Development Of Dynamin Inhibitors As Novel Therapies For Epilepsy
Funder
National Health and Medical Research Council
Funding Amount
$903,376.00
Summary
Epilepsy affects 1% of people, but 30% do not respond to current anti-epileptic drugs (AEDs). Traditional drug discovery has not improved this situation. Our team discovered two exciting new targets for design of better AEDs. One of them blocks seizure in animals. Our aim is to determine how well they work in true animal models of epilepsy. If successful, this will accelerate development of new AEDs with less side-effects, benefiting large sectors of the Australian community.
Epilepsy is an important human disease because it causes physical trauma and sudden death in addition to immense social and economic hardship. The genetic basis of a number of epilepsy syndromes has been identified but the precise mechanism whereby mutations produce seizures is unknown. Several mutations in the alpha4 neuronal nicotinic receptor (a4 nAChR) gene have been identified in Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (ADNFLE). This is a rare form of inherited epilepsy character ....Epilepsy is an important human disease because it causes physical trauma and sudden death in addition to immense social and economic hardship. The genetic basis of a number of epilepsy syndromes has been identified but the precise mechanism whereby mutations produce seizures is unknown. Several mutations in the alpha4 neuronal nicotinic receptor (a4 nAChR) gene have been identified in Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (ADNFLE). This is a rare form of inherited epilepsy characterized by the presence of seizures during light sleep. In vitro studies using the human mutated DNA (i.e. DNA containing the genetic defect) have suggested that this mutation results in reduced activity of the receptor. Therefore a mouse in which this gene is destroyed would be relevant in understanding the human disease. We have generated an a4 nAChR knockout (KO) mouse and plan to use the mouse to test the idea that loss of function of the a4 nAChR in vivo is associated with enhanced seizure activity. The KO mice do not have unprovoked seizures but appear to have an increased number of major motor seizures in response to pentylenetetrazole, an agent which is known to cause seizures by blocking the effects of the brain inhibitory molecule GABA. Interestingly, a4 nAChRs are known to control the release of GABA. We therefore propose that our knockout mice have seizures because they tend to under produce GABA. We will also make and analyse a mouse line with the same genetic mutation as patients with ADNFLE. The experiments are aimed at understanding the way that seizures are generated and spread in the brain in these rare forms of epilepsy. The hope is that understanding these mechanisms will help us better understand and therefore treat common forms of epilepsy.Read moreRead less
The aim of this application is to find new therapeutic strategies for genetic epilepsy. "Disease in a dish" models as well as whole animal models will be generated that contain patient gene mutations and the underlying disease processes will be characterised. Using these models a range of existing and new drugs will be tested to select those that most completely reverse these disease processes. These results will feed into clinical trials in patients with appropriate genetic profiles.
Epilepsy is a devastating disease with many patients poorly treated. We have identified a novel ion channel target in the brain that reduces seizure susceptibility. The aim of this proposal is to fully explore this target in a number of epilepsy mouse models using both pharmacology and molecular techniques.
Modelling Epileptic Encephalopathies Using Induced Stem Cells
Funder
National Health and Medical Research Council
Funding Amount
$506,489.00
Summary
Genetics is poised to have a massive impact on how we diagnose and treat diseases. Precision medicine is a relatively new concept that has been put forward to encompass approaches to finding genetic and functional markers of a disease process so that better treatments that are specifically targeted to a specific patients pathology. Here we will explore the development of stem cells to create "disease in a dish" models for severe forms of epilepsy to be used for development of new therapies.
Long-term Outcomes After Paediatric Traumatic Brain Injury
Funder
National Health and Medical Research Council
Funding Amount
$431,000.00
Summary
Traumatic brain injuries during early childhood often result in long-lasting issues including social behaviour problems and post-traumatic epilepsy. Using a unique model of brain injury in young mice, my research aims to identify the biology underlying the changes that cause these issues, and evaluate novel approaches to improve long-term outcomes after brain injury.
Epilepsy is a serious condition having a massive impact on individuals and the community at large. Our understanding of the genetic causes of epilepsy is growing rapidly. We have created new animal models based on human mutations. We have shown that mutations can change the wiring of the brain during development so that the adult brain is more likely to become epileptic. Projects in this grant test if we can stop this developmental impact- allowing us to treat epilepsy before seizures occur.
Health-Related Quality Of Life In Intractable Paediatric Epilepsy: Using A New Measure To Improve Management
Funder
National Health and Medical Research Council
Funding Amount
$252,940.00
Summary
Until recently there was no adequate measure to assess the quality of life of children with epilepsy. Our Australian centre was the first to develop, validate and publish such an instrument; the Quality of Life in Childhood Epilepsy Questionnaire (QOLCE). We now aim to collect more data using the QOLCE to gain further understanding of the effects of epilepsy and its treatment on the quality of life of children. We will determine if surgery in children stops seizures and improves quality of life. ....Until recently there was no adequate measure to assess the quality of life of children with epilepsy. Our Australian centre was the first to develop, validate and publish such an instrument; the Quality of Life in Childhood Epilepsy Questionnaire (QOLCE). We now aim to collect more data using the QOLCE to gain further understanding of the effects of epilepsy and its treatment on the quality of life of children. We will determine if surgery in children stops seizures and improves quality of life. We also aim to find out if children with different types of epilepsies have unique quality of life issues. Finally, we aim to determine if the quality of a child's life depends on how well they are thinking and learning or how often they are having seizures. We will conduct this study in children with difficult epilepsy recruited from three major children's hospitals (Sydney Children's Hospital, the Children's Hospital, Westmead, Miami Children's Hospital, Florida USA) using a well designed methodology. Each child will have their particular type of epilepsy characterised using video and brain wave analysis. Each parent and older child will receive a quality of life package including the QOLCE to assess life function. In addition, all children will have an assessment of their thinking and learning by a child psychologist. At the completion of this project we will have established whether surgical treatment in children with epilepsy stops seizures and improves quality of life. This will allow clinicians and parents to better understand the effects of surgical treatment in this population. In addition, we will determine if problems in quality of life are associated with specific types of epilepsy. This information can be used to counsel families and tailor interventions and treatments. Finally, we will know whether a child's quality of life is determined by problems with thinking and learning and-or seizures.Read moreRead less
What Drives Abnormal Cerebral Activity In Secondary Generalised Epilepsy
Funder
National Health and Medical Research Council
Funding Amount
$565,809.00
Summary
Secondary Generalised epilepsy (2GE) is a severe, disabling epilepsy syndrome characterised by childhood onset frequent, treatment resistant seizures and developmental delay. Although one of the four major categories of epilepsy, it is poorly understood. This project uses combined EEG (brainwave testing) and MRI to reveal which brain areas are involved in the epileptic activity of 2GE. Advanced analysis techniques will explore which brain regions initiate 2GE epileptic activity.