Novel Substance P Receptors On Autonomic And Sensory Neurons Regulating The Viscera
Funder
National Health and Medical Research Council
Funding Amount
$447,750.00
Summary
Potentially harmful stimulation of the skin or the internal organs activates sensory nerves that send signals to the brain. These events often are perceived as painful. One chemical messenger transmitting these signals first to the spinal cord, and then to the brain, is a neuropeptide called substance P. During many chronic inflammatory conditions, such as inflammation of the bowel, these signalling pathways are sensitised so that stimuli that previously were not painful now are perceived as pai ....Potentially harmful stimulation of the skin or the internal organs activates sensory nerves that send signals to the brain. These events often are perceived as painful. One chemical messenger transmitting these signals first to the spinal cord, and then to the brain, is a neuropeptide called substance P. During many chronic inflammatory conditions, such as inflammation of the bowel, these signalling pathways are sensitised so that stimuli that previously were not painful now are perceived as painful. This sensitisation has several different causes. One contributing factor seems to be related to a change in the receptor molecules that recognise substance P. Last year we discovered a new type of receptor for substance P, that is prominent in the nerve pathways between the gut and the spinal cord. This novel receptor has important characteristics that are different from the classical substance P receptor. However, we are still largely ignorant about how substance P interacts with these new receptors to modify the activity of nerve cells in sensory pathways. Indeed, we propose that these new receptors are likely to make a significant contribution to the sensitisation that occurs in inflammation. We will use a combination of sophisticated cellular and molecular techniques to study the way in which substance P acts on these novel receptors in nerves regulating the visceral organs. Our results are likely to make a significant contribution to the development and interpretation of rational new therapies for treating chronic diseases of the gastrointestinal tract, such as inflammatory bowel disease (IBD). Our studies will reveal signalling mechanisms that also are likely to be used by substance P more widely in the nervous system, that are relevant to other inflammatory conditions like arthritis, and even some forms of depression.Read moreRead less
Mechanism Of Signal Transduction And Receptor Activation In Ligand Gated Ion Channel Receptors
Funder
National Health and Medical Research Council
Funding Amount
$456,000.00
Summary
This project seeks to provide fundamental new information about the means by which neurotransmitter receptors, which mediate fast synaptic neurotransmission, operate. It will use a range of molecular advances made by this and other laboratories to clarify how neurotransmitters enable their receptors to activate and signal. This fundamental information is of major medical significance as defective synaptic transmission, caused by mutations in ligand gated ion channel receptors, give rise to a num ....This project seeks to provide fundamental new information about the means by which neurotransmitter receptors, which mediate fast synaptic neurotransmission, operate. It will use a range of molecular advances made by this and other laboratories to clarify how neurotransmitters enable their receptors to activate and signal. This fundamental information is of major medical significance as defective synaptic transmission, caused by mutations in ligand gated ion channel receptors, give rise to a number of neurological and psychiatric disease states. The ligand gated receptors are also major targets for therapeutic drugs and the information gained in this study may also provide insights into new ways in which drugs could be used to enhance or inhibit synaptic signalling.Read moreRead less
Mechanisms Underlying Short- And Long-term Plasticity At The Mossy Fibre -> CA3 Synapse In The Hippocampus
Funder
National Health and Medical Research Council
Funding Amount
$272,750.00
Summary
Synapses, the contacts between brain cells, are extremely plastic. They can become stronger and weaker depending on the activity they experience. The hippocampus, a structure in the brain, is known to be critical to the formation of conscious memories. The plastic nature of the synapse in this structure is thought to underlie learning and memory. Understanding the mechanisms that are responsible for the changes in synaptic strength in the hippocampus are therefore important to our understanding ....Synapses, the contacts between brain cells, are extremely plastic. They can become stronger and weaker depending on the activity they experience. The hippocampus, a structure in the brain, is known to be critical to the formation of conscious memories. The plastic nature of the synapse in this structure is thought to underlie learning and memory. Understanding the mechanisms that are responsible for the changes in synaptic strength in the hippocampus are therefore important to our understanding of learning and memory. This proposal describes a series of experiments that are designed to determine the mechanisms of plastic changes . We hope, that by understanding these mechanisms, we can start to understand how we learn and remember.Read moreRead less
The Role Of Glutamate Receptor Mediated Excititoxicity In Neurodegeneration And Huntington's Disease
Funder
National Health and Medical Research Council
Funding Amount
$467,310.00
Summary
Glutamate, the principal excitatory neurotransmitter in the brain, acts on three subtypes of ionotropic glutamate receptors (iGluRs), AMPA, kainate and NMDA receptors. Evidence suggests that aberrant NMDA receptor mediated calcium influx into neurons leads to excitotoxic cell death. Calcium influx through AMPA and kainate receptors has also been implicated in excitotoxic neurodegeneration. It is widely thought that excitotoxicity contributes to chronic neurodegenerative disease. We will test thi ....Glutamate, the principal excitatory neurotransmitter in the brain, acts on three subtypes of ionotropic glutamate receptors (iGluRs), AMPA, kainate and NMDA receptors. Evidence suggests that aberrant NMDA receptor mediated calcium influx into neurons leads to excitotoxic cell death. Calcium influx through AMPA and kainate receptors has also been implicated in excitotoxic neurodegeneration. It is widely thought that excitotoxicity contributes to chronic neurodegenerative disease. We will test this hypothesis by investigating degeneration in mutant mice with altered iGluR mediated calcium flux alone and combined with mutant genes known to cause Huntington s disease by: knocking-out the NMDA receptor in select brain regions of mice and determining if that protects against neurodegenerative pathology in those brain regions. generating mutant mice with kainate or AMPA-Rs that flux abnormally high amounts of calcium and determine if that predisposes the mouse brains to neurodegenerative pathology. These experiments will provide valuable animal models enabling a deeper understanding of neurodegenerative processes. The models will also provide invaluable resources for developing therapies to protect against neurodegeneration.Read moreRead less
How Does The P75 Neurotrophin Receptor Transmit Both Pro-survival And Pro-apoptotic Signals In Neurons?
Funder
National Health and Medical Research Council
Funding Amount
$265,500.00
Summary
Signaling by the two NGF receptors, TrkA and p75, determines the survival or death of sensory neurons and of certain brain neurons involved in memory and learning. The most baffling aspect of these receptors is that in most circumstances they cooperate with each other to maximise the survival of neurons when NGF is present, but in some situations they are opposed to each other. In the latter case, NGF treatment can lead to death, rather than rescue, of neurons. In the last three years we have de ....Signaling by the two NGF receptors, TrkA and p75, determines the survival or death of sensory neurons and of certain brain neurons involved in memory and learning. The most baffling aspect of these receptors is that in most circumstances they cooperate with each other to maximise the survival of neurons when NGF is present, but in some situations they are opposed to each other. In the latter case, NGF treatment can lead to death, rather than rescue, of neurons. In the last three years we have developed novel antisense oligonucleotides which can be used to switch off each receptor separately. These have been, and will continue to be, particularly valuable tools for our research. We have also uncovered a novel way in which the two receptors interact (via a signal transduction molecule known as SHC), which provides us with a competitive edge in this area. We have the expertise and equipment to identify and clone the missing factors that account for the paradoxical interactions between p75 and TrkA. A successful outcome from this project will have important benefits by improving our understanding of the factors controlling neuronal fate, and will help to develop treatments for neurodegenerative diseases.Read moreRead less
Differentiation Of Multiple Phenotypes Of Rostral Ventromedial Medulla Neurons And Their Role In Pain
Funder
National Health and Medical Research Council
Funding Amount
$285,990.00
Summary
Chronic pain, defined as pain experienced in three out of a six month pre-interview period affects 17% of males and 20% of females in the Australian population. Opioid drugs such as morphine and codeine are the most effective drugs used to treat moderate to severe pain. However, the utility of these drugs is hampered by the development of a blunted response with repeated use. Furthermore, some clinically important pain states, particularly those caused by nerve injury, do not respond well to opi ....Chronic pain, defined as pain experienced in three out of a six month pre-interview period affects 17% of males and 20% of females in the Australian population. Opioid drugs such as morphine and codeine are the most effective drugs used to treat moderate to severe pain. However, the utility of these drugs is hampered by the development of a blunted response with repeated use. Furthermore, some clinically important pain states, particularly those caused by nerve injury, do not respond well to opioid drugs. Recent basic neurosceince research has identified groups of nerve cells deep within the brain that control sensitivity to pain as pain signals enter the spinal cord. Unfortunately in the presence of some chronic pain conditions, or chronic use of high doses of opioid drugs, these neurons undergo functional changes or adaptations that distort and increase the severity of pain sensation in a more or less permanent manner. This project uses electrical and chemical techniques to identify the basic physiology and pharmacology of single nerve cells in this brain region, so that their normal functions can be properly understood. We will then identify the cellular and molecular adaptations that occur in the nerve cells in animal models of chronic nerve injury and chronic morphine treatment to identify the nature of adaptations responsible for their aberrant function. We will then be in a position to rationally identify novel drug targets that can normalise the function of these nerve cells. This knowledge will provide potential targets for development of novel therapeutics to manage chronic pain.Read moreRead less
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
Regulation Of P75 Death Signalling: How Neurotransmitter- And Neurotrophic- Signals Determine Cell Survival
Funder
National Health and Medical Research Council
Funding Amount
$292,216.00
Summary
Nerve cell survival is dependent on trophic support in the form of growth factors and synaptic input, both of which promote recovery after nerve injury. The survival pathways activated by growth factors are generally well characterised, whereas survival signals activated by synaptic activity are largely unexplored. This proposal aims to discover how synaptic activity prevents nerve cell death by looking at how synaptic activity inhibits the processes active in dying nerve cells.
Molecular Determinants Of Inhibitory Synaptic Function Studied Using Mutant And Transgenic Mice
Funder
National Health and Medical Research Council
Funding Amount
$496,500.00
Summary
Communication between nerve cells is the key to effective brain function and when disturbed, pathological states such as epilepsy, schizophrenia, fear and anxiety, spasticity and motor disorders ensue. This project is based on new data which suggests that the site of this communication, called the synapse, is a much more dynamic structure than previously thought. Based on our work to date, where we have demonstrated the recruitment of selected classes of neurotransmitter receptors into synapses, ....Communication between nerve cells is the key to effective brain function and when disturbed, pathological states such as epilepsy, schizophrenia, fear and anxiety, spasticity and motor disorders ensue. This project is based on new data which suggests that the site of this communication, called the synapse, is a much more dynamic structure than previously thought. Based on our work to date, where we have demonstrated the recruitment of selected classes of neurotransmitter receptors into synapses, our aim is to use a range of naturally occuring mice mutants, as well as transgenic mice to modulate the receptor levels and so to examine the role of synaptic function and synaptic dynamics. The outcomes of this project will provide fundamental new knnowledge aimed at understanding how communication in the nervous system works and may suggest ways in which modulation of this information flow could be used to treat disorders of brain function.Read moreRead less
Regulation Of Brain Development By Members Of The Fibroblast Growth Factor Family
Funder
National Health and Medical Research Council
Funding Amount
$65,685.00
Summary
The brain is the most complex organ in the body. It is made up of many different types of cells broadly classified into two classes called neurons and glia. The growth of the brain from a small population of immature neuroepithelial cells to many different types of neurons and glia is controlled by small potent proteins called growth factors. We understand that many different families of growth factors are involved in the development of the brain but not how they do what they do. We are studying ....The brain is the most complex organ in the body. It is made up of many different types of cells broadly classified into two classes called neurons and glia. The growth of the brain from a small population of immature neuroepithelial cells to many different types of neurons and glia is controlled by small potent proteins called growth factors. We understand that many different families of growth factors are involved in the development of the brain but not how they do what they do. We are studying the members of one particular family known as the Fibroblast Growth Factor family or FGFs. We want to find out how they instruct young brain cells to grow and divide and turn into mature neurons.Read moreRead less