New Players in Ubiquitination: Relevance to innate immunity and inflammatory diseases

MCT Research Forum – March 25th 2019 at Cheyne Lecture Theatre at 3.00pm – 4.00pm

Prof. Paul Moynagh – “New Players in Ubiquitination: Relevance to innate immunity and inflammatory diseases”
Prof. Moynagh obtained his B.A. (Mod) and PhD from Trinity College Dublin and took up a lectureship in UCD Department of Pharmacology in 1995. During his time in UCD Prof. Moynagh became Associate Professor of Immunology and held the position of founding Head of the UCD School of Biomolecular and Biomedical Science. In 2006 he joined National University of Ireland, Maynooth as Director of its Institute of Immunology and currently holds the positions of Head of Department of Biology and Director of the Human Health Research Institute at Maynooth University. Prof. Moynagh has published extensively in the area of immunology-related research and in 2009 was awarded the NUI Centennial Prize for Academic Publishing in Medical and Health Sciences. He was also awarded the 2014 Irish Area Section Biochemical Society (IASBS) medal. This medal is awarded annually to an Irish-based researcher who has made an outstanding contribution during his/her career in the broad area of Biochemistry. Prof. Moynagh’s research focuses on innate immune signalling and the identification of novel regulators of inflammatory pathways with his most recent findings revealing immunomodulatory roles for the Pellino E3 ubiquitin ligases in inflammasome activation (Humphries et al; Nature Communications (2018), antiviral immunity (Siednienko et al; Nature Immunology (2012)), controlling intestinal homeostasis (Yang et al; Nature Immunology (2013)) and regulating insulin resistance (Yang et al; Immunity (2014)). He has generated >€10M of independent research funding and has directed a number of major research initiatives including the coordination of European Commission-funded research programmes. Prof. Moynagh has also played a leading role in the training of PhD students and directed 2 large structured PhD programmes

Dr. Stephanie Annett –“Unravelling the role of FKBPL in obesity”

Dr. Jennifer Dowling – “The Inflammasome: a novel therapeutic target of Hypoxic Brain Injury in Neonates”

All Welcome

Tea/Coffee and Cookies sponsored by

MCT Research Forum – Friday 25th January at 3.00pm

Professor David Ray

“Circadian control of inflammation; stories from the lung”

David trained in general internal medicine in North West England, and obtained a PhD from the University of Manchester. He was a research fellow at UCLA for two years, working on neuroendocrine-immune interaction, before returning to the UK, and obtaining a GSK fellowship to work on glucocorticoid action, and sensitivity in inflammatory disease. He was promoted to Professor of Medicine at the University of Manchester in 2005, and went on to study nuclear receptor and circadian biology in inflammation, and energy metabolism. This work attracted Wellcome Investigator and MRC programme grant support. David is a passionate advocate of research training, serving on the MRC clinical fellowship panel for seven years, three as deputy chair.

Circadian mechanisms regulate most mammalian physiology, with particular importance in the regulation of innate immunity, through the macrophage in particular, and energy metabolism, regulating liver, adipose and muscle. These circuits are also regulated by a number of nuclear receptors, which show a striking interdependency on the circadian machinery; some having ligand availability regulated by the clock, others varying in expression level through the day. We have employed a range of approaches to address the physiological importance of the circadian: nuclear receptor system, ranging from population genetics, experimental medicine studies, CRISPR engineered mice, and cell biology. These approaches have discovered how the important dimension of time regulates metabolism, and coordinates diverse tissues to deliver optimal organismal performance. Importantly, we are identifying how external stressors can decouple these systems, with deleterious effects.

Dr. Judith Coppinger

“Increased extracellular vesicles mediate inflammatory signalling in Cystic Fibrosis”

Judith obtained her PhD from Department of Clinical Pharmacology, RCSI in 2004 before undertaking postdoctoral training at the Scripps Research Institute, San Diego, on new folding mechanisms in Cystic Fibrosis. In 2011, she joined the University of California, San Diego as a faculty member before receiving an SFI award and returning to Ireland. In 2013 she became a principal investigator at University College Dublin where she set up basic/translational research programs in Cystic Fibrosis and Cancer (lung/breast). Judith’s overall research has focused on using omics-based approaches to decipher protein interaction networks dysregulated in disease and identify new therapeutics to target these pathways. Her research projects include examining the therapeutic restoration of CFTR using kinase inhibitors in Cystic Fibrosis and examining exosomes in regulating inflammatory signalling in Cystic Fibrosis at the National Children’s Research Centre. Other projects include investigating BAG3 as a therapeutic target regulating signalling transduction pathways in breast/lung cancer subtypes. Dr. Coppinger is a senior lecturer at the RCSI and a principal investigator at National Children’s Research Centre since 2017.

George Timmons

“Mitochondria – A link between innate immunity, metabolism, and the clock”

George Timmons is a PhD student of the Curtis Clock Lab, led by Dr. Annie Curtis and is part of the Department of Molecular and Cellular Therapeutics and Tissue Engineering Research Group at RCSI. George began his PhD in October 2016 and is now in the 3rd year of his studies. The Curtis Clock Lab focuses on circadian immunometabolism – a new field which looks into the relationship between the molecular clock, cellular metabolism, and immune responses. Specifically, George’s project is investigating how the core clock gene Bmal1 impacts upon mitochondrial metabolism and how these metabolic changes can impact upon the inflammatory response of macrophages.

When: January 25th 2019 at 3.00pm – 4.30pm

Where: Cheyne Lecture Theatre

Tea Coffee and Cookies sponsored by Biosciences will be at 2.30pm

Congratulations to Remsha Afzal!

The Molecular & Computational Biology Symposium 2018 was held at the Conway Institute of Biomolecular and Biomedical Research in University College Dublin (UCD). This symposium is jointly organised annually by UCD PhD students from the Systems Biology and Infection Biology programs.

This event showcased the thriving local research and scientific community that is present at UCD and in Dublin to Irish and international academic researchers as well as industrial companies. It also featured internationally renowned keynote speakers from a wide range of fields within the sphere of computational and molecular biology to present their research.

Remsha Afzal from Dr. Claire McCoy’s lab was selected to be a speaker at this year’s symposium where she won a prize for best presentation for her topic “The role of IL-10 and arginase in immunometabolism”

See more about the symposium at: http://compmolbiosymp.ucd.ie/

Omics in Disease Diagnosis and Therapy

Our new ‘thematic’ MCT Research Seminar Series was launched on November 8th with the opening talks on ‘Omics in Disease Diagnosis and Therapy’. The aim of the new format, with presentations spanning several research groups and diseases to facilitate knowledge exchange and foster cross-collaboration.

Dr Sudipto Das – Genomic and epigenomic approaches as a vital discovery platform

The talk broadly focused on various genomic and epigenomic platforms that have been established in the lab enabling us to interrogate the various alterations that underpin disease-associated features. Using specific clinical case examples, the talk demonstrated how the whole genome, exome and shallow sequencing have allowed us to further our understanding about atypical clinical presentation of known cancer types. Furthermore, the application of targeted methylation sequencing on FFPE tissue and it’s further utilization to stratify metastatic colorectal and heart failure patients using deep learning approaches was also explained.

Dr Katie Benson – Integrating Genomics into the Clinical Care Pathway

Next-generation sequencing is quickly replacing single gene tests in clinical practice. The integration of these genomic tests has been slow as a result of barriers including data processing and interpretation, handling of incidental findings, storage of data and access to genetics services and clinical geneticists. The Epilepsy Lighthouse project, building on the success of the epilepsy electronic patient record (EPR), has used eHealth technologies to facilitate the integration of genomics results into the epilepsy clinic. This has facilitated multidisciplinary team discussions of patients and their genomics results. As part of this project, we have sequenced 97 adult and paediatric Irish epilepsy patients and successfully provided a genetic diagnosis in 24% of cases.

Dr Chiara DeSanti – MicroRNA function in health and disease

Since the sequencing of the human genome back in 2001, non-coding RNAs have been shown to play a critical role in regulating gene expression at a transcriptional, post-transcriptional and translational level. Among the several classes of non-coding RNAs, our group is interested in microRNAs (miRNAs), small non-coding RNA molecules (18-25 nt in length) firstly discovered in C.elegans as negative regulator of gene expression through binding to the 3’untranslated region (UTR) of a target mRNA and inhibiting its translation and/or leading to mRNA degradation. MiRNAs expression was found altered in all human diseases so far, where they have been proposed as diagnostic/prognostic biomarkers and as key players in the pathogenic process itself due to their pleiotropic ability to bind hundreds of mRNAs simultaneously. Therefore, it’s hugely important to define true miRNAs::mRNAs interactions to understand their biological role and the pathways that they affect, in the overall aim of designing therapeutic strategies to enhance or block miRNAs. In order to do so, online target predictions is usually the first step, but experimental validation is needed to verify the in silico-predicted interaction. Several methods have been developed to address this issue, and they can be indirect (i.e. transcriptomic and proteomic changes are measured after over-expression/depletion of a miRNA), or direct (i.e. miRNA::mRNA complexes are captured and physical interactions are assessed, including the RCSI-developed method called miR-CATCH). Gold standard for the validation of high-throughput screening is the luciferase assay, again routinely used in several laboratories across the College. In our group, we are focussing on the role of miR-155 in macrophage polarisation in the context of multiple sclerosis (MS), a neurodegenerative disease where proinflammatory macrophages infiltrate the central nervous system and promote chronic inflammation and damage to myelin sheath. Our hypothesis, supported by preliminary data by our PI Dr MCoy and other researchers, is that miR-155 is promoting the proinflammatory state in macrophages and therefore blocking it would reduce inflammation and alleviate disease progression. Although proof of concepts for antimiR-155 therapy have been attempted in a mouse model of MS (EAE model), we are hoping to boost its efficacy by improving the delivery to macrophages of more stable versions of antimiR-155 or target-site blockers that minimise off-targets effects.

 

 

 

Well done Dr Mariana Cervantes!

Dr Mariana Cervantes (MCT) was successful in obtaining funding from The National Council of Science and Technology (CONACYT) from Mexico under the Support for Postdoctoral Researchers Abroad Linked to the Consolidation of Research Groups scheme. This funding will support her postdoctoral research in circadian biology in the Curtis-Clock Lab, under the guidance of Dr Annie Curtis. The grant titled “Impact of circadian control on mitochondrial metabolism in Dendritic Cells and their implications in vaccination” was funded for $48,000 for 2 years. In this project, Dr. Cervantes will unravel the mechanisms by which the molecular clock regulates dendritic cell function with the objective to improve vaccination strategies.

This grant is awarded to Mexican Postdoctoral researchers who wish to carry out high-level research in prestigious universities worldwide.

MCT Hosts Intergenerational Day Lab Tour

On Thursday 4 October, the Equality, Diversity and Inclusion (EDI) unit welcomed almost 30 family members of staff to RCSI St Stephen’s Green campus for the first-ever RCSI Intergenerational Day. Throughout the day, the guests had the opportunity to learn about a variety of activities at RCSI. MCT hosted a lab tour where guests were introduced to several MCT Principal Investigators who discussed their work and demonstrated how their research is carried out. Four stations focusing on the themes of Breast Cancer, Novel Cancer Therapies, Multiple Sclerosis and Circadian Rhythm and its Impact on Health were featured, led by Dr Sudipto Das, Dr Maria Morgan, Prof Tracy Robson, Dr Claire McCoy and Dr Annie Curtis. Guests were guided around the labs by the MCT Operations Team John O’Brien, Olwen Foley, Anne Grady, Mary Ledwith and Seamus McDonald. Scientists Stephanie Annett; Gillian Moore; Conor Duffy; Chiara DeSanti; Mariana  Cervantes Silva, Richard Carroll and George Timmons also volunteered on the day.
Prof Gianpiero Cavalleri contributed to the day’s activities with a talk on the Irish DNA Atlas. The MCT research projects presented were a hit with our audience evident by the number of attendees, their level of engagement and thoughtful questions. Guests included relatives of MCT staff including Mr Joseph Tighe father of Orna and Mrs McDonald & Curtis – mothers of Seamus and Annie respectively. Julia Morrow of the EDI unit commented that ‘between the MCT lab visit and Gianpiero’s talk, more than one guest commented they wish they could go back and have a more science-oriented career!’ It’s never too late we say!
Written by Maria Morgan

A new mechanism by which the body clock controls the inflammatory response from macrophages

The Curtis lab from MCT in partnership with the O’Neill lab at Trinity College have revealed insights into how the body clock controls the inflammatory response, which may open up new therapeutic options to treat excess inflammation in conditions such as asthma, arthritis and cardiovascular disease. By understanding how the body clock controls the inflammatory response, we may be able to target these conditions at certain times of the day to have the most benefit. These findings may also shed light on why individuals who experience body clock disruption such as shift workers are more susceptible to these inflammatory conditions.
The body clock, the timing mechanism in each cell in the body, allows the body to anticipate and respond to the 24-hour external environment. Inflammation is normally a protective process that enables the body to clear infection or damage, however, if left unchecked can lead to disease. The new study published in the Proceedings of the National Academy of Sciences (PNAS), a leading international multidisciplinary scientific journal.
Dr Annie Curtis, Research Lecturer in the Department of Molecular and Cellular Therapeutics at RCSI and senior author, explained that: “Macrophages are key immune cells in our bodies which produce this inflammatory response when we are injured or ill. What has become clear in recent years is that these cells react differently depending on the time of day that they face an infection or damage, or when we disrupt the body clock within these cells”.

Some members of the Curtis lab involved in this project: Dr. Richie Carroll (far left), Dr. Annie Curti,  Dr. Mariana Cervantes, George Timmons (far right)

Dr. Jamie Early, the first author on the study, said: “We have made a number of discoveries into the impact of the body clock in macrophages on inflammatory diseases such as asthma and multiple sclerosis. However, the underlying molecular mechanisms by which the body clock precisely controls the inflammatory response were still unclear. Our study shows that the central clock protein, BMAL1 regulates levels of the antioxidant response protein NRF2 to control the inflammatory response from macrophages.
“The findings although at a preliminary stage, offers new insights into the behaviour of inflammatory conditions such as arthritis and cardiovascular disease which are known to be altered by the body clock”, added Dr Early.
Funded by Science Foundation Ireland, the research was undertaken in collaboration between RCSI, Trinity College Dublin and the Broad Institute in Boston, USA.

Here is the  link to the paper titled ” Circadian clock protein BMAL1 regulates IL-1β in macrophages via NRF2

Annie Curtis

Mechanobiology – the ‘dark matter’ of cancer and immunity

MCT research seminar

The way we act very much depends on our surroundings; not the least on the weather conditions. In a similar way, cells in our body very much depend on what is going on around them. It has been known for a long time that the specific niches in which cells reside impact on the cellular phenotype. While most researchers have looked at chemical signals – either released into the environment or reflecting the composition of the extracellular matrix – it is becoming increasingly clear that also physical properties, such as stiffness and topography, are sensed by a wide variety of cells and influences their decisions.

It is our pleasure to welcome Prof Viola Vogel this Monday at RCSI for the MCT research seminar.

July 16th, 4.00 pm, Albert Lecture Theatre “How does the mechanobiology of extracellular matrix steer cancer progression?

Prof Vogel and her laboratory at ETH Zurich have pioneered the field of mechanobiology. Her earlier work focused on how proteins act as mechanochemical switches to transduce mechanical signals from the ECM into the cell. More recent work addresses the importance of tissue strain in the development of tumours. Prof Vogel will also share her latest results on how physical constraints affect decision making of macrophages.

Anyone who is interested in getting a different viewing angle on cancer and immunity is heartily invited! To steer your personal decision making towards attending the talk, refreshments will be served from 3.30 pm on in the Atrium.

Ingmar Schoen

Circadian Immunometabolism. What it is and why your immune system will not thank you for eating curry chips at 2am after the disco

MCT Research Seminar

The Curtis Clock laboratory has a real interest in metabolism, which is a really broad term and means different things to different people. We are interested in how different fuels (sugars , fats, proteins) are metabolised (broken down) within immune cells, and if this has an impact on how that immune cell functions. The key metabolic organelle within a cell is the mitochondria, that is where the breakdown parts of these fuels end up and are converted to energy (ATP). We are a Clock lab, so our raison d’etre (so to speak) is to unravel how different fuels are metabolised within immune cells at different times of day and how the mitochondria work at different times of day, and how that impacts the response of the immune cell at that time of day. This is what we now term “Circadian Immunometabolism”. This leads me on nicely to our title, before the age of electricity, our forefathers never ate in the middle of the night, we believe that our immune system becomes dysfunctional when it has to deal with food during a time when we now believe our immune system is undergoing repair and restoration. So to begin to get at these big questions, Mariana and George have two exciting projects ongoing. Mariana, who is a postdoc in the laboratory, will show how our mitochondria are changing over the course of the day in dendritic cells (these are cells of the innate immune system and are the ones that feed information to our adaptive immune system) (see Fig. 1). The title of her talk is

“Those mitochondria have got rhythms! Mitochondrial activity and antigen processing in dendritic cells is dependent on the molecular clock protein BMAL1”.

George, a PhD student in the lab, is dissecting down into the cells to figure out how the electron transport chain (the side of action for ATP synthesis) is controlled by the clock. The title of his talk is

“Metabolic pathways in a macrophage lacking a molecular clock”

Mitochondria have a very important role in cellular metabolism, their morphology is completely different during the day (elongated) (yellow) or during the night (fragmented) (blue) nucleus (gray)

Annie Curtis

More details of what we do can be found here: www.Curtisclocklab.com