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Transfer RNA fragments in the mechanism and treatment of epilepsy

  • Full or part time
    Prof D Henshall
    Dr M Hogg
  • Application Deadline
    Monday, December 02, 2019
  • Competition Funded PhD Project (Students Worldwide)
    Competition Funded PhD Project (Students Worldwide)

About This PhD Project

Project Description

Epilepsy is a neurological disorder caused by hyperexcitable brain networks that give rise to seizures. Many epilepsies have a genetic cause whereas some develop following a brain injury. Epilepsy affects around 50 million people worldwide and approximately 1 in 3 people with epilepsy do not respond to currently available medication. This leaves many people with uncontrollable seizures that can occur at any time with little warning. An improved understanding of the mechanisms of epilepsy is needed to discover new targets for seizure control and disease modification.

Researchers within the FutureNeuro Research Centre at RCSI have made pioneering discoveries about the role of noncoding RNAs in epilepsy (see http://www.futureneurocentre.ie). Most recently, we identified a completely new class of signalling molecule derived from transfer RNAs (tRNAs) – noncoding RNA molecules that help build the amino acid chains that make up proteins in all cells. We found fragments of tRNAs were elevated in patients with epilepsy in advance of a seizure occurring (Hogg et al, J Clin Inves 2019). This suggests it might be possible to predict when a seizure will occur by monitoring levels of these tRNA fragments in the blood. Efforts are now underway to develop a device capable of rapidly measuring these fragments in blood samples to enable people with epilepsy to assess their seizure risk at home. A short video explaining our research can be found at https://youtu.be/rzbKVCzgfCE, and our discovery was reported in the Irish Times here: https://www.irishtimes.com/news/health/irish-breakthrough-in-predictingepileptic-seizures-may-lead-to-simple-test-1.3920010.

The objective of this StAR PhD project will be to establish when, how and why these tRNA fragments are generated in the epileptic brain and what they are doing. We know that tRNAs are cleaved as part of a highly conserved stress response. Starting with this knowledge, you will model and study seizure-like activity in models of human epilepsy, employing a variety of cell and molecular techniques to identify the link between neuronal activity, stress and tRNA fragment production and release. To understand their function, you will knock-down or over-express individual and combinations of tRNAs using pharmacologic, imaging, genetic and electrophysiological techniques, to study what happens to cell and network behaviour when they are manipulated. The results will advance our understanding of this major new class of molecule linked to epilepsy and new approaches to treatment and prevention.

Your research project will be supervised by experts in tRNA biochemistry and epilepsy and carried out in the world-class laboratories at RCSI including the SFI-funded FutureNeuro Research Centre. This provides access to multi-disciplinary teams of scientists including geneticists, neuroscientists, pharmacologists, biochemists, imaging experts and clinicians. You will gain experience with cellular models of epilepsy including primary cell culture and iPSC-derived neurons, cell and molecular imaging, small RNA purificationand analysis techniques, antisense knockdown, and electrophysiology. When completed, you will have gained a broad range of molecular, cellular and neuroscience techniques along with specialised techniques for epilepsy research, such as electrophysiology and have contributed to understanding new disease mechanisms.

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