of Molecular and Cellular Therapeutics (MCT)
at RCSI is opening its doors for a science week
interactive tour. Visitors will get to interact with
high-profile scientists, explore our labs and
perform some hands-on science activities.
Anyone considering a career in science is
welcome but we particularly encourage young
women/girls to attend, to promote the full
participation of girls and women in science.

TUESDAY, 14th NOVEMBER, 2017 5PM – 6.30PM
RCSI, ST STEPHENS GREEN, DUBLIN 2

MCT Lab Safari

Click here to register!

The event is free but pre-registration is required
Queries: Tel: 01 402 2420 Email: agrady@rcsi.ie
*This is a real working research lab so due care must be taken and all instructions must be followed.

 

Introducing Ingmar Schoen

Hi everyone in MCT! Thanks for the warm welcome!
 As some of you know, I have joined RCSI as a StAR research lecturer in June. My plan is to establish a lab on ‘MechanoVascular Biology and Microscopy’. What do I mean by this?
 The first part ‘MechanoVascular Biology’ sets the scope. I am interested in how cells in the cardiovascular system use mechanical forces to achieve their tasks. As mechanical and chemical cell functions are tightly related, both play important roles in health and disease. Most research has focused on one or the other aspect, but not both. The novel research field of ‘mechanobiology’ takes an integrative approach to better understand how physical forces co-regulate chemical processes on the molecular level. In my previous work at ETH Zurich, I have studied how fibroblasts sense matrix stiffness and respond to it. Here at RCSI, I want to study platelets in the context of thrombosis and, over the years, investigate their interplay with endothelial cells.
The second part ‘Microscopy’ highlights one of the major working horses in my lab. Following the credo ‘seeing is believing’, watching cells can tell you a lot about how they do things. I use microscopy to test hypothesis but also to discover unexpected behaviour. Over the years, I have developed several new microscopy techniques to look at sub-second dynamic processes, directly measure cellular tractions, or determine the nanoscale architecture of multi-protein structures. These are great tools to better understand how the processes starting from platelet activation and ending with the consolidation of the thrombus are regulated in space and time. For this we will use in vitro models, but I am keen to move in the future towards in vivo imaging.
By now, you may have noticed from my scientific viewpoint and my enthusiasm for technology that my background is in physics. I studied physics with a specialization on biophysics at the Technical University Munich. My PhD work at the Max Planck Institute of Biochemistry focused on electrical stimulation of neurons with extracellular electrodes. After a short postdoc at the Ludwig Maximilians University Munich where I studied bi-molecular binding kinetics in living cells, I moved to ETH Zurich in Switzerland. That’s where I have started with mechanobiology and super-resolution fluorescence microscopy, which I know bring over to RCSI.
 A long way is lying ahead of me to cross the bridge towards clinical research. I look forward to having many inspiring discussions with you, already thank you for the ones we had so far, and hope that I can make a valuable contribution to the research here at RCSI!
Looking forward to seeing you at MCT Research Talks on 16th October 2017 at 12.00 TR4!
Kind wishes,
Ingmar
 

Timely Announcement for Nobel Prize

 

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.

 

Introducing Jennifer Dowling

I have recently arrived as a Postdoctoral Researcher in Dr Claire McCoys Lab in the Molecular and Cellular Therapeutics Department (MCT) at RSCI. I specialise in immune signalling pathways and inflammatory complexes underlying infectious and inflammatory diseases, including multiple sclerosis (MS), sepsis and highly virulent strains of influenza. 

After obtaining my BSc in Biotechnology in 2005 from Dublin City University I was awarded a postgraduate scholarship from the Irish Research Council and went on to complete my PhD in Immunology in 2009 (DCU). I conducted my postdoctoral training in innate immune signalling with Prof Luke O’Neill in Trinity College Dublin with a strong focus on understanding the mechanisms regulating a key inflammatory complex in immune cells known as the inflammasome.

I was subsequently recruited to the Centre for Innate Immunity and Infectious Diseases at the Hudson Institute of Medical Research, Melbourne, Australia under the supervision of Prof Ashley Mansell and continued my work in this field. Here I secured funding from the Angior Family Foundation to support my research on blocking the detrimental inflammation that occurs during sepsis.

I am excited to be joining MCT and the McCoy Lab. Like Claire, I have a passionate interest in medical research and chose to work in inflammation because it has a central role in the progression of a broad range of diseases. I am also passionate about community engagement, science communication and educating the next generation about the importance of medical research and the role of inflammation in disease.

Jennifer Dowling

Congratulations!

Dear all,

Please join me in sending congratulations to the following staff: Sudipto Das and Jennifer Dowling on their appointment as Honorary Lecturer[s] within MCT, recently approved by Academic Council.

Sudipto Das on the award of best poster presentation in the Post-doctoral researcher category for poster titled “Using next-genera-on sequencing strategies to guide precision oncology in cases with atypical clinical presentation” at the Irish Society for Human Genetics Annual Conference held at Croke Park, Dublin on 15th Sep, 2017.

Jamie Early, student with Annie Curtis, for the best short talk at the Irish Society for Immunology Annual meeting. The title of talk: The circadian clock protein BMAL1 regulates inflammation in macrophages via the NRF2 antioxidant defense pathway”.

And finally to ‘Dr’ Rana Bakhidar PhD, who successfully defended her thesis last week. The title of her thesis is ‘Nanoparticles Used in Drug Delivery and Targeting: Understanding the relationships between Nanoparticle Quality And Interaction With Platelets’. Supervisor: Dr. Sarah O’Neill and Co-supervisor, Dr Zeibun Ramtoola, School of Pharmacy,

Well done to all!
Best wishes,

Tracy

Tracy Robson
Professor & Head of Molecular & Cellular Therapeutics (MCT)

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.