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!

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 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

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

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