MCT Research Forum

Monday 14th January 12.00 – 1.30

Drug Discovery and Development

Prof. Celine Marmion

‘Teaching an Old Drug New Tricks – Developing Multi-Targeted Metallodrug Candidates Beyond Cisplatin’

Prof. Dermot Cox

Challenges in developing small molecule drugs

Hannah Rushe

‘Novel therapeutics to prevent uncontrolled bleeding’

Lunch sponsored by Bioscience at 1.30pm

Venue: Cheyne Lecture Theatre

Ancestral origins of increased breast cancer risk and mortality: blame the parents

MCT Research Seminars – 19th December 2018

Leena A. Hilakivi-Clarke, Ph.D. is a professor of Oncology at Georgetown University. She received PhD in 1987 from University of Helsinki, Finland, where she studied the role of maternal exposures during pregnancy in affecting offspring’s later brain development and behaviour. Next, she was a Fogarty postdoctoral fellow (1987-1990) at the National Institute of Alcohol Abuse and Alcoholism in Bethesda, Maryland. In 1991, she joined the Lombardi Comprehensive Cancer Center at Georgetown University, Washington DC. Since then, Dr. Hilakivi-Clarke has been investigating how maternal dietary exposures or exposures to the endocrine-disrupting chemical during pregnancy affect daughter’s breast cancer risk, response to endocrine therapy and risk of recurrence. She discovered that the effects of maternal exposures are not limited to F1 generation but extend to at least F3 generation (great granddaughters). In addition, she has studied the effect of these exposures on mother’s breast cancer risk as well as the impact of childhood exposures on breast cancer risk and recurrence. Exposures include ethinyl estradiol, plant-derived phytochemicals, dietary fats and obesity. Her current goals include being able to identify breast cancer patients who have been ancestrally exposed to factors that may impair their response to endocrine therapy and/or increase their risk of recurrence using their pretreatment tumours. She is also exploring combination therapies, including HDAC/DNMT inhibitors and immune therapies that would prevent recurrence in daughters ancestrally exposed to factors that impair their response to antiestrogens. Her publication record consists of over 160 journal articles. She is a recipient of multiple grant awards through her research career, including being a program director for NCI funded U54 program project entitled “Timing of dietary exposures and breast cancer risk” to investigate nutritional modulation of genetic pathways leading to breast cancer.

Time: 1.00pm – 2.00pm

Venue: Bouchier-Hayes Auditorium, No 26 York St

Lunch will be at 12.30 outside the Auditorium

All Welcome!

PhD student elevator pitch session

Chairs: Thomas Frawley and Orla Fox

Venue: Houston Lecture Theatre

Date: December, 3d 2018

Time: 12.00

Presenters: 

Rebecca Watkin

George Timmons

Aisling Rehill

Hannah Rushe

Remsha Afzal

Conor Duffy

Martin Kenny

Frances Nally

Sean Patmore

James O’Siorain

Shannon Cox

Lauren Fagan

A light lunch will be served after the talks. Sponsored by Biosciences Ltd.

All Welcome!

 

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.

 

 

 

Gut Feelings: The Microbiome as a Regulator of Brain and Behaviour across the Lifespan

MCT Research Seminars – November 19th,  2018.

Ever had a “gut feeling” about something? It turns out, the connection between our gut and our brain might be stronger than we think. John F. Cryan, Prof. & Chair of Anatomy & Neuroscience and Principal Investigator at APC Microbiome Ireland, Cork Ireland will share surprising facts and insights about how our thoughts and emotions are connected to our guts. As a TEDMED speaker, Prof. Cryan shares his fascination with biomedicine and why it offers a perfect way to explore the interaction between the brain, gut and microbiome, and how this relationship applies to stress- and immune-related disorders such as depression, anxiety, irritable bowel syndrome, obesity, and neurodevelopmental disorders including autism.

Prof. Cryan has published over 440 articles and is a co-author of “The Psychobiotic Revolution: Mood, Food, and the New Science of the Gut-Brain Connection” (National Geographic Press, 2017). He has received numerous awards including UCC Researcher of the Year in 2012; UCC Research Communicator of the Year 2017, the University of Utrecht Award for Excellence in Pharmaceutical Research in 2013 and being named on the Thomson Reuters Highly Cited Researcher list in 2014 and Clarivate Analytics Highly Cited Researcher list in 2017 and 2018. He was elected a Member of the Royal Irish Academy in 2017. He has received a Research Mentor Award from the American Gastroenterology Association and the Tom Connor Distinguished Scientist Award from Neuroscience Ireland in 2017. He was awarded an Honorary Degree from the University of Antwerp, Belgium in 2018 and is currently President of the European Behavioural Pharmacology Society.

Date: November, 19th 2018

Time: 3.00pm

Venue: Tutorial Room 4

All Welcome

Regenerative inflammation in the CNS: Innate and adaptive immune mechanisms in myelin repair

MCT Research Seminars – October, 8th 2018

Dr Dombrowski’s research focuses on immune mechanisms in tissue damage and repair. Tissue damage can occur in infectious (e.g. bacteria, virus, fungi) or sterile settings (e.g. trauma, autoimmune attack). The Dombrowski group is primarily interested in the underlying immunological mechanisms that direct tissue repair and regeneration with the goal to identify novel therapeutic targets for immune-mediated diseases such as Multiple Sclerosis (MS).
Despite driving pathology in many diseases, the immune system is required for tissue regeneration. Innate immune receptors sense disruption of tissue homeostasis initiating a regenerative immune response that leads to the repair of the damaged tissue. Our central goal is to elucidate the mechanisms of regenerative inflammation, in particular, the role of the innate immune system in myelin regeneration in MS.
In MS the myelin sheath that covers nerve fibres is damaged due to an autoimmune attack against proteins in the myelin sheath. As a result, the nerve fibres die leading to a loss of function, which can result in paralysis and other neurodegenerative symptoms. There is no cure for MS to date and there are no therapies that can restore damaged myelin in order to prevent nerve loss.
Current projects of the group investigate the function of inflammasomes during myelin damage and regeneration in the central nervous system (CNS) and the effects of IL-1 cytokines on oligodendrocyte progenitor cells, stem cell-like cells in the CNS that produce myelin. Other projects in the group investigate the role of inflammasomes in regenerative inflammation after infectious tissue damage and the role of e-cigarette vapour as an inflammasome activator. Dr Dombrowski has published her work in high-impact journals (e.g. Nature Neuroscience 2017) and her research has been recognized in prestigious awards including an Early Career Fellowship from The Leverhulme Trust and the invitation to the 64th Lindau Nobel Laureate Meeting for Physiology and Medicine as one of ten UK representatives.

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.

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