Ion Channels and Human Disease Group
- Dr Steve Petrou
Group Leader
Dr Steven Petrou BSc (Hons) (Melb) PhD (Melb)
Contact Details
Email: | |
Phone: | +61 (0)3 8344 1957 |
Fax: | +61 (0)3 9347 0446 |
Number of
Staff: 15
Students: 5
Research Interests
The Ion Channels and Human Disease group, led by Dr Steven Petrou, has a keen interest in researching the fundamental basis of epilepsy.
This includes
- Identifying the genes involved in inherited forms of the disease and studying how they alter brain function to cause epilepsy or “Epileptogenesis”
- Developmental biology and epilepsy
- The genomic response of the brain in mouse models of human familial epilepsy
- Identification of therapeutics opportunities to treat epilepsy.
Current Projects
Creation of syndrome specific models of human familial epilepsy syndromes and exploit these for drug development.
Syndrome specific models of epilepsy are the key to understanding the fundamental origins of this disease and to the development of better therapeutics and treatments. The goal of this project is to develop genetically modified mouse models of specific human epilepsy syndromes. These studies begin with the function validation of epilepsy causing gene mutations found in patient populations by our collaborator, Prof Sam Berkovic. The majority of these mutations are found in a class of proteins called ion channels. These membrane spanning proteins create gated switches in neurons, control excitability of neurons and underlie the basic functioning of the brain. We assess the effects of mutations by using patch clamp electrophysiology, two electrode voltage clamp and a range of cell biological methods. Once disease causing mutations are identified in human studies, mouse models are created that harbour the identical mutations. Development of new mice is underway based on susceptibly genes, to date we have created three mice centred around idiopathic generalised epilepsy, idiopathic partial epilepsy and temporal epilepsy. With these models in hand our studies should reveal mechanisms of seizure genesis, thus providing fertile ground for development of novel therapeutics.
Perform a detailed investigation into the mechanisms of epileptogenesis in our syndrome specific models.
Validation of syndrome specific mouse models of epilepsy requires detailed study at the molecular, neuronal, network and whole animal level. We search for similarities in cellular behaviour and seizure activity between our mice and the patients with the mutation as this provides us with greater confidence that fundamental mechanisms of seizure genesis may be shared. Our search for the mechanism of epileptogenesis requires the use of miniaturised single neuron recording devices for use in unrestrained and awake animals as well as use of in vivo patch clamp recordings in anesthetised mice. We couple these studies with EEG and behavioural tests as our markers of syndrome type. We have used molecular biological methods to engineer switching of gene mutations on and off in living mice to investigate the study of direct versus developmental effects of mutations. We envisage that a range of different models will have to be created to cover the major refractory epilepsies seen in man.
Genomic consequences of epilepsy gene mutations: Development of 4D mouse brain gene maps.
It is unclear how single gene mutations contribute to epileptogeneis. Differences in the pattern of seizure onset point towards a need to understand two important steps in order to reveal the mechanism of epileptogenesis:
- determine whether mutations have anatomical or developmental consequences that might result in the formation of seizure foci or in abnormal cortical synchronisation.
- map the developmental trajectory of abnormal gene expression within the brain using a high throughput in situ hybridization approach.
This project will use a combination of array analysis and in situ hybridization to examine spatial and temporal changes in gene expression during the epileptogenic process, which will aid our understanding of the response of the genome to epilepsy mutations and give spatial clues to guide our functional studies.
Laboratory Techniques
Our laboratory has taken the approach that novel opportunities for therapeutic intervention will arise by
- the creation of syndrome specific epilepsy models based on human genetic lesions
- a detailed analysis of the fundamental mechanisms that underlie disease genesis and progression.
To achieve these goals we employ a multidisciplinary approach that combines
- Molecular neurobiology
- Precision in vivo virus delivery for acute and chronic gene expression
- Quantitative neuronal morphology
- Biophysics and computer modelling
- Single cell and brain slice electrophysiology
- Macro and micro digital imaging and 3D brain reconstruction
- EEG, unit recording and behavioural analysis of mice
Funding
- Program Grant Berkovic SF, Jackson G, Petrou S, Reutens D, Scheffer I, Connolly A, Gecz J, Mulley J. Epilepsy: A collaborative research program from genome to patient, 2006-2010.
- National Heart Foundation. Cousins H and Petrou S. Molecular identification of a novel calcium channel in arteriolar smooth muscle, 2006-2007.
- National Institutes of Health. Jones MV and Petrou S. Altered Function of a GABA-A receptor epilepsy mutation, 2003-2007.
- Neurosciences Victoria. Petrou S. Development of a miniaturized hyperdrive system for in vivo unit recording in brains of freely moving mice, 2004-2007.
- Howard Florey Institute Grant. Petrou S. 2003-2008.
- Inaugural Molly McDonnell Foundation Scholarship (Epilepsy Society of Australia). C Reid, 2007
- NHMRC project grant #454655 (2007-2009): Altered HCN channel expression and function in acquired epilepsy, C. A. Reid and S. Petrou
Research
