Focal cortical dysplasia (FCD) is a malformation of cortical development and the most common cause of drug-resistant epilepsy, leading to epilepsy surgery in adults and children. Recently, somatic mutations in genes in the mechanistic target of rapamycin (mTOR) pathway have been identified in surgically resected human FCD tissue. The mTOR pathway plays key roles in nervous system development and mutations resulting in hyperactivation of the mTOR pathway cause different neurological diseases associated with epilepsy, autism and intellectual disability. This project combines the interests and expertise of Professor Joseph Bateman, an expert in mTOR signalling, and Dr Laura Mantoan, an expert in FCD and translational epilepsy research and clinical lead for adult epilepsy and epilepsy genetics at KHP. The aims of this project are (i) to investigate the molecular mechanisms by which hyperactivation of the mTOR pathway alters neurodevelopment and leads to epilepsy in FCD type II and (ii) to develop a drug screening platform as precision medicine tool designed for individual patients and their unique mutations. The overarching objectives for the PhD are:
Year 1 (or rotation): Generation of an induced pluripotent stem cell (iPSC) model of FCDII.
Year 2: Characterisation of iPSC model, analysis of neuronal phenotypes.
Year 3: In depth molecular and electrophysiological analyses of iPSC model and molecular analyses of FCD patient tissue.
Year 4: Development of individualised drug screening platform, correlation of iPSC and patient tissue data, manuscript and thesis writing.
Key skills taught will include: generation of iPSC cell lines and neuronal differentiation, gene editing, cutting-edge neurophysiological and imaging techniques (calcium imaging, microelectrode arrays, epilepsy models) and biochemical methods for analysing molecular changes in cultured neurons and patient cortical tissue. The student will be embedded in our mTOR Pathway Diseases node, part of the new NIHR/MRC UK Rare Diseases Research Platform.