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
Optimising Combinations Of Calcium Channel Inhibitors For Treatment Of Secondary Degeneration After Neurotrauma
Funder
National Health and Medical Research Council
Funding Amount
$679,772.00
Summary
Traumatic injury to the central nervous system is made worse by damage that spreads away from the initial point of impact. Excess calcium entering cells is a key contributor to spreading damage but treatment with single calcium channel inhibitors has been disappointing. We will use combinations of calcium channel inhibitors to block multiple calcium channels and ensure the optimised combination is effective in clinically relevant models of neurotrauma.
Neuron To Glia Signalling: Learning How Synaptic Signalling Can Promote CNS Remyelination
Funder
National Health and Medical Research Council
Funding Amount
$609,650.00
Summary
An immature cell type in the brain, known as the oligodendrocytes progenitor cell (OPC), receives direct electrical communication from neurons. This communication regulates the behavior of the OPC, affecting its ability to divide and generate new brain cells. This project will identify the signaling molecules that guide the OPC to for this specialized contact with the nerve cell. Understanding this communication has important implications for the treatment of Multiple Sclerosis.
Targeted Nanoparticles To Deliver Combinations Of Calcium Channel Inhibitors To Prevent Myelin Damage During Secondary Degeneration After Neurotrauma
Funder
National Health and Medical Research Council
Funding Amount
$895,244.00
Summary
Following injury to the central nervous system the damage spreads into nearby areas, leading to worse outcomes for the patient. We will generate nanoparticle systems to deliver effective therapies directly to the most vulnerable cells, critical for function. We will modify the nanoparticles so that they can get to the injury site, both early after injury, and after longer periods of time have elapsed. We will then test the nanoparticle systems to see if they are effective at preserving function
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.
Controlling Neuroinflammation In Alzheimers Disease
Funder
National Health and Medical Research Council
Funding Amount
$639,577.00
Summary
Alzheimer’s disease (AD) is the most common neurodegenerative disorder worldwide, with 269,000 Australians currently diagnosed with AD and is expected to soar to about 981,000 by 2050. AD accounts for greater than 60% of all cases of dementia. This grant investigates the role that neuroinflammation plays in the progression and exacerbation of AD and will identify new therapeutic strategies to combat this insidious disease.
Developing Novel Selective Glycine Receptor Potentiators As A Means To Control Pain.
Funder
National Health and Medical Research Council
Funding Amount
$552,647.00
Summary
It has been estimated that >3M Australians suffer from pain at a cost to the economy of >$34B, with chronic pain (persisting beyond 1-6 mths) accounting for ~half this burden. There is an urgent and compelling social and economic case for the development of safer and more effective pain therapeutics. This project takes inspiration from a new class of Australian marine natural products that selectively regulate a key pain pathway, and will optimize and develop these as a new class of pain d ....It has been estimated that >3M Australians suffer from pain at a cost to the economy of >$34B, with chronic pain (persisting beyond 1-6 mths) accounting for ~half this burden. There is an urgent and compelling social and economic case for the development of safer and more effective pain therapeutics. This project takes inspiration from a new class of Australian marine natural products that selectively regulate a key pain pathway, and will optimize and develop these as a new class of pain drug.Read moreRead less
Understanding Neuroinflammation In Alzheimer's Disease
Funder
National Health and Medical Research Council
Funding Amount
$1,043,216.00
Summary
This project opens a new line of enquiry into the cellular signalling mechanisms involved in the progression of AD and establishes whether targeting the involvement of type-1 IFN signalling influences the evolution of AD. New and novel approaches are clearly required to treat AD. Importantly, we believe that neuroinflammation is common to all causes of dementia and targeting the neuroinflammatory pathways has much wider implications than targeting the primary causative pathway.
The Role Of Action Potentials In Local Calcium Signalling And Induction Of Different Forms Of LTP
Funder
National Health and Medical Research Council
Funding Amount
$330,691.00
Summary
Our understanding of how the brain learns and remembers things is still limited. There is good evidence that changing the strength of the connections (synapses) between brain cells (neurons) can allow information to be stored. One type of synaptic change is called long-term potentiaton (LTP), which is a long-lasting increase in the efficacy of communication between neurons. Recently, I have described 3 different forms of LTP in a region of the brain that is known to be important for learning and ....Our understanding of how the brain learns and remembers things is still limited. There is good evidence that changing the strength of the connections (synapses) between brain cells (neurons) can allow information to be stored. One type of synaptic change is called long-term potentiaton (LTP), which is a long-lasting increase in the efficacy of communication between neurons. Recently, I have described 3 different forms of LTP in a region of the brain that is known to be important for learning and memory. These forms of LTP have different persistence characteristics - LTP 1 is relatively short-lasting, LTP 2 is of intermediate duration, and LTP 3 is very long-lasting and perhaps even permanent. Each form of LTP is selectively triggered by an increase in calcium in a different part of the neuron. In the present study, I will investigate the relationships between electrical activity in different parts of the neuron in order to define the 'rules' for triggering each form of LTP. This information is important for future studies into the specific role played by each form of LTP in learning and memory processing in the brain. A better understanding of the relationship between LTP and learning and memory will assist in developing effective treatment strategies for disorders of memory, including Alzheimer s disease, addictive bahaviour, and learning disorders.Read moreRead less
Investigating Genetic Determinants Of Absence Epilepsy In A Polygenic Rat Model
Funder
National Health and Medical Research Council
Funding Amount
$458,481.00
Summary
The underlying genetic causes of idiopathic generalised epilepsies (IGE) are still largely unknown. In an animal model of IGE we have discovered novel genetic abnormalities an ion channel. This proposal will build upon these novel findings to examine the role these abnormalities have in determining the absence epilepsy phenotype and this work has the potential to provide vital information regarding the mechanisms by which this gene contributes to an IGE seizure phenotype.