Project ID NS-MH2024_04


Co Supervisor 1A Institute of Psychiatry, Psychology & Neuroscience, School of Neuroscience, Department of Basic & Clinical NeuroscienceWebsite

Co Supervisor 1B Institute of Psychiatry, Psychology & Neuroscience, School of Neuroscience, Department of Basic & Clinical NeuroscienceWebsite

Additional Supervisor Prof. Deb Pal

Investigating novel molecular mechanisms causing focal cortical dysplasia

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.

Representative Publications

P. Baskaran, S.R. Mihaylov, E. Vinsland, K. Shah, L. Granat, S.K. Ultanir, A.R. Tee, J. Murn, J.M. Bateman (2022). Phosphorylation of the novel mTOR substrate Unkempt regulates cellular morphogenesis. J. Biol. Chem. 299: 102788.

M. Girodengo, S.K. Ultanir, J.M. Bateman (2022). Mechanistic target of rapamycin signaling in human nervous system development and disease. Front. Mol. Neurosci. 15: 1005631. K.T. Maierbrugger, R. Sousa-Nunes, J.M Bateman (2020). The mTOR pathway component Unkempt regulates neural stem cell and neural progenitor cell cycle in the Drosophila central nervous system. Dev. Biol. 461: 55-65.

Jindal M, Delaj L, Winston J, Goel R, Bhatti S, Angelova- Chee M, Selway R, Mantoan Ritter L. Safe and effective implantation and use of vagal nerve stimulation in new-onset refractory status epilepticus in early pregnancy: a case report. Front. Neurol., 15 May 2023 Sec. Epilepsy Volume 14 – 2023 |

Mantoan Ritter L, Macdonald DC, Ritter G, Escors D, Chiara F, Cariboni A, Schorge S, Kullmann DM, Collins M. Lentiviral Expression of GAD67 and CCK Promoter-Driven Opsins to Target Interneurons in Vitro and in Vivo. J Gen Med, 2016 Jan-Mar;18(1-3):27-37.

Wykes RC*, Heeroma JH*, Mantoan L*, Zheng K, Macdonald DC, Deisseroth K, Hashemi KS, Walker MC, Schorge S, Kullmann DM. * joint first authors. Optogenetic and Potassium Channel Gene Therapy in a Rodent Model of Focal Neocortical Epilepsy. Science Translational Medicine 2012;4(161):161fs40.