Investigating molecular and physiological determinants of Sudden Unexplained Death in Epilepsy in acquired and genetic animal models of epilepsy

Research Opportunity
PhD, Masters by Research, Honours
Project Status
Future
Department
Medicine and Radiology
Location
Royal Melbourne Hospital
Supervisor Email Number Webpage
Dr Kim Powell kpowell@unimelb.edu.au Personal web page
Dr Pablo Casillas-Espinosa pablo.casillas@unimelb.edu.au Personal web page

Project Details

Epilepsy is associated with an increased risk of sudden unexplained death (SUDEP), possibly due to cardiac arrhythmias, although the precise mechanism remains unknown. SUDEP is considered the most impor¬tant direct epilepsy-related mode of death and accounts for up to 30% of all deaths in the epilepsy population, being particularly prevalent amongst young patients with uncontrolled or drug-resistant, frequent and severe generalized tonic-clonic seizures. Ion channels that coexist in the brain and heart would make ideal candidates for SUDEP because defects in intrinsic membrane excitability could predispose an individual to a dual phenotype of epilepsy and cardiac arrhythmias culminating in sudden death. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and T-type calcium channels play an important role in the generation of pacemaker activity in the brain and heart.

Furthermore, its functional role becomes more marked in the process of pathological cardiac hypertrophy and heart failure. Thus HCN and T-type calcium channels are attractive candidates for investigating molecular mechanisms of SUDEP. Our research has identified a cardiac transcriptional channelopathy of HCN2 and Cav3.1 and Cav3.2 T-type calcium channels, with associated detrimental cardiac electrophysiological changes, in rat models of both genetic generalised epilepsy (GAERS) and acquired temporal lobe epilepsy (kainic acid (KA) induced post-status epilepticus (SE)).

Several projects will be offered to investigate different aspect of SUDEP and cardiac dysfunction in animal models of genetic and acquired epilepsy

  • Project 1: To investigate the molecular mechanisms contributing to the cardiac dysfunction in genetic and acquired animal models of epilepsy.
  • Project 2: To investigate if decreased HCN2 expression translates to a decrease in HCN channel current (If) in cardiomyocytes in animal models of genetic and acquired epilepsy. Project 3: To investigate if by pharmacologically suppressing seizures we can alleviate the altered cardiac electrophysiological function and HCN2 and T-type calcium channel transcriptional repression
  • Skills: The skills expected to be learnt from this project include: Small animal handling and surgery, Drug testing in animal models of epilepsy, electrophysiology recordings and analysis, biochemical and molecular analysis (real time PCR, western blotting).

Research Opportunities

This research project is available to PhD, Masters by Research, Honours students to join as part of their thesis.
Please contact the supervisor to discuss your options.



Faculty Research Themes

Neuroscience

School Research Themes

Neuroscience & Psychiatry



Key Contact

For further information about this research, please contact a supervisor.

Department

Medicine and Radiology

Research Node

Royal Melbourne Hospital