Insight into the neuroprotective function of the prostaglandin receptor EP2
Supervisors:
Dr Bianca Plouffe, School of Medicine, Dentistry, and Biomedical Sciences and Wellcome-Wolfson Institute for Experimental Medicine (Queen's University Belfast)
Dr Brian Hudson, School of Molecular Biosciences (University of Glasgow)
Dr Irina Tikhonova, School of Pharmacy (Queen's University Belfast)
Summary:
Following a brain injury or in neurodegenerative diseases, neurons are damaged, promoting the release of glutamate. Excessive glutamate level is toxic for adjacent neurons, a phenomenon termed as excitotoxicity. To limit the extent of neuronal damage upon injury, the neuroprotective prostaglandin receptor EP2 is activated by the neurons. Unfortunately, the molecular mechanisms involved in EP2-mediated neuroprotection remain largely unknown. The student in charge of this project will identify the key signaling pathways and genes involved in EP2-mediated neuroprotection. This information will facilitate the design of new treatments to limit the adverse consequences of brain injury and neurodegenerative diseases.
Recently, molecules potentiating the activity of EP2 were discovered and reported to reduce excitotoxic damage to neurons. However, the region of EP2 where these molecules bind is unknown. The student will use cutting-edge computational approaches to predict these binding sites, as well as mutagenesis combined with cell-based assays to validate the predictions. The knowledge of the binding sites will be used to design improved molecules. The neuroprotective properties of these improved molecules will be tested in models of neuronal excitotoxicity. Overall, this studentship will develop a wide portfolio of computational and experimental competences highly valuable in drug design research in academia or industry.