Enhancing the face validity of mouse models of single gene childhood-onset epilepsies

·        Background

The ease of use of gene editing tools developed over the last 5 years has resulted in many new models of genetic epilepsies that recapitulate clinical mutations precisely. However, in spite of the severity of the conditions being modelled, these new mouse lines frequently display phenotypic abnormalities but stop short of showing face validity in the form of spontaneous seizures, at least at a high enough frequency to be readily observable. Clearly any therapeutic strategy (whether genetic or drug-based) needs to be tested on suitable animal models, but the translational potential of such studies is limited if there is no ability to test the impact of the intervention on seizures.

·        About the Project

In this project the student will explore several different approaches to solving the problem of low frequencies/absence of spontaneous seizures in the context of one to two specific genes in which de novo mutations cause childhood-onset epilepsy (such as EEF1A2 and CDKL5), and for which well characterised mouse models are available. The use of multiple lines will allow the student to make direct comparisons and judge how widely applicable any specific approach would be. They will explore a range of different methods to enhance face validity including continuous EEG monitoring, in-cage behavioural monitoring coupled with video recording, altering the genetic background of the parent strain, and measuring the threshold for seizure induction.

The student will, in parallel, also investigate molecular mechanisms underlying at least one of these genetic disorders; this could range from the use of proteomics to look at changes in binding partners resulting from specific mutations, to detailed characterisation of expression patterns in specific neuronal populations and/or mapping expression throughout the brain using lightsheet microscopy. This combination of sub-projects will allow the student to be trained in a wide variety of lab disciplines from basic to preclinical research. This approach will also allow the student to generate their own hypotheses to be tested in the later stages of the PhD. They will thus combine important research into practical solutions for the development of face valid preclinical models to maximise their translational potential, with more fundamental research into mechanisms underlying childhood-onset epilepsies. 

About the ERUK-DTC

The ERUK-DTC consists of principal investigators from the University of Edinburgh researching childhood-onset epilepsies. In addition to your research, you will be trained and nurtured to become an innovative, creative thinker, will be trained in state of the art techniques, will gain insight into the needs and thoughts of patients and their families, and become equipped to engage with audiences within and beyond the research world. As an ERUK-DTC graduate, you will be ideally placed to be part of the next generation of scientific research leaders in childhood-onset epilepsies. (For more on the ERUK-DTC, see Muir Maxwell Doctoral Training Centre)

Application procedure

You should hold at least an upper second-class degree or equivalent in a relevant discipline (e.g., genetics, neuroscience). Applications should be emailed to [Email Address Removed] (with “ERUK-PhD” in the subject) including: (i) your CV; (ii) a personal statement (research interests, reasons for applying); (iii) any additional information you would like to be considered e.g., special circumstances/disadvantages faced (optional; 150 word limit). Applicants should also arrange for two academic referees to submit letters of reference via email before the deadline to Cathy Abbott ([Email Address Removed]). All documents should be submitted no later than 5pm on January 9^th, 2023. Short-listed candidates will be notified by email.

Informal enquiries can be sent to [Email Address Removed] or [Email Address Removed]