Recent MCT Papers In High Impact Journals With Commentaries

CNV and Schizophrenia Working Groups of the Psychiatric Genomics Consortium; Psychosis Endophenotypes International Consortium. [including Waddington J]. Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects. Nat Genet. 2017 Jan;49(1):27-35. PMID: 27869829

John Waddington writes about his group’s participation in a global research endeavour that has produced a series of articles in Nature, Nature Genetics and Nature Neuroscience on the pathobiology of schizophrenia The Psychiatric Genomics Consortium (PGC) unites investigators around the world to conduct meta- and mega-analyses of genome-wide genomic data on psychiatric disorders, to achieve goals that cannot be reached by individual or indeed most national programmes. Its website (www.med.unc.edu/pgc) provides information about the organization, implementation and results of the PGC. This consortium began in early 2007 and has rapidly become a collaborative confederation of investigators from 38 countries. There are samples from more than 900,000 individuals currently in analysis, and this number is growing rapidly. The PGC is the largest consortium and the largest biological experiment in the history of psychiatry.
From 2007-11, the PGC focused on several disorders, from schizophrenia through to autism, attention-deficit hyperactivity disorder, bipolar disorder and major depressive disorder. These now extend to large studies of eating disorders, substance use disorders, obsessive-compulsive disorder/Tourette’s Syndrome and post-traumatic stress disorder. Initially, the PGC focused on common single nucleotide polymorphisms (SNPs) but has expanded to include copy number variation (CNVs) and uncommon/rare genetic variation. The PGC has received funding from many sources. It has relied heavily on the goodwill of its members and their donated effort, with the establishment andgenotyping of its primary studies funded by a wide range of national, international and commercial entities.

We have been involved in the Schizophrenia Working Group of the PGC for many years, from its progenitor organisation the International Schizophrenia Consortium, primarily through substantial funding from the Wellcome Trust for five centres across the island of Ireland (one led by us) to contribute DNA from well characterised patient populations to a national dataset curated at Trinity College Dublin. This dataset has then been shared with the PGC. The resultant studies have evolved from the first investigation of CNVs in schizophrenia (3,391 cases, 3,181 controls; Nature 2008; 455: 237-41), through to the largest GWAS study on schizophrenia undertaken to date (36,989 cases, 113,075 controls; Nature 2014; 511: 421-7), to this most recent publication (21,094 cases, 20,227 controls; Nature Genetics 2017; 49: 27-35), the largest study of CNVs in schizophrenia yet undertaken. This has been, and continues to be, an exemplary, rewarding journey of global collaboration to illuminate the pathobiology of the intractable human condition that is psychotic illness.

 


Chion A, O’Sullivan JM, Drakeford C, Bergsson G, Dalton N, Aguila S, Ward S, Fallon PG, Brophy TM, Preston RJ, Brady L, Sheils, O, Laffan M, McKinnon TA, O’Donnell JS. N-linked glycans within the A2 domain of von Willebrand factor modulate macrophage-mediated clearance. Blood. 2016 Oct 13;128(15):1959-1968. PMID: 27554083.

Jamie Marie O’Sullivan writes about this study:

Von Willebrand factor (VWF) is a large multimeric plasma sialoglycoprotein that plays two critical roles in normal haemostasis. First it mediates platelet adhesion to exposed subendothelial collagen at sites of vascular injury. Second, VWF acts as a carrier molecule for procoagulant factor VIII, thereby protecting it from premature proteolytic degradation and clearance. Deficiency of either VWF (von Willebrand disease, VWD) or FVIII (Haemophilia A) is associated with a significant bleeding phenotype. Conversely, elevated plasma levels of the VWF-FVIII complex constitute a dose dependent risk factor for both venous and arterial thrombosis. Consequently, understanding the factors that determine how plasma VWF levels are regulated is not only of basic scientific interest, but also direct clinical importance.

Despite the fact that type 1 von Willebrand disease constitutes the most common inherited bleeding disorder worldwide, the mechanisms underlying the reduced plasma VWF levels in these patients is not well established. However, emerging evidence suggests that reduced circulatory half-life may be important in a significant number of patients. However the biological mechanisms underlying VWF clearance from the plasma remains elusive. Work is on-going within the group of Professor James O’Donnell to investigate the importance of specific VWF domains in modulating half-life in vivo.

In the October issue of Blood the group published novel findings demonstrating a critical role for VWF glycosylation in determining its circulatory half-life. By examining the clearance of various truncated fragments of VWF, we observed that the A domains of VWF contain a receptor-recognition site important in mediating VWF binding to macrophages in vitro, and in regulating VWF clearance by macrophages in vivo. Furthermore site-directed mutagenesis demonstrated a key role for N-linked glycan structures at position N1515 and N1574 within the A domains in protecting VWF against macrophage-mediated clearance. More specifically, the protective effect of these large complex N-linked glycan structures may be due to steric hindrance, with shielding of cryptic binding sites for macrophage clearance receptor low density lipoprotein receptor-related protein 1 (LRP1).

Defining the mechanisms underpinning VWF clearance is not only of direct translational relevance, but may also have important implications for the development of novel therapeutic agents with significant commercial appeal. For example, the estimated cost of clotting factor concentrates to the global market is predicted to exceed €10 billion per annum by 2020. It is therefore perhaps unsurprising that major pharmaceutical companies (including Baxter®, Bayer®, Novo Nordisk® and Octapharma®) are actively pursuing development of longer-acting coagulation factor products (including VWF and FVIII) as a priority. Our novel findings further scientific understanding in relation to the molecular mechanisms involved in regulating coagulation glycoprotein clearance from plasma.


McGettrick AF, Corcoran SE, Barry PJ, McFarland J, Crès C, Curtis AM, Franklin E, Corr SC, Mok KH, Cummins EP, Taylor CT, O’Neill LA, Nolan DP. Trypanosoma brucei metabolite indolepyruvate decreases HIF-1α and glycolysis in macrophages as a mechanism of innate immune evasion. Proc Natl Acad Sci U S A. 2016 Nov 29;113(48):E7778-E7787. PMID: 27856732.

Dr. Anne McGettrick and Sarah Corcoran at Trinity College Dublin lead a team of researchers including Dr. Annie Curtis (now at MCT) on a study that uncovered how the African parasites trypanosomes evade the immune system in their hosts, The biochemists have unearthed a metabolic by-product of trypanosome activity known as indolepyruvate modulates the inflammatory response of the host and evades immune detection. This discovery may offer excellent possibilities for developing anti-trypanosome drugs and therapies because inhibiting the production of indolepyruvate may be key in fighting the parasite. Full details can be found here https://www.tcd.ie/news_events/articles/solving-a-putrid-camel-pee-riddle-may-aid-millions-affected-by-sleeping-sickness/7385

The cerebrovascular nature of neurological disorders

MCT Research Talks – 9th January 2017

Guest speaker: Dr. Matthew Cambell

At MCT, we are very excited to announce our visiting guest speaker Dr Matthew Campbell from the Smurfit Institute of Genetics in Trinity College Dublin. Dr Campbell is a prestigious and young emerging principal investigator in Ireland who has made significant contributions in the fields of Neuroscience, Inflammation and the Vasculature System, core research areas that are also conducted within the MCT department.

Dr. Matthew Cambell

Dr Campbell aims to elucidate and address questions associated with dysfunctional vasculature within neural tissues. Recently published in Nature Medicine, Dr Campbell made a significant discovery uncovering the role of the NLRP3 inflammasome in the development of one of the most common forms of central retinal blindness, AMD. His lab is now pursuing a range of novel therapeutic solutions for the treatment of AMD and recently reported on the translational potential of human IL-18 as an immunotherapy.

Dr Campbell interests also focus on the blood-brain barrier, where he recently reported for the first time on the auto-regulated diffusion of amyloid-β in Alzheimer’s disease. More recently, he has identified molecular mechanisms underlying the development of chronic traumatic encephalopathy (CTE) to concussive injuries in athletes and military personnel. He spearheads a project involving the use of RNA interference (RNAi) to modulate levels of distinct tight junction proteins at the blood-brain barrier. This led to a novel form of patented technology that was termed “Neural Barrier Modulation” which could have broad applications for a range of neurological conditions.

Dr Campbell is the recipient of Ireland’s most prestigious prize for young researchers, the “President of Ireland Young Researcher Award (PIYRA)“, in addition to the international Genentech/ARVO fellowship. He will be speaking today on ‘the cerebrovascular nature of neurological disorders’ at 12 pm in Tutorial Room 2/3. Lunch will be provided for all after the talk.

All welcome!!

Written by Dr Claire McCoy, Lecturer in Biochemistry, MCT, RCSI.

Immunometabolism, Is it under the eye of the clock

Annie Curtis reports

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.

Jamie Early, my PhD student

Jamie Early, my PhD who “lives” in Prof. Luke O’Neills laboratory at TCD and I were invited to submit this first ever review on circadian immunometabolism, and you can find it here.

Additional reading

  1. Early JO, Curtis AM Immunometabolism: Is it under the eye of the clock?Semin Immunol. 2016 Oct;28(5):478-490

Follow me on Twitter @curtisannie

Here’s to a successful 2017!!

Many thanks to all members of MCT; without you, our success would not be possible. Wishing you and your family all the warmth this Holiday Season has to offer. Have a wonderful Christmas and a New Year filled with peace, joy and success.

MCT staff in 2016

Tracy Robson

Its about Time! The role of body clocks in health and disease

Annie Curtis reports

How metabolic and immune parameters vary across the 24 hours (1).

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?

Additional reading:

  1. Early JO, Curtis AM Immunometabolism: Is it under the eye of the clock?Semin Immunol. 2016 Oct;28(5):478-490

Annie Curtis on Twitter @curtisannie

Using genotype data to infer population structure and history

MCT Research Talk – 12th December

The Human Genetic Variation Research Group 

The Monday 12th December MCT Seminar Series will feature presentations from Amy Cole and Edmund Gilbert, of the Human Genetic Variation Research Group at RCSI. Led by Prof. Gianpiero Cavalleri, this research group studies large genetic datasets to investigate population structure, natural selection and the genetic basis of human disease.

Andean native in a small village on the outskirts of Cuzco

Amy Cole’s research focuses on identifying adaptive genetic variants in high altitude populations.  There are more than 140 million people living at high altitude who are exposed to two primary environmental extremes; hypobaric hypoxia and cold. At altitudes >2500 m individuals have between 11-14% effective oxygen availability, instead of the 21% available at sea level. Previous studies have identified genetic signals of selection across the genome, which have facilitated an adaptive phenotype for survival in this hypoxic environment.  Studying these indigenous high altitude populations will enable us to shed light on genes and molecular mechanisms involved in the response to hypoxia. This insight can help shed light on a number of illnesses associated with hypoxic states in low altitude populations, such as pneumonia, chronic obstructive pulmonary disease, asthma and cancer.

Research group en route to Cerro de Pasco

Today Amy presented research on a whole genome sequencing project on native high altitude Quechua individuals, recruited from the city of Cerro de Pasco, Peru, during a field trip in 2015.  Amy recently completed a three-month lab placement at MD Anderson Cancer Center with Professor Chad Huff’s research group. Here Amy performed a number of computational analyses to identify regions of the genome that are under selection in this cohort.

Edmund Gilbert’s research involves investigating the genetic structure and diversity found within the Irish. As an island population on the west of Europe, the Irish population is, from the genetic perspective, relatively homogenous compared to populations of the European mainland. As a results of this elevated homogeneity, the Irish population is well suited to studies of genetic disease. Such studies have recently shifted focus towards rare variants, which are more geographically stratified than more common variants. Therefore understanding the population structure within Ireland is key for the optimal design of genetic disease causing rare variant identification within the Irish.

Today Edmund will be presenting research investigating the extent of fine-scale population structure found within Ireland. He has been using SNP-array genotype data from the genetic ancestry DNA cohort called the “Irish DNA Atlas”. The Atlas is a cohort of individuals with Irish ancestry from three generations ago who have all eight of their great-grandparents born within 50 km. Edmund will be presenting analysis based on the suite of software known as fineStructure; investigating both fine-scale structure as well as the genetic ancestry of this structure.

Amy Cole, Edmund Gilbert, Gianpiero Cavalleri

MCT student, Lisa Dwane, talks about her research and recent achievements

cropped-RCSI-logo-1.jpgFollowing completion of my Pharmacology degree in UCD, I began a PhD in breast cancer research under the supervision of Dr. Darran O’Connor, a career I have always been very determined to follow. My research is focused on endocrine-driven breast cancer and understanding the molecular mechanisms that drive this subtype of cancer. Currently, half of breast cancer patients that receive anti-endocrine therapies will relapse, so there is an urgent need for the identification of novel therapeutic targets. Our research is focused on the deubiquitinating enzyme USP11, which we believe plays a key role in driving endocrine-driven breast cancer. When we silence USP11 in vitro, we see a reduction in estrogen receptor activity and cell viability. During the final year of my PhD, I hope to elucidate the mechanism by which USP11 plays this role, and determine the prognostic relevance of USP11 in breast cancer. This could potentially lead to a better understanding of endocrine-driven breast cancer and with further validation, USP11 may represent a novel therapeutic target.

Lisa Dwane presents her research at the Irish Cancer Society’s Researcher of the Year Award. december, 1st, 2016. TCD
Lisa Dwane presents her research at the Irish Cancer Society’s Researcher of the Year Award. December, 1st, 2016. TCD

As a pharmacologist, I was thrilled to win best oral presentation at the Irish Association of Pharmacologists Annual Meeting! The standard of talks throughout the day were excellent, with a wide range of topics explored. I was also a finalist for the Irish Cancer Society’s Researcher of the Year Award, which took place 1st December at Trinity College Dublin. The purpose of the evening was to communicate our research to a lay audience, which proved more difficult than expected! Although I didn’t take home the award it was a very enjoyable evening, and the experience was invaluable. As scientists it is important for us to share and communicate our research with the general public and this was a skill I gained from the night!

Winners and finalists for the Irish Cancer Society’s Researcher of the Year Award
Winners and finalists for the Irish Cancer Society’s Researcher of the Year Award

Targeting drug resistance in neuroblastoma

MCT Research Talks 5th December 2016  rcsi-logo

Cancer Genetics Group

Neuroblastoma is a childhood cancer caused by the abnormal growth and development of neural crest cells (1). The disease commonly affects children age 5 years or younger. Approximately 50% of children have cancer cells that have migrated to distant sites in the body and formed tumour masses at the time of diagnosis. The main challenge in treating neuroblastoma is to combat tumour metastasis and development of resistance to multiple chemotherapeutic drugs. Despite major advances in available therapies, children with drug resistant and/or recurrent neuroblastoma have a dismal outlook with 5 year survival rates of less than 20%.

Research of Prof. Stallings lab is focused on elucidating the molecular events that contribute to the development and progression of neuroblastoma (2).  A major area of research involves the identification and functional analysis of microRNAs that contribute to chemotherapy resistance in neuroblastoma, along with the development of microRNA-mediated therapeutics.

The main research projects were presented at the Departmental meeting on December, 5th.

Microscopic examination of drug resistant neuroblastoma cells KellyCis83. Cells look healthy and can be kept for another 2-3 days to form a more dense population.
Microscopic examination of drug resistant neuroblastoma cells KellyCis83. Cells look healthy and can be kept for another 2-3 days to form a more dense population.

The first talk by Olga Piskareva has explored how current concepts of development of drug resistant, tumour microenvironment and cell-to-cell communication can be applied to reconstruct relapsed or drug resistant neuroblastoma microenvironment using 3D tumour models.

TEM analysis of exosome fractions. Vesicle sizes range from 30 to 200nm in Kellycis83 (A) and Kelly (B) neuroblastoma cells. (C) EVs which appear larger than the 100 nm upper limit for exosomes (D) Close up of the dried exosome preps identify the typical bowl shaped morphology associated with TEM images of exosomes. (3)
TEM analysis of exosome (EV) fractions. Vesicle sizes range from 30 to 200nm in Kellycis83 (A) and Kelly (B) neuroblastoma cells. (C) EVs which appear larger than the 100 nm upper limit for exosomes (D) Close up of the dried exosome preps identify the typical bowl shaped morphology associated with TEM images of exosomes (3).

The second talk was presented by Ciara Fallon. Ciara is our StAR PhD student. She has selected the project ‘Exosome mediated drug resistance in high-risk neuroblastoma’ as her first choice.  At the moment she is doing her lab placement in Cancer Genetics group as a part of the RCSI StAR PhD Programme. Built upon results of the former BioAt PhD Student Ross Conlon (3), Ciara’s project is focused on the validation of exosomal miR-548d-5p as a regulator of cell viability and proliferation in cisplatin sensitive and resistant neuroblastoma cell lines.

Finally, the last, but not least was a talk by John Nolan. His talk entitled “MiRNA-124-3p Reduces Cell Viability in Cisplatin Resistant Neuroblastoma Cell Models” was focused on the results submitted to the Royal College of Surgeons for the Degree of Doctor of Philosophy. His studies cover the development of cross resistance to other drugs, investigation of common altered proteins and signaling pathways in cisplatin resistant neuroblastoma cell lines and validation of miRNA that can target these proteins and stop cell proliferation. Part of the results was published last year in Cancer Letters (4).

The work carried out in Prof. Stallings lab is supported through the research grant to Prof. Ray Stallings and PhD fellowship to John Nolan by National Children’s Research Centre, Crumlin Hospital. ncrc

References:

  1. Davidoff, A. M. Neuroblastoma. 2012 Semin. Pediatr. Surg. 21, 2–14.
  2. Piskareva, O., Stallings, R. Neuroblastoma. In: Epigenetic Cancer Therapy edited by Grey S., Elsevier 2015.
  3. Conlon, R., Analysis of microRNA bearing exosomes in models of drug resistant neuroblastoma. PhD Thesis. Dublin: Royal College of Surgeons in Ireland; 2015.
  4. Piskareva, O., Harvey, H., Nolan, J., Conlon, R., Alcock. L., Buckley, P., Dowling, P., O’Sullivan, F., Bray, I., Stallings, T.L. The development of cisplatin resistance in neuroblastoma is accompanied by epithelial to mesenchymal transition in vitro. 2015 Cancer Letters, 364:142-55.

Reported by Olga Piskareva

Dr HH Stewart Award to Aya Al-Hasani

MCT is delighted to report that Aya Al-Hasani, one of our undergraduate Medical Students, has come second place in the Biochemistry Section of National Universities of Ireland, Dr HH Stewart Award. The top three students from RCSI are invited to take part in the exams, for each category.  Students are sent the essay title a week in advance, are not allowed to confer with staff, and sit the essay under exam conditions.

 Aya reflects on her award:

Aya AL-Hasani at Royal Hospital Kilmainham, Wednesday 09 November 2016. http://www.nui.ie/images/news/2016/awards2016_Flash/index.asp
Aya AL-Hasani at Royal Hospital Kilmainham, Wednesday 09 November 2016.
http://www.nui.ie/images/news/2016/awards2016_Flash/index.asp

During my first few years at RCSI, my hardest subject was biochemistry. Those complicated signalling pathways seemed absolutely useless to learn at that time. I then started to realise that biochemistry is essentially the platform for understanding all diseases and treatments. Suddenly, biochemistry became my favourite subject! I was so inspired by Prof. Cavalleri, MCT, who was organised and passionate in his teaching. I chose my favourite topic “obesity” after being invited to sit the HH Stewart exam. I was delighted to know that I won the second prize. It meant a lot for me to compete and win an Irish national competition. I just wished my parents were able to see me in the ceremony.

Aya attended the ceremony at Royal Hospital Kilmainham on Wednesday 09 November 2016.

Well done Aya!

HEAD OF DEPARTMENT’S WELCOME

 

Prof. Tracy Robson Head of Molecular & Cellular Therapeutics (MCT), Royal College of Surgeons in Ireland
Prof. Tracy Robson Head of Molecular & Cellular Therapeutics (MCT), Royal College of Surgeons in Ireland

It gives me great pleasure to welcome you to MCT’s blog page. Our department is based within the Royal College of Surgeon’s in Ireland (RCSI) situated on Dublin’s beautiful St Stephen’s Green.  This was one of the initial attractions for my move to Dublin from Queen’s University Belfast in Aug 2016, in addition to the vibrant and innovative environment that RCSI provides, through its achievements in education and research.

Our research focuses on understanding the molecular basis of disease in order to develop and apply our findings to the identification of biomarkers and new drug targets. Our aim is to improve the diagnosis, treatment and, ultimately, prevention of disease; enabling MCT to be at the forefront of personalized medicine. With newly renovated state-of-the-art facilities, strong links with Beaumont Hospital, our clinician-scientist teams are leading therapeutic and biomarker discovery in the areas of autoimmune and inflammatory disease, cancer, cardiovascular disease, infection, platelet biology and neurological and psychiatric disease. This is facilitated by strong collaboration with industry allowing us to translate our findings appropriately, revolutionizing healthcare through discoveries and innovations that improve people’s lives.

I hope that you enjoy reading our blog page which seeks to capture the dynamic nature of the teaching and research environment within MCT and pays testimony to the significant accomplishments of our all of our staff and students.  I hope that we can inspire you ………

Tracy Robson