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Full NameProfessor Gerard Curley
Department:Dept of Anaesthesia and Critical Care
Organisation:Royal College of Surgeons in Ireland
- infectious disease and the immune system
- cell and developmental biology/regenerative medicine
- physiology and non-communicable disease
Postgrad Medical Specialties
- Emergency Medicine
- Infectious diseases
- Respiratory Medicine
Other Medical Specialties:
Intensive Care Medicine
Two areas are under study in my laboratory.
(1) The first investigates optimization of novel therapies, including mesenchymal stem cell (MSC) therapy, for Acute Respiratory Distress Syndrome and sepsis. We use in vitro functional assays (epithelial and endothelial permeability and wound repair, monocyte inflammation, polarization status, phagocytosis and bacterial killing), conventional animal models (rodent and murine Ventilator Induced Lung Injury, LPS, E. coli pneumonia, caecal ligation and puncture), large animal models and the isolated perfused human lung to test promising therapeutic strategies.
(2) The second investigates the mechanism of action of MSCs during inflammation and repair. We are examining the fate of MSCs in the pulmonary vasculature using a microfluidics device in vitro and intra-vital sub-pleural imaging in live mice. We are also focused on the interaction of MSCs with monocytes and macrophages, and in particular on macrophage phenotype, phagocytosis and bacterial killing as a key therapeutic effect of MSCs in sepsis. We have identified a novel MSC-induced macrophage phenotype with enhanced microbicidal capability, including NADPH-oxidase 2 (NOX2) mediated reactive oxygen species production during phagocytosis. Other work aims to identify the molecular mechanisms underpinning receptor-mediated phagocytosis in MSC-educated macrophages.
1. Curley GF, Jerkic M, Dixon S, Hogan G, Masterson C, O’Toole D, Devaney J, Laffey JG. Cryopreserved, xeno-free human umbilical cord mesenchymal stromal cells reduce lung injury severity and bacterial burden in rodent E. coli induced Acute Respiratory Distress Syndrome. Crit Care Med. 2017 Feb;45(2):e202-e212.
2. McAuley DF, Curley GF, Hamid UI, Laffey JG, Abbott J, McKenna DH, Fang X, Matthay MA, Lee JW. Clinical grade allogeneic human mesenchymal stem cells restore alveolar fluid clearance in human lungs rejected for transplantation. Am J Physiol Lung Cell Mol Physiol. 2014 May 1;306(9):L809-15.
3. Curley GF, Ansari B, Hayes M, Devaney J, O’Toole D, O’Brien T, Laffey JG. Effects of intra-tracheal Mesenchymal Stem Cells therapy during recovery and resolution following Ventilator Induced Lung Injury. Anesthesiology. 2013 Apr;118(4):924-932.
4. Curley GF, Hayes M, Ansari B, Shaw G, Ryan A, Barry F, O’Brien T, O’Toole D, Laffey JG. Mesenchymal stem cells enhance recovery and repair following ventilator-induced lung injury in the rat. Thorax. 2012 Jun;67(6):496-501.
5. Curley GF, Contreras M, O’Toole B, Higgins B, O’Kane C, McAuley D, Laffey JG. Evolution of the inflammatory and fibroproliferative responses during resolution and repair following Ventilator Induced Lung Injury. Anesthesiology. 2011 Nov;115(5):1022-32.
Severe sepsis and septic shock are the biggest cause of mortality in critically ill patients, and contribute to one-half of hospital deaths (Liu, JAMA, 2014). Improved treatment of sepsis could offer meaningful improvements in population mortality. We have demonstrated that Mesenchymal Stem Cells (MSC) offer considerable promise as a novel therapeutic strategy for sepsis. However, techniques to understand, measure and control the potency and persistence of MSC are needed. A key interaction is that of MSC and monocytes/macrophages. Macrophages are a central component of the mechanism by which MSC can mediate microbial killing and limit injurious inflammation. However, the mechanisms by which MSC reduce inflammation and enhance bacterial clearance are poorly understood.
We hypothesize that MSC enhance monocyte recruitment, macrophage phagocytosis and bacterial killing via release of extracellular vesicles (EVs) containing lipids capable of influencing macrophage phenotype. In ongoing work we have demonstrated that MSC recruit monocytes and enhance phagocytosis, induce a mixed population of M1- and M2-like macrophage, with enhanced NOX2 activation, ROS production and bacterial killing in some cells. A clear mechanistic understanding of these novel insights can predict MSC clinical efficacy, allow rational manipulation of MSC for enhanced effect and identify novel small molecule alternatives to cells in sepsis. This provides a strong rationale to explore the mechanisms of MSC-induced polarization and bacterial killing in macrophages as a determinant of MSC mechanism of action in sepsis, with impact on the use of this therapy in clinical trials.
We will use novel experimental models including confocal imaging of phagocytosis/phagolysosome maturation, multi-channel flow cytometry of MSC-extra-cellular vesicles, intra-vital imaging of intact mouse lung, and the clinically relevant isolated-perfused human lung to further our understanding of MSC kinetics and MSC interactions with macrophages during infection and lung injury.