Targeting Purinergic Pathway in drug-resistant epilepsy using human Neurons and Glia.

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Epilepsy is a neurological disorder characterized by recurrent seizures affecting 65 million people worldwide of which 6 million live in Europe alone with around 30% of patients not responding to currently available treatment. The ATP-gated P2X7 receptor (P2X7R) has recently emerged as a promising target for epilepsy, showing anticonvulsant and disease-modifying properties in animal models. However, to develop P2X7R-based therapeutics the cell types involved in pathological P2X7R activation must be determined, and whether results from rodent models can be replicated in human tissue must be tested. Using human induced pluripotent stem cell-derived neurons and glia and resected brain tissue from epileptic patients, TaPPiNG-EPI proposes to investigate the cell-specific alterations and pathological contribution in the P2X7R pathway and pharmacological targeting of hyperexcitability using P2X7R antagonists. These studies will be complemented by the investigation on the alterations in P2X7R pathway in GFP-P2X7 reporter mice available in the host institution (RCSI). Through international secondments and intersectoral collaborations TaPPiNG-EPI brings together experts in purinergic signalling, industrial partners, epilepsy clinicians as well as leading European academic labs with diverse expertise. The interdisciplinary and intersectoral components of TaPPiNG-EPI combined with international collaborations and secondments in academia, the excellent training record of the supervisor and RCSI and the outstanding resources for learning and development available at RCSI will give me the tools necessary to achieve research independence and my transition to a highly employable future neuroscientist with a focus on epilepsy.