Project title
Understanding the cellular and genetic development of childhood epilepsy
Supervisors
Background
Epilepsy is the most common severe neurological disease in children. Some children are severely disabled by their epilepsy, presenting with frequent seizures early in life. In this group of children, structural abnormalities of the brain are frequent, and these children require surgery to control their seizures.
The structural abnormalities are usually developmental lesions of the cerebral cortex caused by somatic, or sometimes germline, genetic variants. The commonest subtypes are Focal Cortical Dysplasia (a group of malformations often associated with genetic variants in mTOR pathway genes) and Long-Term Epilepsy Associated Tumours (LEATs, developmental tumours associated with variants in MAP Kinase genes).
Our understanding of the pathogenesis of these lesions is limited because we understand little of the diversity of abnormal cell types within them, how they arise during development or how these different cell types interact to cause the disease.
We have identified particular cell types and cellular phenotypes that characterise different molecular subtypes of FCD and LEATs. In this project, the student will extend this work to investigate how different genetic variants determine the cellular composition of the lesions and how these map onto normal development.
Aim
The aim is to understand the pathogenesis of structural causes of childhood epilepsy. In particular, the student will identify the cellular composition of these cortical lesions and map them to the normal developmental pathways.
Methods
The project will use human tissue removed at epilepsy surgery to investigate the cellular composition of the lesions. Two complementary strategies will be used to identify the cellular composition of the lesions: 1) Using bulk profiling data (e.g., from RNA sequencing) to deconvolute the cellular composition of the lesion, and 2) using cell technologies (e.g., single-nucleus RNA sequencing) to directly identify cell types and cell states within the cortical lesions. This data can be mapped against existing developmental pathways and correlated with the underlying genetic drivers. Finally, this will make predictions that can be tested directly in the tissue, either via immunohistochemistry or using cell cultures.
Timeline
- Year 1 – Training in the use of tissue and informatics. Bioinformatics of existing datasets and preparation of additional tissue for single-cell sequencing.
- Year 2 – Further genomic analysis and validations based on the preliminary data from year 1.
- Year 3 – Validation of findings and writing up.
References
- Stone et al. (2023) DNA methylation‐based classification of glioneuronal tumours synergises with histology and radiology to refine accurate molecular stratification Neuropathology and Applied Neurobiology 49:e12894.
- Li et al. (2021) Identifying cellular signalling molecules in developmental disorders of the brain: Evidence from focal cortical dysplasia and tuberous sclerosis Neuropathology and Applied Neurobiology 47:781-795.
- Stone et al. (2018). Comprehensive molecular characterisation of epilepsy-associated glioneuronal tumours. Acta Neuropathologica, 135:115-129.
- Blumcke et al. (2018). Histopathological Findings in Brain Tissue Obtained from Epilepsy Surgery. New England Journal of Medicine, 377:1648-1656.
- Yasin et al. (2013). mTOR-dependent abnormalities in autophagy characterize human malformations of cortical development: evidence from focal cortical dysplasia and tuberous sclerosis. Acta Neuropathologica, 126:207-218.
Who should students contact?
Tom Jacques (t.jacques@ucl.ac.uk)
Research topic
Developmental Biology, Genetics