Projects

Biophysical models of epileptic networks

Epileptic seizures are events that overtake entire brain networks. How seizures are triggered, how they spread and how they eventually terminate is poorly understood. In recent years, a number of epilepsy mutations have been identified and some of these have been introduced into mice thereby creating experimental models of human epilepsy. This gives us an unprecedented opportunity to understand how brains become epileptic. Part of this process will require building detailed biophysical models of brain networks, such as hippocampus, cortex or thalamus to link biophysical deficits at the molecular level to macroscopic behaviour at the network level. The project requires significant programming to build data import tools and for interaction with the simulation environment. The candidate will interact closely with experimental biologists, engineers and theoretical neuroscientists.

Ion transport blockers as antivirals

We have demonstrated that a number of amiloride derivatives have antiviral activity in tissue culture against viruses belonging to 2 medically important genera of the Picornavirus family: coxsackievirus B3 (CVB3, causes myocarditis) and human rhinovirus 2 (HRV2, a common cold virus). The compounds were more effective against CVB3 than against HRV2. Our data suggested that the antiviral activity against coxsackievirus B3 was due to inhibition of viral RNA replication, with the antiviral target likely to be a viral protein. In the case of HRV2, virus release from infected cells was also inhibited. We have generated amiloride-resistant CVB3 mutants by passaging the virus in the presence of the compound. We are currently sequencing the genomes of the resistant virus isolates to identify mutation(s) causing resistance, and thus identify viral protein(s) targeted by amiloride and its derivatives. Once the protein is identified, the studies will be conducted to elucidate the detailed mechanism of antiviral activity. We have analysed anti-CVB3 activity and cytotoxicity of 29 compounds belonging to a large group of chemicals, acylguanidines, which includes amiloride derivatives. The resulting structure-activity data were used to delineate medicinal chemistry strategy aimed at improving the antiviral activity and cytoxicity of the compounds.  

Multi-scale modelling of identified neural microcircuits

In our lab we are developing experimental techniques to fully map and interact with entire networks of cultured neurons at the cellular and sub-cellular level. These networks display complex dynamical behaviours that are thought to be the basis computation in the brain. Data from these networks provide an unprecedented opportunity for building and testing computational models of neural networks. Initially, models will be highly detailed using detailed morphology and electrophysiology to mimic the biological network in silico. Biological systems contain enormous numbers of complex nonlinear interactions but it is not known which of these are necessary for the tissue to perform its biological function and which there for other purposes (eg metabolic, development). A major aim of the this project is to explore simplified models that are able to capture the behaviour of the real network. The first part of the project requires significant programming to build data import tools and for interaction with the simulation environment. The second part requires application of multi-scale modelling techniques and mathematical analysis to guide reduction of the initial models.

In vitro analysis of epilepsy gene mutations

This is an ongoing project where epilepsy gene mutations discovered by genetic methods are subject to electrophysiological analysis to provide functional validation.  We employ a range of methods ranging from automated two electrode voltage clamp in Xenopus oocytes to whole cell patch clamp and cell biological studies using GFP fusions or antibody staining.