Mechanism of signal transduction in order to understand the driving forces of disease progression and to identify targets for therapy.

Identified that the pro-inflammatory cytokines interleukin-1b and interferon g act in synergy to induce beta-cell death and thus contribute to type I diabetes. Induction of nitric oxide synthase is necessary and sufficient to cause pancreatic beta cell apoptosis. Current in vivo studies assess the potential of IFNg neutralization to revert the progression of type I diabetes and promote pancreas recovery.

The potential of adult MSCs to repair ischemic heart damage was studied. The contribution of the components of ischemic conditions (hypoxia, nutrient deprivation, oxygen deprivation, inhibition of glues metabolism) to loss of cardiac muscle contractility and cell death was determined. Found that MSCs well tolerate the conditions which are damaging to cardiomyocyte function and survival. MSCs are able to retain functionality during prolonged ischemia by surviving on glycolytic energy production. Active glycolysis on the other hand provides an essential survival factor in MSCs and inhibition of glycolysis triggers rapid MSC death.

Regulation of apoptotic pathways in cancer cells and to the engineering of death ligands (TNF family of cytokines) for selective death receptor activation or receptor neutralization.

First demonstration that high affinity, receptor-selective variants of the death ligand, TRAIL, generated by computational design are more efficient death receptors activators and inducers of tumour cell death than wild type TRAIL. Found that the apoptosis-inducing potency of TRAIL is limited by its promiscuity, i.e. its ability to bind to four receptors due to formation of inactive heteromeric receptor complexes and fast kinetics of receptor activation is a key element in induction of apoptosis. Identified point mutations in TRAIL that provide receptor selectivity and thus enhance anti-tumour efficacy.

Current studies aim to develop a so called ratiometric analysis of protein expression. The working hypothesis is that rather than the absolute amount of a given protein, its amount relative to other proteins playing a role in a given biological process (i.e. the expression ratio of proteins) determines the biological response of a cell to any given stimulus.

Sara Cahill B.Sc.; H. Dip. Micro; M.Sc., 2002-2006

       Ph.D. thesis Title: Mechanisms and of caspase activation in T cell activation

Eoin Murphy, B.Sc., 2006-2008

       M.Sc. thesis title: TRAIL and Bortezomib: a dual targeted approach against acute myeloid leukaemia

Louise Mylotte, B.Sc., 2004-2008

       Ph.D. thesis title: Mechanism of mesenchymal stem cell-mediated cardiac repair

Deva Mahalingam, MB BCh BAO, MRCP(UK) & MRCP(I), 2005-2009

       Ph.D. thesis title: Novel regulators of TRAIL-induced apoptosis

Marianne van Dijk, M.Sc., 2007-2011

       Ph.D. project title: Mechanism of TRAIL resistance in non-transformed cells

1. Prof. Michael O’Dwyer (Haematology, UCHG), 
2. Prof. Paul Murphy (Chemistry), 
3. Prof. Lokesh Joshi (Head of Glycoscience Research Cluster, National Centre for Biomedical Engineering Science), 
4. Prof. Cathal Seoighe (Stokes Professor of Mathematics, Department of Mathematics), 
5. Prof. Afshin Samali (Head of ER Stress Research Group;  Discipline of Biochmeistry), 
6. Dr. Adrienne Gorman (Head of Cell Death and Cell Survival group; Discipline of Biochemistry); 
7. Dr. Ralf Zwacka (Head of Molecular Therapeutics Group; NCBES)