Introducing Jennifer Dowling

I have recently arrived as a Postdoctoral Researcher in Dr Claire McCoys Lab in the Molecular and Cellular Therapeutics Department (MCT) at RSCI. I specialise in immune signalling pathways and inflammatory complexes underlying infectious and inflammatory diseases, including multiple sclerosis (MS), sepsis and highly virulent strains of influenza. 

After obtaining my BSc in Biotechnology in 2005 from Dublin City University I was awarded a postgraduate scholarship from the Irish Research Council and went on to complete my PhD in Immunology in 2009 (DCU). I conducted my postdoctoral training in innate immune signalling with Prof Luke O’Neill in Trinity College Dublin with a strong focus on understanding the mechanisms regulating a key inflammatory complex in immune cells known as the inflammasome.

I was subsequently recruited to the Centre for Innate Immunity and Infectious Diseases at the Hudson Institute of Medical Research, Melbourne, Australia under the supervision of Prof Ashley Mansell and continued my work in this field. Here I secured funding from the Angior Family Foundation to support my research on blocking the detrimental inflammation that occurs during sepsis.

I am excited to be joining MCT and the McCoy Lab. Like Claire, I have a passionate interest in medical research and chose to work in inflammation because it has a central role in the progression of a broad range of diseases. I am also passionate about community engagement, science communication and educating the next generation about the importance of medical research and the role of inflammation in disease.

Jennifer Dowling

Congratulations!

Dear all,

Please join me in sending congratulations to the following staff: Sudipto Das and Jennifer Dowling on their appointment as Honorary Lecturer[s] within MCT, recently approved by Academic Council.

Sudipto Das on the award of best poster presentation in the Post-doctoral researcher category for poster titled “Using next-genera-on sequencing strategies to guide precision oncology in cases with atypical clinical presentation” at the Irish Society for Human Genetics Annual Conference held at Croke Park, Dublin on 15th Sep, 2017.

Jamie Early, student with Annie Curtis, for the best short talk at the Irish Society for Immunology Annual meeting. The title of talk: The circadian clock protein BMAL1 regulates inflammation in macrophages via the NRF2 antioxidant defense pathway”.

And finally to ‘Dr’ Rana Bakhidar PhD, who successfully defended her thesis last week. The title of her thesis is ‘Nanoparticles Used in Drug Delivery and Targeting: Understanding the relationships between Nanoparticle Quality And Interaction With Platelets’. Supervisor: Dr. Sarah O’Neill and Co-supervisor, Dr Zeibun Ramtoola, School of Pharmacy,

Well done to all!
Best wishes,

Tracy

Tracy Robson
Professor & Head of Molecular & Cellular Therapeutics (MCT)

A possible therapeutic avenue in Cystic Fibrosis

Cystic fibrosis (CF) is an inherited chronic disease that primarily affects the lungs and digestive system. CF is caused by mutations in the Cystic Fibrosis Transmembrane Regulator (CFTR) gene, a chloride channel responsible for helping conduct chloride and other ions across epithelial membranes. The loss of a functional CFTR channel disrupts ionic homeostasis resulting in mucus production that clogs the lungs and pancreas and results in a vicious cycle of chronic infection and inflammation as the disease progresses.

There are almost 2,000 different variants in the CFTR gene and 70 % of CF patients contain a mutation at position 508, which results in the loss of Phe508 and disruption of the folding pathway of CFTR. ΔF508 CFTR is a trafficking mutant that is retained in the endoplasmic reticulum (ER) and unable to reach the plasma membrane. Efforts to enhance exit of ΔF508 CFTR from the ER and improve its trafficking are of utmost importance for the development of treatment strategies. Clinically, progress has been made in recent years identifying therapeutics that target CFTR dysfunction in patients with specific mutations. However, small molecules that directly target the most common misfolded CFTR mutant, ΔF508, and improve its intracellular trafficking in vitro, have shown modest effects We performed a study aimed to identify new therapeutic targets that will help address the unmet clinical need for CF patients homozygous for  the ΔF508 mutation.We aimed to understand the protein interactions regulating CFTR transport using mass spectrometry-based proteomics. Using mass spectrometry based protein interaction profiling and global bioinformatics analysis we revealed mammalian target of rapamycin (mTOR) signalling components to be associated with ∆F508 CFTR.  Our results showed upregulated mTOR activity in ΔF508 CF bronchial epithelial cells. In addition to a well described role in several cancer subtypes, excessive activation of the mTOR pathway has been reported to be involved in age-related misfolding diseases. There are a range of inhibitors that target the PI3K/Akt/mTOR pathway and after screening a selection of inhibitors, we identified 6 different inhibitors that demonstrated an increase in CFTR stability and expression. Mechanistically, we discovered the most effective inhibitor, MK-2206 exerted a rescue effect by restoring autophagy in ΔF508 CF cells. These findings highlight this pathway as a possible therapeutic avenue worth further exploration in Cystic Fibrosis.

Judith Coppinger and her team: Mark Ward and Zivile Useckaite

We aimed to understand the protein interactions regulating CFTR transport using mass spectrometry-based proteomics. Using mass spectrometry based protein interaction profiling and global bioinformatics analysis we revealed mammalian target of rapamycin (mTOR) signalling components to be associated with ∆F508 CFTR.  Our results showed upregulated mTOR activity in ΔF508 CF bronchial epithelial cells. In addition to a well-described role in several cancer subtypes, excessive activation of the mTOR pathway has been reported to be involved in age-related misfolding diseases. There are a range of inhibitors that target the PI3K/Akt/mTOR pathway and after screening a selection of inhibitors, we identified 6 different inhibitors that demonstrated an increase in CFTR stability and expression. Mechanistically, we discovered the most effective inhibitor, MK-2206 exerted a rescue effect by restoring autophagy in ΔF508 CF cells. These findings highlight this pathway as a possible therapeutic avenue worth further exploration in Cystic Fibrosis.

This study was a collaboration between several groups at University College Dublin, Cystic Fibrosis Unit, St Vincent’s Hospital, Royal College of Surgeons in Ireland, Beaumont Hospital and the University of Mainz, Germany. Ongoing work in this area is taking place at the National Children’s Research Centre. Further details can be found here in a recent publication on this work.

The 13th World Congress of Biological Psychiatry

In keeping with the strategic objective of further increasing our international profile in the research domain, Professor John Waddington (Emeritus, MCT) has recently returned from the World Congress of Biological Psychiatry, Copenhagen, where he was invited to organise, Chair and speak in a symposium on ‘Psychosis is disrespectful to diagnostic boundaries: Nosological and pathobiological implications of psychoses beyond the schizophrenia spectrum’. He was also invited to Co-Chair and speak in a second symposium on ‘Beyond unitary models of psychosis: Confronting complex aetiology and dimensionality’. This reinforces the high standing in which our investigators are held in the international scientific community. 

Irish Centre for Vascular Biology Achievements

Bayer announced awards of $2 Million in Hemophilia Research and Patient-care Grants to 16 People at The International Society on Thrombosis and Haemostasis 2017, held in Berlin in July.

Congratulations to Dr. Roger Preston, Irish Centre for Vascular Biology[ICVB], (MCT) who was awarded a prestigious Special Project Award (€200,000) from the Bayer Haemophilia Award Programme to develop novel pro-hemostatic agents for the enhanced treatment of patients with haemophilia.

There was a strong representation from MCT at the ISTH Congress including Professor Dermot Kenny, Professor James O’Donnell, Dr. Roger Preston and their respective teams, and Dr. Dermot Cox, President, SSC* 2018. [*SSC:The Scientific and Standardization Committee].

Orla Willis Fox, Phd student with Dr. Roger Preston (ICVB/MCT), was awarded an ISTH Young Investigator Award for submitting one of the highest ranked abstracts. Her abstract title was ‘Inhibition of Activated Protein C Aspartyl Beta-hydroxylation Restricts Anticoagulant Function but Enhances Cytoprotective Signaling Activity’.

Professor James O’Donnell, ICVB/MCT presented an invited state-of-the-art lecture on his landmark studies on VWF and Cerebral Malaria,Dr. Michelle Lavin, ICVB/MCT on LOVIC [The Low Von Willebrand factor Ireland Cohort (LoVIC)] study, Dr. Sonia Agulia, ICVB/MCT on The Role of Sialylation in low VWF levels andSoracha Ward, ICVB/MCT gave a presentation on VWF Clearance.

Professor James O’Donnell at the International Society on Thrombosis and Haemostasis Congress, Berlin

Additionally, there was significant interest among the attendees in the ISTH SSC 2018 Annual Meeting which will be held in Dublin 2018;  Dr. Dermot Cox, President, SSC 2018 anticipates a record attendance of 3,000 delegates for the Dublin meeting. Olwen Foley , (MCT) managed the Irish stand.

ICVB/MCT

Orphan Drug Status for ALM201 for Ovarian Cancer

Over the last 10 years, Prof Tracy Robson has collaborated closely with Almac Discovery on the development of the therapeutic peptide, ALM201, based on her initial research into the anti-angiogenic properties of FKBPL.  ALM201 is part of the active anti-angiogenic domain of FKBPL and is a potent inhibitor of angiogenesis both in vitro and in vivo.  The technology was patented by Professor Robson and licensed to Almac Discovery.  Following collaborative pre-clinical work showing robust efficacy, this ‘first-in-class’ FKBPL-based antiangiogenic peptide has entered phase I/II clinical trials in the ovarian setting (EudraCT No: 2014-001175-31). Whilst the trial is ongoing, we have received exciting news that the U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation to the drug candidate ALM201 in the treatment of ovarian cancer. The FDA Office grants orphan drug designation to encourage the development of drugs for the prevention, or treatment of a medical condition affecting fewer than 200,000 people in the US and grants market exclusivity for a seven-year period if the sponsor complies with certain FDA specifications. Receiving Orphan Drug Designation for ovarian cancer underlines the fact that ALM201 may address a significant unmet medical need for this important disease.

Tracy Robson

Inflammasomes – key molecules in inflammation and novel targets for the treatment of inflammatory diseases

MCT Research Talks – 19th June 2017

Dr Rebecca Coll is a Research-Industry Fellow at the University of Queensland, studying innate immunity and novel anti-inflammatory drugs. Rebecca received her PhD in Immunology in 2013 under the supervision of Professor Luke O’Neill at Trinity College Dublin and moved to Associate Professor Kate Schroder’s group at the Institute for Molecular Bioscience in UQ in 2014. Over the last five years, her research has focused on inflammasomes – protein complexes at the heart of inflammation and disease – and how these complexes can be targeted therapeutically to prevent damaging inflammation.

Dr. Rebecca Coll

Rebecca led the biological characterisation of MCC950, a small molecule inhibitor of the NLRP3 inflammasome and an exciting prospect as a new therapy for treating patients with NLRP3-mediated diseases. In 2016, Rebecca received the Research Australia Discovery Award for her work on MCC950.

 

Claire McCoy

 

Imagine playing Marco Polo on the big football pitch?

Do you remember playing Marco Polo and trying to acoustically locate and tag the players? Imagine playing Marco Polo on the big football pitch when each player has their eyes closed and trying to locate a football. You would probably visualise the pitch in your head and try to create a virtual reality.
What if none of the players ever saw the pitch? Football? How could it be possible to play? Is it possible at all? I have never thought of that until recently. But, there are enthusiasts around who make the difference for blind people and let them enjoy football and the game. We are lucky to know one of them! It is our John O’Brien.

John has started the football coaching journey recently. He and Stephen Bolger (of our security team at Bilfinger) have been coaching the Irish National Blind Football team and are enrolled on the FAI (Football Association of Ireland) Coach Education Pathway. Under Stephen and John’s guidance, along with their fellow coaches, Ireland put in some great performances in the tournament and finished in sixth place – a great achievement for their first international tournament.

Adapted from the news by the RCSI Communication Department

Head of the MCT Department, Prof Tracy Robson says “It seems that as well as skilfully managing our MCT laboratories, John clearly has other hidden talents. It’s amazing that John is giving up his free time to coach the Irish National Football Team; a wonderful outreach activity. We are all very proud of you John…..”

You do not need to be millennials to create the world where everyone has a sense of purpose.

Come and ask John how he does it and what is next!

Olga Piskareva