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Full NameProfessor Colm O'Brien
Organisation:University College Dublin
Other Research Fields:
Postgrad Medical Specialties
Other Medical Specialties:
The lab explores the role of lamina cribrosa (LC) cells in the ECM remodelling of the LC in glaucoma. Even in the ex-vivo cell culture environment, glaucoma LC cells show a pro-fibrotic pattern of ECM gene production, and epigenetic changes such as DNA methylation. Demonstrating expression of the myofibroblast phenotype marker alpha-SMA, we have investigated how these cells respond to glaucoma like stimuli such as TGF beta, cyclic stretch and hypoxia. These cells also have markers of oxidative stress, mitochondrial dysfunction and raised intracellular cytosolic calcium and signalling pathways eg the NFAT/calcineurin pathway. They have mechano-sensitive ion channels such as the maxi-k and L-type calcium channels. Currently we are looking at other mechano-sensitive mechanism such as integrins and substrate stiffness. To date, we have supervised over 40 post-graduate student thesis degrees (PhD, MD, MSc) to completion.
Title: Investigate the Effects of Substrate Stiffness on Lamina Cribrosa Cell Bioenergetics in Glaucoma
Cupping of the optic nerve in glaucoma results in a thin, stiff lamina cribrosa (LC), due to extracellular matrix (ECM) remodelling causing compression and collapse of the LC beams. Risk factors include elevated intraocular pressure and reduced ocular perfusion pressure, which, at a biological level, result in cell membrane stretch and oxidative stress. Age is also a significant factor with resultant increase in tissue stiffness. LC cells involved in the ECM remodelling express markers of myofibroblast activation (alpha-SMA), mitochondrial dysfunction and elevated in intracellular calcium – which are also features of ‘cancer associated fibroblasts’. CAF utilise energy substrates other than oxidative phosphorylation (eg glutaminolysis, one carbon metabolism) to maintain and ‘feed’ their rapidly proliferating cells, and have become a major focus in cancer research due to the possibility of cutting off these alternative energy supplies to kill off the CAF. We have pilot data indicating similar abnormalities in the activated glaucoma myofibroblast LC cells. Our goal, in this thesis project, is to investigate the effect of increased substrate stiffness on the bioenergetics and metabolomics pathways in the glaucoma LC cells, focussing in particular on the role of the YAP/TAZ mechanosensors, and the glutaminolysis pathway, looking at potential therapeutic targets using functional assays such as proliferation, migration and contractility.