ASIC1a, A New Therapeutic Drug Target For Cardiac Ischemia
Funder
National Health and Medical Research Council
Funding Amount
$1,382,224.00
Summary
Cardiovascular disease is the biggest killer in the world, in large part due to the lack of drugs to protect the heart from the damage caused by injuries such as heart attack. Our team of world-leading scientists and clinicians has identified a novel therapeutic target (ASIC1a) against which drugs could be targeted to protect the heart against these injuries. The aim of this project is to develop novel cardioprotective drugs that target ASIC1a so we can test them in human clinical trials.
Despite dramatic improvements in diagnosis, prevention and treatment of heart disease, cardiovascular disease remains the commonest cause of death in Australia. The continuing decline in mortality from ischaemic heart disease has been offset by an increase in the incidence of sudden cardiac death due to abnormal heart rhythms. By understanding the basic mechanisms underlying cardiac arrhythmias we are seeking to develop more effective therapies to treat and/or prevent sudden cardiac death.
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
How Do Anaesthetics Work? A Rational Basis For Safer General Anaesthesia.
Funder
National Health and Medical Research Council
Funding Amount
$592,008.00
Summary
General anaesthetics are a mainstay of modern medicine, but have a small safety margin, requiring skilled anaesthetists for their safe use. There is growing evidence that general anaesthetic exposure may have long-term effects on brain function in both newborns and the elderly. This project will provide a detailed molecular description of anaesthetic action and specificity. It will provide the basis for designing new anaesthetics that are safer, both immediately and for long-term brain function.
Disturbances to the normal rhythm of the heart beat cause ~15% of deaths in our community. We wish to understand why the electrical signals in the heart can become chaotic. We will study a particular heart rhythm disturbance called acquired long QT syndrome to see if it is possible to develop a computer model that can accurately predict when and how arrhythmias will occur.
The Biophysical Basis Of HCN Channels In Human Peripheral Nerve
Funder
National Health and Medical Research Council
Funding Amount
$50,315.00
Summary
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels play an important role as pacemakers in the cardiac and nervous systems. HCN channel dysfunction is implicated in a number of disorders including neuropathic pain and epilepsy. My aim is to determine the kinetics and voltage dependence of HCN channels in human peripheral nerve in vivo. Understanding these channels is a prerequisite to the development of safe targeted therapies against neuropathic pain.
Investigation Of Lipid-protein Interactions Of Mechanosensitive Ion Channels
Funder
National Health and Medical Research Council
Funding Amount
$409,785.00
Summary
Living organisms are imminently exposed to mechanical stimuli such as gravity, touch or sound. Sensing mechanical stimuli is therefore crucial for survival. One biological tool for sensing mechanical stress are the mechanosensitive ion channels that open in response to tension in cell membranes. We will study the interactions and coupling between membrane lipids and mechanosensitive ion channels. These interactions are essential for the function of these fascinating sensory biological molecules.
Structure-function Studies Of Ion Permeation And Selectivity In Recombinant Glycine Receptor Channels
Funder
National Health and Medical Research Council
Funding Amount
$331,300.00
Summary
Ligand-gated ion channels (LGICs) are members of a superfamily of receptor channels, with very significant structural and functional similarities, which play a major role in fast synaptic neurotransmission within the brain and spinal cord, and underlying the complex behaviour of the nervous system, but when dysfunctional can result in major neurological problems. Glycine is one of the two most important inhibitory neurotransmitters in the central nervous system. Impaired glycine-mediated neurotr ....Ligand-gated ion channels (LGICs) are members of a superfamily of receptor channels, with very significant structural and functional similarities, which play a major role in fast synaptic neurotransmission within the brain and spinal cord, and underlying the complex behaviour of the nervous system, but when dysfunctional can result in major neurological problems. Glycine is one of the two most important inhibitory neurotransmitters in the central nervous system. Impaired glycine-mediated neurotransmission underlies a range of inherited neurological diseases and already, it has been shown that the human disorder, familial Startle disease (hyperekplexia) occurs because of point mutations that have impaired the permeation and activation of the glycine receptor (GlyR). Similarly, certain epilepsies are now known to be caused by mutations in, or close to, the channel region in the excitatory acetylcholine receptors (AChRs), which affect channel activation and ion permeation. However, because of their very significant structural and functional similarities, information obtained in one member of the LGIC family of receptors has strong potential application to the other members and the GlyR with its simpler structure has certain advantages for investigation. The first aim of this project is to investigate how the molecular biological structure of these ion channels controls permeation, how it affects how different ions are selectively allowed to move through it and how it affects channel activation. A second related aim is to learn more about the process of desensitization of GlyR receptors, whereby a sustained presence of a high concentration of agonist can cause a reduction in receptor response. A third aim is to specifically investigate the mechanisms underlying the mode of molecular disruption resulting from two new Startle disease mutations, which, in addition to their own inherent clinical value, can also give general information about receptor function.Read moreRead less
How Does Sudden Cardiac Death Occur In Familial Hypertrophic Cardiomyopathy?
Funder
National Health and Medical Research Council
Funding Amount
$1,312,606.00
Summary
Familial hypertrophic cardiomyopathy is a leading cause of sudden cardiac death but the mechanisms for the induction of arrhythmia are unknown. This proposal has the potential to impact sudden death in the young and enable significant expansion of Australia’s research capacity into the treatment of familial hypertrophic heart disease in humans.
The Contribution Of Subunit Interfaces To Receptor Activation In Ligand Gated Ion Channels
Funder
National Health and Medical Research Council
Funding Amount
$309,070.00
Summary
This project seeks to provide insights into new mechanisms that could be used to enhance or inhibit neuronal signalling. The family of pentameric neurotransmitter receptors that are key components in the process of neuronal signalling and are the target of this study. It will investigate the molecular motions that occur when the receptor shifts from the resting state to the activated state in the presence of neurotransmitter. This critical to understanding the normal function of these receptors ....This project seeks to provide insights into new mechanisms that could be used to enhance or inhibit neuronal signalling. The family of pentameric neurotransmitter receptors that are key components in the process of neuronal signalling and are the target of this study. It will investigate the molecular motions that occur when the receptor shifts from the resting state to the activated state in the presence of neurotransmitter. This critical to understanding the normal function of these receptors in the brain and how they can be modulated.Read moreRead less