The Effects Of Human Epilepsy Mutations On Synaptic GABA-A Receptors Studied By Localization-based Superresolution Microscopy
Funder
National Health and Medical Research Council
Funding Amount
$524,215.00
Summary
The genetic epilepsies are debilitating neurological disorders that are frequently associated with mutations in genes encoding neurotransmitter-gated receptors in the brain. The goal of this project is to understand mechanisms that cause changes in neuronal communication and lead to epilepsy on a single receptor level. This will lead to an improved understanding of the mechanisms of epileptogenesis and new insights into ways of treating different epilepsies.
Excitatory Interneurons: A Sensory Amplifier For Pathological Pain
Funder
National Health and Medical Research Council
Funding Amount
$649,848.00
Summary
Changes to the nervous system during pathological pain remain poorly understood. This poses a barrier to new and more effective pain therapies. We have recently shown that a population of excitatory nerve cells, which express a protein called calretinin, form an amplifier network within the spinal cord that enhances pain signalling. This application will determine how calretinin-positive nerve cells contribute to pathological pain and can subsequently be targeted to provide pain relief.
Decoding Dysfunctional Spinal Cord Circuitry In Chronic Pain.
Funder
National Health and Medical Research Council
Funding Amount
$516,101.00
Summary
Chronic pain is common, with one in five Australians having long-term pain that is serious enough to cause disability. Unfortunately this type of pain is difficult to treat, and current medicines are ineffective in many people, with unwanted side-effects. The aim of this project is to understand how signalling in the spinal cord changes following the development of chronic pain so we can find better strategies to reverse the symptoms and treat pain more effectively.
Using Artificial Synapses To Investigate The Functional Pathology Underlying Epilepsy
Funder
National Health and Medical Research Council
Funding Amount
$515,256.00
Summary
Epilepsy is a common neurological disorder. Some forms arise from hereditary mutations to GABA-A receptors. To advance our understanding of epileptogenesis, it is necessary to understand how mutations affect GABA-AR function. We will use a novel ‘artificial synapse’ system to characterise these mutant receptors. This will define how epilepsy is caused and inform us how to best tailor drug treatments for different epilepsy conditions.
Mechanisms Of Cortical And Respiratory Degenerations In Amyotrophic Lateral Sclerosis
Funder
National Health and Medical Research Council
Funding Amount
$333,900.00
Summary
This study will be the first to chronicle how and when motor neurons (MNs) in the brain and spinal cord degenerate before, during and after ALS symptoms in 2 different mouse models. The MNs studied control breathing muscles and are a key disease progression and mortality indicator in patients. I expect drastic shape and electrical abnormalities, providing information useful to clinicians about how and when brain and spinal cord MNs degenerate, uncovering new therapeutic targets and time-points.
The Alpha5 GABA-A Receptor: Delineating An Emerging Therapeutic Target
Funder
National Health and Medical Research Council
Funding Amount
$481,178.00
Summary
GABA-A receptors mediate inhibitory synaptic transmission in the brain. Receptors containing ?5 subunits are therapeutic targets for many neurological disorders. We aim to characterise the functional properties of the main ?5-containing isoforms using high-resolution imaging and whole-cell recording. Our goal is to understand which ?5-containing isoform should be preferentially targeted (and how) when seeking to treat the various disorders in which these receptors have been implicated.
Inhibitory Neurotransmitter Receptors As Therapeutic Targets For Chronic Pain And Anxiety Disorders
Funder
National Health and Medical Research Council
Funding Amount
$763,409.00
Summary
There are currently few effective long-term treatments for chronic pain and anxiety disorders. Here we propose to develop innovative therapies for both of these debilitating neurological disorders. In addition, we plan to improve our current understanding of how these disorders occur in the first place. This may identify novel potential therapeutic strategies for treating pain, anxiety and a host of other neurological disorders.
Stimulus Induced Synaptic Plasticity In The Amygdala
Funder
National Health and Medical Research Council
Funding Amount
$428,777.00
Summary
Acute pain provides important warnings about dangers in our environment. However some clinical conditions produce chronic-persistent pain that outlasts the original injury and its useful role. This persistent pain is a debilitating condition that affects 20% of the Australian population and is characterized by painful sensory experience and a negative emotional state. The clinical management of persistent pain remains problematic due to the intolerable side effects associated with the escalating ....Acute pain provides important warnings about dangers in our environment. However some clinical conditions produce chronic-persistent pain that outlasts the original injury and its useful role. This persistent pain is a debilitating condition that affects 20% of the Australian population and is characterized by painful sensory experience and a negative emotional state. The clinical management of persistent pain remains problematic due to the intolerable side effects associated with the escalating doses required for adequate pain relief and the limited efficacy of current drug therapies in some clinically important pains states. The persistence of pain after the original injury has resolved suggest the development of adaptations that result in the ongoing pain. The changes in neurobiology underlying persistent pain are poorly defined. A better understanding of this neurobiology will result in better therapeutic approaches to persistent pain. The amygdala is a brain region that is important for pain processing, endogenous analgesia and emotion. A neuronal pathway that delivers information about pain to the amygdala has recently been shown to be critical for the development of persistent pain. Little is known about whether this critical neuronal pathway is modified by pain. This project will determine using electrical and chemical techniques how a brief or persistent painful stimulus changes the delivery of painful information to the neurons in the amygdala. The changes produced by a brief painful stimulus likely represent the initial changes in the development of a persistent pain state. This information may allow us to more fully understand the transition from acute to persistent pain and the changes defined may be sensitive to pharmacological modulation. Preventing or inhibiting these pain induced changes may provide better treatment for persistent pain or ideally prevent people undergoing the transition from acute to persistent pain.Read moreRead less
Therapeutic Potential Of Glycine Receptors In Pain Sensory Pathways
Funder
National Health and Medical Research Council
Funding Amount
$292,223.00
Summary
Inflammation caused by infection or injury leads to a heightened sensation of pain and can convert non-painful stimuli (e.g., touch) into painful stimuli. This effect is mediated by the production of prostaglandins both in peripheral tissues and in the spinal cord. Prostaglandins have recently been shown to decrease the magnitude of the inhibitory neurotransmission that normally occurs onto pain sensing neurons in the spinal cord. This has the effect of raising the excitability of these neurons, ....Inflammation caused by infection or injury leads to a heightened sensation of pain and can convert non-painful stimuli (e.g., touch) into painful stimuli. This effect is mediated by the production of prostaglandins both in peripheral tissues and in the spinal cord. Prostaglandins have recently been shown to decrease the magnitude of the inhibitory neurotransmission that normally occurs onto pain sensing neurons in the spinal cord. This has the effect of raising the excitability of these neurons, thereby making it easier for weak pain stimuli to be relayed to the brain. Inhibitory neurotransmission onto pain sensing neurons is largely mediated by the alpha3 glycine receptor subunit that is not found anywhere else in the body. Very little is known about the physiological and pharmacological properties of these receptors. We hypothesise that drugs that increase the activation of alpha3 glycine receptors may provide a novel treatment for pain. This project will firstly identify new drugs that can increase the activation of these receptors. It will then test whether these drugs are likely to work in vivo. The project will also establish why these receptors are found only on pain neurons. Together, this information will establish whether alpha3 glycine receptors represent a promising new therapeutic target for inflammatory pain, and will place us in an excellent position to begin the next step of identifying novel therapeutic lead compounds.Read moreRead less