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The role of circadian genomics in epilepsy and pharmaco-resistance


   School of Life Sciences

  Dr Krithika Sundararaman, Dr Francesca Panin, Assoc Prof Arjun Sen  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Research group

Biomedical Research Group - https://aru.ac.uk/science-and-engineering/research/institutes-and-groups/biomedical

Proposed supervisory team

Dr Krithika Sundararaman - https://aru.ac.uk/people/krithika-sundararaman

Dr Francesca Panin - https://aru.ac.uk/people/francesca-panin

Dr Arjun Sen (University of Oxford)

Themes

Genetics - https://aru.ac.uk/science-and-engineering/research/institutes-and-groups/forensic-and-investigative/genetics

Bioinformatics

 

Summary of the research project

This project aims to explore one of the promising areas of epilepsy genetics: the role of clock genes in development of seizures and its contribution to pharmaco-resistance in epilepsy.

Epilepsy is a distressingly common neurological disorder characterised by aberrant bursts of electrical activity in the brain, or seizures, leading to various symptoms, including altered consciousness, unusual behaviours, and uncontrolled movements. Literature shows an apparent link between both seizure frequency and type of epilepsy to the circadian cycle - the internal process that regulates our daily physical, mental and behavioural changes. Circadian rhythm is the result of the expression of a set of clock genes. The interaction, regulation and expression of clock genes is vital for the homeostasis and tuning of many important functions, including the sleep/wake cycle and day/night activity patterns. Recent studies demonstrate that clock genes are altered in neurodevelopmental disorders and identified common associations between seizures and sleep-wake states. The frequency of seizures can be associated to a specific time of the day, for example being highest in the middle of the wake period, thus suggesting an important role of ‘time-of-day’ factors in the expression of the seizures. It can, therefore, be hypothesised that alterations of specific clock genes link to the onset of seizures and to the type of epilepsy. Exploration of whether circadian rhythms control distinct mechanisms of neuronal hyperexcitability might offer new insights into seizure genesis and lead to new therapeutic strategies. One further application will also be to identify specific associations between disrupted clock genes/mechanisms and pharmaco-resistance in epilepsy, which is failure to achieve seizure control with anticonvulsant medications. Specific associations between altered clock genes/mechanisms and epilepsy will serve as biomarkers of vulnerability to epilepsy and pharmaco-resistance and will facilitate the development of personalized treatments in the longer run.

Methodology

To address the aims and objectives of the proposed study, data from the 100,000 genomes project, led by Genomics England, will be used. The neurology domain of the Genomics England project (GEL) comprises the whole-genome sequencing (WGS) data of thousands of people with epilepsy, including their detailed clinical information and family history. We already have access to the GEL research environment and any new projects are readily approved by the GEL research team. The whole-genome sequences of epilepsy cases will be screened for rare variants in a curated list of clock genes by utilizing different bio-informatic tools involved in next generation sequencing data analysis. The variants will further be analysed for different parameters, including their frequency in different public databases and their pathogenicity, which will be evaluated using in-silico tools. The final set of credible clock gene variants will be clinically evaluated using the available clinical information of these cases.

Expected outcomes

Better understanding how circadian mechanisms contribute to regulation of seizures would have important clinical applications including: i) diagnosing the type of epilepsy, ii) determining specific associations between the onset of seizures and alterations of genes that regulate sleep patterns iii) identifying possible causes for pharmaco-resistance.

Where you'll study

Cambridge - https://aru.ac.uk/science-and-engineering/research/institutes-and-groups/forensic-and-investigative/genetics

Funding

This project is self-funded.

Details of studentships for which funding is available are selected by a competitive process and are advertised on our jobs website - https://aru.ac.uk/about-us/working-

here as they become available.

Next steps

If you wish to be considered for this project, you will need to apply for our Biomedical Science PhD - https://aru.ac.uk/study/postgraduate/biomedical-science-research . In the section of the application form entitled 'Outline research proposal', please quote the above title and include a research proposal.


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