Investigating molecular and physiological determinants of Sudden Unexplained Death in Epilepsy in acquired and genetic animal models of epilepsy
Group LeaderDr Kim Powell
T: +61 3 9035 6394
Location: Department of Medicine, Melbourne Brain Centre
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 important 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 on 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.
- Pablo Casillas, Post-Doc
- Emma Braine, Research Assistant
- NHMRC project grant
This research project is available to PhD students to join as part of their thesis.
Please contact the Research Group Leader to discuss your options.
- Powell KL, Jones NC, Kennard JTT, Ng C, Urmaliya V, Lau S, Ozturk E, Dezsi G, Megatia I, Delbridge LMD, Pinault D, Reid CA, White PJ, O’Brien TJ (2014) HCN channelopathy and cardiac electrophysiological dysfunction in genetic and acquired rat epilepsy models. Epilepsia 55(4):609-620.