Molecular Mechanisms That Help Organise Effective Synaptic Transmission.
Funder
National Health and Medical Research Council
Funding Amount
$555,825.00
Summary
This study will test the idea that adhesion molecules alpha4- and beta2-laminin are needed for proper development and function of motor nerve - muscle connections. This study will provide insights into how such molecules control effective nerve-muscle communication, in both health and disease. We also believe that our results will provide the basic knowledge needed for identifying pharmacological targets that could improve such connections, and to promote reconnections between nerve and muscle.
Roles Of Brain-derived Neurotrophic Factor In Plasticity Of Injured Sensory Neurons
Funder
National Health and Medical Research Council
Funding Amount
$461,443.00
Summary
The fundamental problem of how nerve cells respond to a nerve injury has long been studied by neuroscientists and clinicians. After a nerve injury outside the brain or spinal cord, ie, in the periphery, some sensory nerve cells die, some regenerate to reconnect to their targets, and some sprout to make abnormal connections. Recent evidence from our lab and others indicates that the nerve sprouting is linked to chronic pain experienced by nerve-injury patients. However, how these changes occur st ....The fundamental problem of how nerve cells respond to a nerve injury has long been studied by neuroscientists and clinicians. After a nerve injury outside the brain or spinal cord, ie, in the periphery, some sensory nerve cells die, some regenerate to reconnect to their targets, and some sprout to make abnormal connections. Recent evidence from our lab and others indicates that the nerve sprouting is linked to chronic pain experienced by nerve-injury patients. However, how these changes occur still remains largely unknown. Our recent studies showed that growth factors, particularly brain-derived neurotrophic factor (BDNF) which is made by the sensory nerve cells, may play important roles in mediating these changes. This proposed project, directly evolved from our recent exciting findings, aims to further examine roles and action mechanisms of BDNF and its relatives in regulating the responses of sensory nerve cells to a nerve injury. We propose that after an injury, BDNF promotes survival of some nerve cells, enhances sensory nerve regeneration in both periphery and spinal cord, and also mediates abnormal nerve sprouting and is involved in neuropathic pain. With strong expertise and powerful tools in hand, we have designed a series of experiments to investigate the roles and action mechanisms of BDNF and its related molecules in these processes. Results from this project will help us understand mechanisms underlying the responses of nerve cells to a nerve injury, and should provide much needed information which would help in designing new methods for enhancing nerve cell survival and nerve regeneration as well as for inhibiting nerve injury-induced chronic pain in nerve-injury patients.Read moreRead less
Molecular And Cellular Mechanisms Of Axon Guidance In The Vertebrate Nervous System
Funder
National Health and Medical Research Council
Funding Amount
$447,750.00
Summary
There are, at least, two major obstacles that have to be overcome in the design of therapies to assist the repair of injured brain tissue. First, the nerve cells that are damaged have to be encouraged to regrow - typically this regrowth is inhibited in the brain; and second, this regrowth has to be directed so that the correct connections are re-established. This project will begin to unravel some of the mechanisms that nerve cells use to wire up together during development. This information can ....There are, at least, two major obstacles that have to be overcome in the design of therapies to assist the repair of injured brain tissue. First, the nerve cells that are damaged have to be encouraged to regrow - typically this regrowth is inhibited in the brain; and second, this regrowth has to be directed so that the correct connections are re-established. This project will begin to unravel some of the mechanisms that nerve cells use to wire up together during development. This information can be used to assist in trying to modulate and facilitate directed regrowth following injury.Read moreRead less
Molecular And Cellular Mechanisms Of Axon Growth And Guidance In The Vertebrate Nervous System
Funder
National Health and Medical Research Council
Funding Amount
$467,545.00
Summary
There are millions of nerve cells in the vertebrate brain, each forming very precise and specific connections within neural circuits. During development of the embryo most of these cells are wired together. A Telstra technician will use the different colours of telephone cables to correctly connect them. Likewise, the growing processes of nerve cells in the brain use specific markers or labels as cues to establish the correct wiring. The aim of the present project is to characterize the specific ....There are millions of nerve cells in the vertebrate brain, each forming very precise and specific connections within neural circuits. During development of the embryo most of these cells are wired together. A Telstra technician will use the different colours of telephone cables to correctly connect them. Likewise, the growing processes of nerve cells in the brain use specific markers or labels as cues to establish the correct wiring. The aim of the present project is to characterize the specific role of some of these labels on nerve cells during development. This project will provide new fundamental knowledge about how brain cells are wired together during development of the embryo. This knowledge is essential for establishing strategies to enhance repair of brain cells following ischemic, excitotoxic or mechanical injury.Read moreRead less
Proteolytic Cleavage Of The P75 Neurotrophin Receptor Mediates Cell Death
Funder
National Health and Medical Research Council
Funding Amount
$238,500.00
Summary
The p75 neutrotophin receptor (p75NTR) is a major inducer of nerve cell death, and is active in a wide range of neurodegenerative conditions, including Alzheimer's disease, motor neuron disease, multiple sclerosis, stroke and nerve trauma. This study aims to understand and to characterise the events that regulate this receptor. In particular, we will investigate the role that cleavage or controlled breakdown of the receptor plays in mediating its cell death activity. A fundamental aspect of this ....The p75 neutrotophin receptor (p75NTR) is a major inducer of nerve cell death, and is active in a wide range of neurodegenerative conditions, including Alzheimer's disease, motor neuron disease, multiple sclerosis, stroke and nerve trauma. This study aims to understand and to characterise the events that regulate this receptor. In particular, we will investigate the role that cleavage or controlled breakdown of the receptor plays in mediating its cell death activity. A fundamental aspect of this proposal is determining whether cleavage is due to presenilin-dependent activity, given that presenilin mutations have been demonstrated in most familial Alzheimer s disease cases. While this will increase our understanding of one of factors contributing to Alzheimer's disease, it also has much broader implications. A wide range of pharmaceuticals which regulate presenilin cleavage are already being developed and clinically tested for their efficacy in the treatment of Alzheimer s disease. Should our research demonstrate that p75NTR cleavage is the key process that regulates neuronal degeneration it will have major ramifications for approaches to the treatment of other p75NTR-associated neurodegenerative conditions.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
How Does The LRP Receptor Megalin Promote Regenerative Neuronal Growth?
Funder
National Health and Medical Research Council
Funding Amount
$408,739.00
Summary
Promoting the regenerative growth of neurons to allow recovery from traumatic brain injury or Alzheimer's disease is a major goal of neuroscientists. This project continues the Chief Investigators' work in which they have discovered the regenerative potential of a protein and focuses on how this protein interacts with a key neuronal receptor, megalin, which appears to drive the regenerative process. This work will identify new targets for therapies for a range of nervous system disorders.
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
Suppressor Of Cytokine Signalling-2 (SOCS2) And Its Role In Neuronal Development And Function
Funder
National Health and Medical Research Council
Funding Amount
$451,980.00
Summary
Injury to the brain or spinal cord at present often results in permanent damage, such as paralysis, which is largely due to a failure of neurons to regrow at the injury site. In order to overcome this, we are trying to find ways of making new neurons grow, either from stem cells present in the nervous system or transplanted from cells grown in tissue culture. However, little is known about how a neural stem cell decides to become a neuron or another cell type, such as a glial cell and so we are ....Injury to the brain or spinal cord at present often results in permanent damage, such as paralysis, which is largely due to a failure of neurons to regrow at the injury site. In order to overcome this, we are trying to find ways of making new neurons grow, either from stem cells present in the nervous system or transplanted from cells grown in tissue culture. However, little is known about how a neural stem cell decides to become a neuron or another cell type, such as a glial cell and so we are examining factors which influence this process, which is called differentiation. Growth factors are important mediators of this process and suppressor of cytokine signalling (SOCS) proteins are important in determining how cells respond to growth factors. The overall aims of this project are to determine the role that SOCS genes and in particular, SOCS2 play in neural stem cell differentiation into neurons and glia, neuron process outgrowth and neuronal and glial injury responses in the nervous system. This will be examined in normal cells and cells which over-express or do not express SOCS2 genes. Understanding the biology of neural growth factor responsiveness may eventually allow us to devise therapeutic strategies for use following brain-spinal injury or disease, including generation of neurons from stem cells.Read moreRead less