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Theoretical Investigations Into Permeation Dynamics In Calcium- And Potassium-Selective Membrane Ion Channels
Funder
National Health and Medical Research Council
Funding Amount
$517,243.00
Summary
All electrical activities in the brain are regulated by opening and closing of ion channels. Thus, understanding their mechanisms at a molecular level is a fundamental problem in biology. There are many different types of ion channels, each type fulfilling a different role. We now know the exact atomic structures of several types of the proteins forming ion channels. Using this newly unveiled information, we propose to build exact physical models of two important classes of ion channels, namely, ....All electrical activities in the brain are regulated by opening and closing of ion channels. Thus, understanding their mechanisms at a molecular level is a fundamental problem in biology. There are many different types of ion channels, each type fulfilling a different role. We now know the exact atomic structures of several types of the proteins forming ion channels. Using this newly unveiled information, we propose to build exact physical models of two important classes of ion channels, namely, the calcium channels and potassium channels, using the technique known as 'homology' modelling. Then, making use of powerful supercomputers and the special computer programs we have devised, we propose to follow the motion of ions as they move through the channel and study how some chemical compounds or drugs interfere with the normal functioning of the channel. Specifically, we will attempt to understand how verapamil, which is used to treat irregular heart beats and high blood pressure, interact with the calcium channel. Once we fully understand how these channels work, we will be able to understand the causes of, and possibly find the cures for, many neurological and muscular disorders, such as cardiac arhythmia and hypertension.Read moreRead less
Epileptic convulsions are common, disrupt social life and may occasionally cause death. They can occur spontaneously in individuals whose brains appear to be physically normal. Apart from the fact that epilepsy may run in families, the processes leading to spontaneous convulsions are not known. We measure the brain's electrical rhythms (EEG) to find out which rhythms are disturbed in people with epilepsy and whether these rhythms disrupt the brain to cause attacks. In preliminary studies in pati ....Epileptic convulsions are common, disrupt social life and may occasionally cause death. They can occur spontaneously in individuals whose brains appear to be physically normal. Apart from the fact that epilepsy may run in families, the processes leading to spontaneous convulsions are not known. We measure the brain's electrical rhythms (EEG) to find out which rhythms are disturbed in people with epilepsy and whether these rhythms disrupt the brain to cause attacks. In preliminary studies in patients with generalised epilepsy, we have identified abnormally strong rhythms that are almost certainly related to epilepsy causation and our studies are in part aimed at making our findings into a diagnostic test. Our findings may even enable individuals with epilepsy to test themselves for their immediate risk of seizure. Both of these outcomes should enable improved treatment for epilepsy. In addition to benefits in epilepsy, there are potential benefits in the diagnosis of cerebral degenerative disorders if changes in the rhythms also occur in these conditions.Read moreRead less
I aim to understand the genetics of the epilepsies. Through detailed analysis of different types of epilepsy, and associated features such as intellectual disability and autism, I will describe new epilepsy syndromes, and together with gene discovery, implement novel targeted therapies. This translational program will transform clinical practice by informing diagnosis, prognostic and genetic counseling, and lead to targeted precision therapies to improve outcomes for each patient.
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
Variation in our genetic makeup can cause serious brain disorders such as epilepsy. The goal of this research is to determine how variation in an epilepsy patients genes produce fundamental changes in brain function that lead to epilepsy. This is a multidisciplinary program that combines clinical, genetic, electrophysiological, morphological and computational approaches to create a fundamental understanding of the genesis of this important disease.
Epilepsy is a debilitating neurological disorder characterised by spontaneous seizures. For a third of epilepsy patients, drugs cannot prevent epileptic seizures from occurring without causing severe side effects. Therefore alternative treatments are needed. This work will develop epileptic seizure warning methods. This will alleviate the stress of randomly occurring seizures by giving patients the chance to move to safety before a seizure occurs, therefore enhancing their quality of life.
Neurological Manifestations Of Experimental Neuronal Voltage-gated Potassium Channel Autoimmunity.
Funder
National Health and Medical Research Council
Funding Amount
$65,148.00
Summary
Antibodies against neuronal voltage-gated potassium channels (VGKC) are seen in various neurological illnesses, most commonly epilepsy and memory loss. The role of VGKC antibodies in the development of brain disease will be studied by immunizing rabbits against VGKC and transferring these antibodies to mice.
The PDZ Scaffold NHERF-1; A Novel Regulator Of Astrocyte Function?
Funder
National Health and Medical Research Council
Funding Amount
$444,500.00
Summary
Astrocytes are a vital cell type in the human brain. They provide nutrients to neurons, remove toxic chemicals such as glutamate (a neurotransmitter), as well as stabilising the levels of molecules such as water and ions such as sodium, bicarbonate and potassium. Astrocytes perform all these tasks by means of specialised protein molecules called transporters that are embedded in their cell membranes. These transporters are not uniformly distributed; they are positioned in those parts of the astr ....Astrocytes are a vital cell type in the human brain. They provide nutrients to neurons, remove toxic chemicals such as glutamate (a neurotransmitter), as well as stabilising the levels of molecules such as water and ions such as sodium, bicarbonate and potassium. Astrocytes perform all these tasks by means of specialised protein molecules called transporters that are embedded in their cell membranes. These transporters are not uniformly distributed; they are positioned in those parts of the astrocyte membranes where the particular biological job has to be performed. How are they targeted to, and retained in these places? We have preliminary data suggesting that a specialised protein called NHERF-1, can bind a group of these proteins, called glutamate transporters, thereby anchoring them to the skeleton of the cell. If we are correct then we should be able to manipulate this interaction, both in live brain tissues, and in simple cell culture systems, using a variety of physiological and molecular biology techniques. If we are correct in our hypothesis, then our findings will have immense value in trying to reduce damage that occurs in human brains in conditions such as strokes, where a breakdown in the control of glutamate around neurons causes extensive and irreversible brain damage.Read moreRead less
Development Of Novel Anti-epileptic Drugs Targeting Vesicular Endocytosis
Funder
National Health and Medical Research Council
Funding Amount
$202,950.00
Summary
Our team developed a drug program targeting a novel mechanism for epilepsy treatment, neuronal synaptic vesicle endocytosis. This project will develop the most promising series of drugs. Preclinical development is advanced, lacking only efficacy data across models predictive of the spectrum of human epilepsies to enable candidate selection for clinical trials. The program will advance a totally new concept for the treatment of epilepsy.
The Clinical Impact Of Event-based Motion Correction In Paediatric PET-CT Brain Imaging
Funder
National Health and Medical Research Council
Funding Amount
$276,104.00
Summary
Movement of the head during PET-CT brain imaging can prevent accurate diagnosis by blurring and distorting the image. The problem is perhaps most acute in paediatric patients, many of whom must be anaesthetized or sedated to avoid motion. This work will establish whether a recently developed motion correction method can improve the clinical utility of PET-CT brain images in young patients, and reduce the need for sedation and anaesthesia during the PET scan.