Neuroprotection By Ndfip1 In Brain Injury - Identifying Targets And Understanding Mechanisms
Funder
National Health and Medical Research Council
Funding Amount
$836,225.00
Summary
Brain injury from trauma and motor vehicle accidents is a serious health issue, affecting approximately 30,000 Australians per year. About 10% of the victims suffer serious long term consequences, including mental, physical and behavioural impairment. We have discovered a new brain protein capable of preventing neurons from dying following injury. This grant will improve our understanding of how this protein works, and provide a scientific foundation for devising therapies.
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.
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
Role Of Osteopontin In Ischemic-like Injury To The Retina
Funder
National Health and Medical Research Council
Funding Amount
$357,862.00
Summary
The molecule osteopontin (OPN) is implicated in the response of certain tissues to disease. We have new evidence that the level of OPN in the visual retina increases markedly following injury. We hypothesise that OPN is produced by specialised retinal cells in response to injury and functions to promote the survival of nerve cells. The proposed research seeks to investigate this hypothesis and the results will contribute to a greater understanding of the role of OPN in retinal diseases.
Deciphering How PTEN Phosphatase Mediates Excitotoxic Neuronal Death
Funder
National Health and Medical Research Council
Funding Amount
$519,715.00
Summary
In stroke patients, oxygen deprivation indirectly induces massive nerve cell death by activating a cell death-promoting enzyme called PTEN. We aim at unravelling (i) how PTEN is activated by oxygen deprivation, (ii) where the activated PTEN is localised in cells, and (iii) how the activated and optimally localised PTEN induces nerve cell death. The study will benefit development of therapeutic strategies to protect against brain damage in stroke.
Understanding the biological mechanisms of nerve degeneration is an essential step toward the development of novel therapies for human neurodegenerative conditions such as Parkinson's, Alzheimer's and Huntington's diseases, and for spinal cord injuries. The studies presented in this proposal, using the powerful molecular and genetic tools available for the small nematode worm C. elegans, will provide new insights into the cellular and molecular mechanisms responsible for nerve degeneration.
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
Dissecting The Molecular Mechanisms Driving Cell Migration During Neurulation Triggered By The Netrin Receptor, Neogenin
Funder
National Health and Medical Research Council
Funding Amount
$432,750.00
Summary
In humans, abnormalities in brain and spinal cord formation during early embryogenesis result in congenital syndromes such as spina bifida and anencephaly. These defects occur at a rate of 1-1000 pregnancies and are therefore a major contributor to pre- and perinatal deaths. In the early embryo, the brain and spinal cord begin as a hollow tube of cells (the neural tube) that subsequently expands into the complex structures seen at birth. It is known that the neural tube is formed by a complex pr ....In humans, abnormalities in brain and spinal cord formation during early embryogenesis result in congenital syndromes such as spina bifida and anencephaly. These defects occur at a rate of 1-1000 pregnancies and are therefore a major contributor to pre- and perinatal deaths. In the early embryo, the brain and spinal cord begin as a hollow tube of cells (the neural tube) that subsequently expands into the complex structures seen at birth. It is known that the neural tube is formed by a complex process in which early neural cells migrate toward the midline of the embryo and subsequently coalesce. This project seeks to determine the function of one molecular signaling pathway (the neogenin pathway) that has been implicated in driving these cell migration events. We will initially use the frog, Xenopus laevis, as our embryonic model since the developmental processes that form the Xenopus neural tube closely parallel those ocurring in the human embryo. This model will allow us to identify the molecules in the neogenin signaling pathway. We will also create mice that carry a mutation in the neogenin gene so that we can study neogenin function in the mammal. We anticipate that these studies will provide important insights into the development of the central nervous system and also into the aberrant molecular processes underlying neural tube defects in man.Read moreRead less