Asthma is of particular relevance to the area of circadian control of immunity, since it is a disease with very strong clinical evidence demonstrating regulation by circadian variation. Airway hypersensitivity and asthma attacks are more common at night in humans. The molecular basis for this is unknown and no model of asthma in animals with genetic distortion of the molecular clock exists.
In this study, we showed that mice lacking the main clock transcription factor BMAL1 in myeloid cells have increased lung inflammation demonstrated by higher numbers of eosinophils and increased IL-5 (key pathogenic cytokine in asthma that recruits eosinophils).This suggests that Bmal1 is a potent negative regulator, in myeloid cells in the context of allergic asthma. Our findings might explain the increase in asthma incidents during the night in humans when BMAL1 expression is low.
Prof Tracy Robson (MCT), Prof Jochen Prehn (Physiology & Medical Physics) and Dr Darran O’Connor (MCT) have recently returned from 1 week at the College of Pharmaceutical Sciences, Soochow University, Suzhou, China where they participated in a workshop with faculty to explore research collaborations and future joint funding applications under the newly announced SFI-NSF Partnerships for International Research and Education. Supported by an Erasmus+ programme coordinated by Prof Marc Devocelle (Department of Pharmaceutical and Medicinal Chemistry), the workshop involved presentations from RCSI and Soochow investigators describing their work and discussion to identify areas of synergy. Afternoon lectures by RCSI faculty were opened to postgraduate and postdoctoral researchers from Soochow, leading to a vigorous and stimulating discussion and Prof Xinliang Mao from Soochow will visit RCSI next month to further strengthen future collaborative research opportunities.
At the invitation of the President of the British Pharmacological Society, Professor John Waddington (Emeritus, RCSI) has been elected to Fellowship of the Society; this is in recognition of his career contributions to research, education and service in the discipline of pharmacology, not just in Ireland but globally. He has recently returned from 3 weeks at the College of Pharmaceutical Sciences, Soochow University, China, under his joint appointment as a Professor of Pharmacology. While there, he continued collaborative research, gave undergraduate lectures and fostered further joint endeavours between RCSI and Soochow University, which is in the top 5% of Chinese research universities.
Irish Association for Cancer Research – Annual Meeting takes place at Newpark Hotel, Kilkenny on Thursday 23 and Friday 24 February 2017.
MCT cancer researchers secured oral presentations at different sessions. Prof Ray Stallings is a guest speaker at the Plenary Session focused on challenges in childhood cancers. He will be discussing ‘Modulation of neuroblastoma phenotype with epigenetically regulated miRNAs’.
Stephanie Annett will be giving a talk ‘FKBPL as a novel prognostic biomarker and therapeutic agent in high-grade serous ovarian cancer’ at Proffered Paper Session on Thursday morning. Two Irish Cancer Society funded PhD students will be discussing their findings at the Irish Cancer Society Scholar and Fellow Presentation session. Louise Walsh – ‘RNA sequencing identifies bromodomain proteins as a therapeutic strategy for invasive lobular carcinoma’ and Brian Mooney – ‘Expression of the cocaine- and amphetamine-regulated transcript recruits BAF chromatin remodelling complexes to the estrogen receptor’.
Epilepsy is a common neurological disorder that affects ~40,000 people in Ireland. There are many different types of seizures which are caused by uncontrolled electrical impulses in the brain. Anti-epileptic drugs control seizures for ~50% of people with epilepsy but up to ~30% of patients remain uncontrolled despite treatment with multiple drugs. Epilepsy is caused by a number of factors include stroke, trauma and infections. However, more recently we have learned that epilepsy can be caused by genetic mutations. Some epilepsies are heritable while others arise de-novo. Many patients with an intellectual disability (ID) also have epilepsy. Many of these patients lack a specific diagnosis due to limited testing and available investigations. We sequenced a cohort of 99 adult patients with epilepsy and ID on a custom gene panel of ~150 genes. A likely pathogenic variant was identified in 20 patients in 19 different genes, including SCN1A, DCX and DEPDC5, well-known epilepsy genes. Furthermore, we identified copy number variants in two patients which are likely causative. Further work is needed to investigate the phenotype-genotype correlations identified in this study and any potential treatment options that may arise.
The Irish Travellers are a small nomadic population, making up about 0.6% of the total population on the island of Ireland, or between 29,000 and 40,000 individuals. Within the population cousin marriages (consanguineous marriages) are common, and the population is socially isolated from the surrounding settled Irish population.
The researchers, who also include MCT PhD student Edmund Gilbert, Shai Carmi of the Hebrew University of Jerusalem, and Sean Ennis of University College Dublin, used SNP-array based genotype data to compare the population genetics of the Irish Travellers to neighbouring Irish and British populations, as well as world-wide groups and European Roma Gypsies.
The study found that although the Irish Travellers were genetic closest to the settled Irish population, they showed significant differences. The study also confirmed the lack of recent shared genetic ancestry between the Irish Travellers and Roma Gypsies. The Irish Travellers, therefore, represent a subset of Irish genetic diversity, and the significant differences can be attributed to genetic drift, brought on by hundreds of years of genetic isolation and a decreasing population size. The analysis showed Irish Travellers also exhibit within-population sub-structure with four apparently distinct groups emerging, and interestingly these groups mirror different forms of the Shelta language and sociological groups within the Irish Travellers.
The dating of the origin of the Irish Travellers is of considerable interest, but this is a distinct date from the genetic origins of each population. This study has estimated a time of genetic divergence of the Irish Travellers and the settled Irish population using genomic tracts of shared identity. This method estimated the divergence to about 12 generations (360 years) ago, which is far older than common belief that the Irish Traveller population arose from the time of the Great Famine. The size of the dataset limited the authors to exploring the relatively simple model of one divergence event, future work is required to expand the study to explore more complex demographic models. The Irish Traveller population was shown to have high proportions of the genome where both maternal and paternal copies are identical, at similar levels to other consanguineous populations around the world.
The research was also welcomed by author and Traveller activist, Michael McDonagh said, “As a Traveller who has spoken on the history and identity of Irish Travellers to many groups ranging from children to academics, you sometimes rely on anecdotal information in trying to put across a serious message about Irish Traveller history. I am delighted that now we have qualified evidence that substantiates the argument I have made for many years, which is that Travellers did not descend from the Famine in Ireland. This research allows us to bring Irish Traveller history back many and gives us a factual identity.”
A New Year…and a new challenge for MCT postdoctoral researcher Gillian Moore
Between the post-Christmas blues, cold days and that painful wait for the next pay day, January can be a pretty long and gruelling month. This year, deviating from the norm, my January kicked off to a great start with my eagerly awaited move to RCSI. Before Christmas I was delighted to find out that I would be working alongside Prof. Tracy Robson in the Department of MCT and I’m really excited for 2017, and the new opportunities and challenges this postdoctoral research position has to offer.
An ongoing research collaboration between the Robson research group and leading oncology pharmaceutical company, ALMAC Discovery, resulted in the development of ALM201, an anti-cancer peptide-based drug currently in Phase I clinical trial for patients with solid tumours. ALM201 is structurally based on the naturally occurring protein, FKBPL. FKBPL and its peptide-derivative, ALM201, have demonstrated potent anti-angiogenic properties, and notably, a unique ability to target cancer stem cells. Targeting of cancer stem cells has arguably become the Holy Grail of cancer therapy in recent years. Within the mass of every tumour there is a subpopulation of cancer cells with the ability to self-regenerate. It is this cell population that are responsible for the initiation and propagation of a tumour, and recurrence of disease following resistance to chemo and/or radiotherapy. If we can robustly target the bulk of the tumour in addition to any residual cancer stem cells then we can potentially circumvent progression and indeed recurrence of disease.
Ovarian cancer is one of the top ten most common cancers in women and is associated with a poor prognosis, primarily due to the late presentation of disease. In the coming months, the next stage in the clinical trial of ALM201 will involve the treatment of a cohort of ovarian cancer patients. Recent, unpublished preclinical data in the Robson group has indicated promising anti-cancer stem cell efficacy of ALM201 in the ovarian cancer setting. I am interested in understanding the molecular mechanisms that underpin this observed anti-cancer stem cell activity of ALM201. A new phase of academic research funding from ALMAC Discovery will enable us to carry out this work. While the specific targeting of ovarian cancer stem cells is a relatively new research field, it has potential to provide much needed alternate treatment options for this aggressive tumour type and may have implications for other malignancies.
It’s great to be part of MCT at RCSI and I’m looking forward to sharing our research findings as the project develops.
For most people with epilepsy, long term treatment with anti-epileptic drugs (AEDs) are necessary to prevent the seizure, and 40% do not respond to the first line of AED, leading to an often lifelong odyssey of trial and error towards effective treatment that is often not found. Epilepsy is primarily treated using AEDs, but these are associated with a considerable risk for adverse drug reactions (ADRs), some of which have been shown to have a genetic predisposition. For example, the genetic variant HLA-A*3101 is a common risk factor for rash and severe blistering skin reactions with the drug carbamazepine (Tegretol) in Europeans. However there are few other predictors of some more common ADRs.
The EpiPGX Consortium was established to identify genetic biomarkers of epilepsy treatment response from patient centres across Europe. The EpiPGX Consortium has generated genetic profiles on over 8000 patients with matching detailed drug response and medical histories. In order to investigate the links between genetic profiles and ADRs in epilepsy, Dr. Mark McCormack will travel to UMC Utrecht, the Netherlands for one year on a Marie-Skłodowska-Curie Fellowship from the European Commission.
The aim of this fellowship is to identify clinically useful genetic variants to predict adverse reactions to AEDs. This will help optimize personalized treatment, limit the trial and error approach of AED choice, and thus improve medication safety and quality of life in epilepsy.
Our Immune-clock laboratory has a real interest in metabolism and how alterations in metabolic pathways termed “metabolic reprogramming” can shape the type of immune response. This area called “Immunometabolism” has exploded in the last 5 years, and the implications are massive. It appears that macrophages use one metabolic pathway to become highly proinflammatory and another metabolic pathway to resolve inflammation and promote wound healing. So why is our laboratory so interested in this? Well, if you think about daily changes in our environment, the two biggest are the sleep/wake cycle and the other is feeding/fasting. It is now clear that clocks in metabolic tissues like the liver/pancreas/adipose tissue prepare the body to deal with this daily rhythm in feeding/fasting. Based on this, our interest is to figure out if the clock within macrophages is somehow altering its metabolism over the course of the day and is that leading to changes in macrophage function, particularly the inflammatory response.
Body clocks tend to garner quite a bit of attention from the media. Folks are obsessed with sleep, either they cant get enough or they are getting too much, and all of us can relate to the symptoms of jet lag and morning versus evening types. Therefore it’s a great topic to discuss with wider audiences. I really enjoy chatting with people about the implications of our internal timing system and that research now shows that living in synchrony with your body clock can improve overall health. For the SFI Science week I was asked to provide an interview to the Daily Star called “The Science of Sleep Explained”. I was also asked to go on the “Alive and Kicking” show on Newstalk Radio with Ciara Kelly, you can listen to the interview: What type of sleeper are you? Are you an owl or a lark?