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!

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.

 

 

 

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

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 Scopes Awards at Haematology Association of Ireland Meeting 2018

MCT was well represented at this year’s Haematology Association of Ireland meeting in Cork. A number of PhD students and Post-docs from the Irish Centre for Vascular Biology, has their work selected for presentation at this prestigious annual meeting. Moreover, three of these presentations were awarded prizes;

Presidents Prize: Clive Drakeford, PhD student
Best Scientific Oral Presentation: Dr Sean McCluskey, PostDoc
Best Scientific Poster Presentation: Soracha Ward, PhD student

Soracha Ward (PhD student with Prof. James O’Donnell) presenting her poster

Additionally, two PhD students, Sean Patmore and Aisling Rehill, scored in the top 20% of submitted abstracts and had their work selected for oral presentations at the meeting.

Dr. Sean McCluskey [post doc with Roger Preston] and Clive Drafeford [student with Prof. James O’Donnell]
Congratulations to all involved!

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

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.

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