Translating Bio-Repositories into New Clinical Insights

MCT Research Forum – February, 25th 2019 at 12.00, Cheyne LT

Prof. Paul McNally – “Biorepositories in Childhood Cystic Fibrosis: A Journey of Discovery”
Paul graduated from the UCD School of Medicine in 1998. He completed his paediatric medical training in Ireland, and subsequently completed a 2-year MD in Cystic Fibrosis (CF) lung disease in the Royal College of Surgeons in Ireland. Paul undertook pulmonology fellowship training in the Children’s Hospital of Philadelphia from 2007 to 2009. He was appointed as a consultant in Paediatric Respiratory Medicine at Our Lady’s Children’s Hospital (OLCHC) in 2009. In August 2015, Paul was appointed as Associate Professor of Paediatrics at RCSI. Paul is director of the CF centre in OLCHC and leads the CF research group at NCRC. Paul is clinical lead for Paediatric Respiratory Medicine in the Dublin Paediatric Hospitals. He is a board member of the CF Registry of Ireland and the National Children’s Research Centre. Paul is a member of the working group of the National Clinical Programme for Cystic Fibrosis and is a member of the advisory board for the National Clinical Programme for Paediatrics. Paul has recently been appointed as the director of research and innovation for Children’s Health Ireland (Dublin’s three children’s Hospitals). Paul’s main research interest is early CF lung disease, in particular around the question of why some children have more severe lung disease, and how we can detect these children earlier and modify their treatment.

Dr. Michelle Lavin – “The future of data repositories and e-Health in Irish clinical research”
Dr. Michelle Lavin is a Consultant Haematologist and the Clinical Lead for the Irish Personalised Approach to the Treatment of Haemophilia (iPATH) study, based in the Irish Centre for Vascular Biology, RCSI. She completed her PhD in Trinity College Dublin, focused on the pathophysiology and clinical impact of Low Von Willebrand Factor (VWF) levels. Her research is centred on inherited bleeding disorders; developing insights into phenotypic variability and working to improve clinical outcomes. She serves a Co-Chair on the International Society on Thrombosis and Haemostasis (ISTH) VWF Scientific Subcommittee and a clinical advisor to the World Federation of Haemophilia.

Chair: Soracha Ward
A light lunch will be served after the talks

Sponsored by Biosciences

MCT Research Forum – Friday 25th January at 3.00pm

Professor David Ray

“Circadian control of inflammation; stories from the lung”

David trained in general internal medicine in North West England, and obtained a PhD from the University of Manchester. He was a research fellow at UCLA for two years, working on neuroendocrine-immune interaction, before returning to the UK, and obtaining a GSK fellowship to work on glucocorticoid action, and sensitivity in inflammatory disease. He was promoted to Professor of Medicine at the University of Manchester in 2005, and went on to study nuclear receptor and circadian biology in inflammation, and energy metabolism. This work attracted Wellcome Investigator and MRC programme grant support. David is a passionate advocate of research training, serving on the MRC clinical fellowship panel for seven years, three as deputy chair.

Circadian mechanisms regulate most mammalian physiology, with particular importance in the regulation of innate immunity, through the macrophage in particular, and energy metabolism, regulating liver, adipose and muscle. These circuits are also regulated by a number of nuclear receptors, which show a striking interdependency on the circadian machinery; some having ligand availability regulated by the clock, others varying in expression level through the day. We have employed a range of approaches to address the physiological importance of the circadian: nuclear receptor system, ranging from population genetics, experimental medicine studies, CRISPR engineered mice, and cell biology. These approaches have discovered how the important dimension of time regulates metabolism, and coordinates diverse tissues to deliver optimal organismal performance. Importantly, we are identifying how external stressors can decouple these systems, with deleterious effects.

Dr. Judith Coppinger

“Increased extracellular vesicles mediate inflammatory signalling in Cystic Fibrosis”

Judith obtained her PhD from Department of Clinical Pharmacology, RCSI in 2004 before undertaking postdoctoral training at the Scripps Research Institute, San Diego, on new folding mechanisms in Cystic Fibrosis. In 2011, she joined the University of California, San Diego as a faculty member before receiving an SFI award and returning to Ireland. In 2013 she became a principal investigator at University College Dublin where she set up basic/translational research programs in Cystic Fibrosis and Cancer (lung/breast). Judith’s overall research has focused on using omics-based approaches to decipher protein interaction networks dysregulated in disease and identify new therapeutics to target these pathways. Her research projects include examining the therapeutic restoration of CFTR using kinase inhibitors in Cystic Fibrosis and examining exosomes in regulating inflammatory signalling in Cystic Fibrosis at the National Children’s Research Centre. Other projects include investigating BAG3 as a therapeutic target regulating signalling transduction pathways in breast/lung cancer subtypes. Dr. Coppinger is a senior lecturer at the RCSI and a principal investigator at National Children’s Research Centre since 2017.

George Timmons

“Mitochondria – A link between innate immunity, metabolism, and the clock”

George Timmons is a PhD student of the Curtis Clock Lab, led by Dr. Annie Curtis and is part of the Department of Molecular and Cellular Therapeutics and Tissue Engineering Research Group at RCSI. George began his PhD in October 2016 and is now in the 3rd year of his studies. The Curtis Clock Lab focuses on circadian immunometabolism – a new field which looks into the relationship between the molecular clock, cellular metabolism, and immune responses. Specifically, George’s project is investigating how the core clock gene Bmal1 impacts upon mitochondrial metabolism and how these metabolic changes can impact upon the inflammatory response of macrophages.

When: January 25th 2019 at 3.00pm – 4.30pm

Where: Cheyne Lecture Theatre

Tea Coffee and Cookies sponsored by Biosciences will be at 2.30pm

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.