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.
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.
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.
Development And Refinement Of Neural Connections In The Adult Brain In Health And Disease
Funder
National Health and Medical Research Council
Funding Amount
$8,061,596.00
Summary
Our group will use innovative approaches such as advanced imaging and cell-sorting and development of animal models to determine how new neurons are generated, how they travel to different parts of the brain and how they integrate into the existing brain circuitry. These discoveries will point to new ways in which to treat brain damage both during ageing and during pathology. Since team members have previously been involved in progressing molecular discovery to clinical trials, we are also in a ....Our group will use innovative approaches such as advanced imaging and cell-sorting and development of animal models to determine how new neurons are generated, how they travel to different parts of the brain and how they integrate into the existing brain circuitry. These discoveries will point to new ways in which to treat brain damage both during ageing and during pathology. Since team members have previously been involved in progressing molecular discovery to clinical trials, we are also in a good position to exploit these discoveries in partnership with the biopharmaceutical industry.Read moreRead less
A -induced Cell Death Signalling By The P75 Neurotrophin Receptor.
Funder
National Health and Medical Research Council
Funding Amount
$546,382.00
Summary
The amyloid peptide A is central to the cause of Alzheimer's disease. We have recently found that A can activate the cell death receptor p75NTR which is found in the nerve cells that die in Alzheimer's disease. This project will study whether this death pathway underpins the neuronal death associated with Alzheimer's disease. It will also determine the mechanism by which A activates p75NTR death signalling, and identify biochemical ways to prevent this from occurring.
Synaptic Inhibition And The Control Of Excitability In The Rodent Piriform Cortex
Funder
National Health and Medical Research Council
Funding Amount
$459,738.00
Summary
We are studying the properties of neurons (nerve cells) and brain circuits that enable mammals to recognise and remember odours. Our experiments will focus on neurons in the odour-processing region of the cerebral cortex of mice. This work will answer fundamental questions about how the brain interprets sensory inputs in order to build a coherent picture of the external world. Our findings will also provide a deeper understanding of the causes of epilepsy, leading to improved treatments.
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
Amyloid Precursor Proteins Novel Role In Alzheimers Disease Through Regulating Neuronal Iron Homeostasis.
Funder
National Health and Medical Research Council
Funding Amount
$949,667.00
Summary
Our group has discovered a novel role of amyloid precursor protein (APP) in cellular iron balance. The smallest form of APP, prevalently found in the brain, is able to convert a damaging iron variety (Fe2+) into the safer Fe3+. Alternative, larger, forms of APP are found to inhibit this effect. This project will establish how APP controls iron homeostasis within brain neuronal cells and how this activity is impaired in disease, thus development a mechanism for diagnostic tests and therapeutics.