Cellular and molecular models for epigenetic studies of human disease

MCT Research Seminars – 20th September at 4.00pm

My research group focusses on understanding the models of genetic susceptibility to human disease, especially those affecting children. Primarily, we focus on the study of the epigenome, as a regulator of transcriptional activity that can mediate memory of prior events, whether developmental cues or environmental perturbations.

The research is facilitated by Einstein’s Center for Epigenomics, its Epigenomics Shared Facility and the Computational Epigenomics Group, where the development of the Wasp System software cyberecosystem is nurtured.

In essence, our research involves the targeting mechanisms of DNA methylation, the role of non-canonical nucleic acid structures and the heritability of chromatin states. We have been guided by our epigenomics studies to consider the broader possibility that mosaicism for cellular events is a much more common cause of human disease phenotypes than currently appreciated. We are therefore expanding our research interests to encompass genetic mosaicism, with an interest in isolated congenital malformations and covert chromosomal aneuploidy.

Targeting the microbial pharmacists within us to lower blood pressure

MCT Research Talks – September, 17th 2018

Dr Francine Marques is a National Heart Foundation Future Leader Fellow at the Baker Heart and Diabetes Institute, and a former National Health and Medical Research Council (NHMRC) and Heart Foundation Early Career Fellow (2013-2017). She completed a BSc with first class Honours in Genetics and a Masters in Molecular Biology and Genetics, at the Federal University of Rio Grande do Sul in Brazil. She then moved to Australia, where she was offered a competitive Endeavour International Postgraduate Research Scholarship (EIPRS) to complete a PhD at the University of Sydney. Dr Marques was awarded her PhD in 2012, in the field of the molecular genetics of hypertension. Her research interests include finding new therapies and early markers to prevent cardiovascular disease, in particular high blood pressure and heart failure. Her research has shown that a diet reach in fibre is able to lower blood pressure and improve heart function through the modulation of the bacteria in our gut. Dr Marques has published >50 peer-reviewed papers, including in the journals Circulation, Molecular Psychiatry and Nature Reviews Cardiology. She receives funding from the NHMRC, the National Heart Foundation and the Foundation for High Blood Pressure Research. She is part of the executive committee of the High Blood Pressure Research Council of Australia as a co-program manager and part of the mentoring committee of the International Society of Hypertension. She is also an adjunct senior lecturer at Monash University and Federation University Australia.

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

RCSI StAR International Summer Internship Programme

This summer RCSI welcomed our very first cohort of ten international students as part of our Inaugural RCSI StAR International Summer Internship Programme. Students came from Washington University, Cornell University, University of California, Berkeley, University of Oregon, Queen’s University Belfast, University of Liverpool and TCD to spend two months in laboratories around RCSI. To mark the end of the programme we held a research symposium where students show-cased their research and experience. It was a huge success, with Kieran White, University of Liverpool winning the overall prize for the best presentation on ‘Nanotherapeutics for Glioblastoma’ (supervisor Professor Annett Byrne). Kieran has already accepted a PhD position with Prof Byrne on her GlioTrain programme. Thanks to Prof Darran O’Connor and Prof Tracy Robson (MCT) for leading this initiative.

We will also be running the StAR summer internship next year – stay tuned. Here is the link to last year’s programme which will be updated within the next month: http://www.rcsi.ie/starugprogramme

 

Research Summer School Programme 2018

A fantastic few weeks of research is now completed, culminating in the Wrap Up Symposium on Friday, July 27th, 2018. This year not only had we our own students from RCSI but we also welcomed undergraduate students from Hoshi University, Tokyo, Japan; Soochow University, Suzhou, China; the RCSI StAR Summer Internship Programme; FutureNeuro and the Faculty of Dentistry. There was great stuff being done on a number of fronts, not only in the labs but also out on our clinical sites as well as an increase in the number of students involved in some fab systematic reviews. It was incredible to see the breadth of research done by our undergraduate students in such a short period of time. It is a credit to them, their research supervisors and teams. We eagerly look forward to next year’s programme.

Some insights from student’s perspective:

“It was educational in a different way; I expected to learn more about the disease I am working with get an outcome but instead, I feel like I am better equipped to analyse papers and data and methods that are very useful in the future as a clinician.”

“Amazing! Big thanks to Gill and Sarah O’Neill”

“It was a knowledgeable and valuable learning experience that was never dull in any way.”

Reported by Sarah O’Neill

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

Many common psychiatric conditions are deeply connected on a genetic level

Global collaborations can help answer fundamental questions that are resistant even to national endeavours. Drs Mark McCormack and Christopher Whelan (MCT) and Professors Kieran Murphy (Psychiatry) and John Waddington (Emeritus, MCT) have participated in an important international study, the results of which have just been published in Science [2018 Jun 22;360(6395)] under the auspices of the Brainstorm Consortium. This landmark study, ‘Analysis of shared heritability in common disorders of the brain‘, analyses genetic data assembled globally from 265,218 patients having one of 25 neuropsychiatric disorders and 784,643 control participants, together with 1,191,588 individuals having 17 other, potentially relevant characteristics. Psychiatric disorders share an unexpected degree of common genetic risk: for example, genes associated with risk for schizophrenia are also associated, to varying extents, with significant risk for bipolar disorder, major depressive disorder, autism spectrum disorder, attention deficit/hyperactivity disorder, obsessive-compulsive disorder and anorexia nervosa; in contrast, neurological disorders such as epilepsy, stroke, Parkinson’s disease, migraine and multiple sclerosis appear more genetically distinct from one another. This highlights the importance of common genetic variation as a risk factor across psychiatric disorders.

https://www.irishtimes.com/news/health/many-psychiatric-disorders-have-common-genetic-links-major-study-1.3539455

 John L. Waddington PhD, DSc, FBPhS, MRIA
Professor Emeritus

 

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

Harnessing FKBPL to target cancer and vascular disease

Pathological blood vessel formation (angiogenesis), or the inability of endothelial cells to perform their physiological function (endothelial dysfunction), are defining features of disease. The endothelium actively controls vessel integrity, vascular growth and remodelling, tissue growth and metabolism, immune responses, cell adhesion, angiogenesis, haemostasis and vascular permeability.  It is, therefore, a vital and largely unexploited target for novel therapies.

Prof Tracy Robson’s team have identified and characterised a novel anti-angiogenic protein, FK506 binding protein like – FKBPL, significantly advancing our understanding of the anti-angiogenic process, in particular, how tumours recruit blood vessels to support their growth. This led to a collaborative study with Almac Discovery to develop therapeutic peptides based on FKBPL’s active domain to explore their potential in cancer by targeting the ability of tumours to recruit blood vessels to grow, invade and metastasise beyond the site of the primary tumour.  The team are also testing the ability of these peptides to sensitise tumours to current therapies and to target cancer stem cells that lead to the onset of resistance and/or recurrent disease.   Importantly, these studies led to a ‘first in man’ phase I clinical in cancer patients where the clinical candidate drug, ALM201, was very well tolerated over a wide range of doses.  Prof Robson’s team (Dr Stephanie Annett and Dr Gillian Moore) will discuss this data together with new data suggesting a strong role for FKBPL in vascular endothelial dysfunction and possible implications therefore in other diseases associated with vascular disease.

Graham Cotton, Tim Harrison, Tracy Robson, Gillian Moore, Seamus Browne and Stephanie Annett (left to right)