Excitotoxicity occurs upon brain injury or neurodegenerative diseases and exacerbates associated neuronal damages. The prostaglandin E2 receptor (EP2) has neuroprotective properties against excitotoxicity and novel molecules increasing EP2 activity have been recently discovered. Our project aims to identify the EP2 allosteric sites of these molecules to enhance their neuroprotective effect.
Following a brain injury or in neurodegenerative diseases, neurons are damaged, promoting the release of an excitatory neurotransmitter called 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 E2 receptor 2 (EP2) is activated by the neurons.
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 identification of the EP2 residues binding to these molecules can facilitate optimisation of these compounds to potentiate even more their neuroprotective potential.
The student in charge of this project will use cutting-edge computational approaches to predict EP2 binding sites. Then, using site-directed mutagenesis and bioluminescence resonance energy transfer (BRET)-based biosensors, the student will validate the predictions in a heterologous cellular model. Finally, using CRISPR/Cas9 technology, the student will validate in a physiologically relevant neuronal cellular model the EP2 binding sites by functional assays monitoring neuronal excitotoxicity.
This hybrid dry/wet lab approach will stimulate the development of strong computational and experimental skills required for drug design research, which are highly desirable assets in both academia and industry.
*Please note this project is under joint supervision between the School of Pharmacy and School of Medicine, Dentistry and Biomedical Sciences
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