The Role Of Central And Peripheral Synaptic Activity In The Developmental Death Of Motoneurons.
Funder
National Health and Medical Research Council
Funding Amount
$463,145.00
Summary
Information processing in the nervous system relies on the effective communication between neurons and their target cells which make up our neuronal circuitry. At the centre of all this is the synapse, the specialized contact between a neuron and its target cell, be it another neuron in the brain or a target organ such as skeletal muscle. Our primary goal is to determine how the formation of synaptic connections during development regulates neuronal survival. In this proposal we have focussed on ....Information processing in the nervous system relies on the effective communication between neurons and their target cells which make up our neuronal circuitry. At the centre of all this is the synapse, the specialized contact between a neuron and its target cell, be it another neuron in the brain or a target organ such as skeletal muscle. Our primary goal is to determine how the formation of synaptic connections during development regulates neuronal survival. In this proposal we have focussed on the neuromotor system as it is a well characterised part of the nervous system. During development, 50% of motoneurons die at a time when they are making contact with skeletal muscle, and when contacts onto motoneurons by other neurons are being established. We believe that the formation of effective synaptic contacts onto motoneurons, as well as connections by motoneurons onto muscle are the key regulators of motoneuron survival. We are in a position to be able to address what regulates motoneuron death; as we have a number of mice which lack key molecules needed for the formation of specialisations that allow neuronal contacts to be made between motor neurons and their muscle, and with other neurons within the spinal cord. By examining the function of motoneurons, counting them and screening for molecular changes in these mice, we will be able to dissect out the mechanism of how a motoneurons' fate is determined during developmental motoneuron death. This research could help in developing strategies aimed at improving neuronal connections to improve neuronal viability. Our research will have important implications for our understanding about the basis of adult neuro-degenerative diseases, such as motor neuron disease and Alzheimer's, which are in part characterised by a molecular breakdown in neuronal connections that ultimately result in neuronal death.Read moreRead less
How Does Iron Accumulation Affect Parkinson’s Disease And What Controls It?
Funder
National Health and Medical Research Council
Funding Amount
$545,517.00
Summary
Currently there is no cure for Parkinson's disease, and although we have a number of treatments to manage the disease there is an urgent need for a further understanding of the disease process. This proposal will investigate the critical role that iron plays in the cause of neuronal cell death that results in Parkinson's disease, and will investigate methods for regulating metal levels in the brain.
A Comparative Study Between The Effects Of C-terminally Truncated A-synuclein Metabolites And Full Length A-synuclein In Aged Rat Hippocampal Neurons
Funder
National Health and Medical Research Council
Funding Amount
$231,284.00
Summary
I am a neurologist from Xi�an Jiaotong University, China. My major research interest is in neurodegenerative diseases, especially Parkinson and Alzheimer�s disease. I enter this field because I know ageing population will have an enormous impact on the world�s economy. I started collaboration with Dr. Weiping Gai in Flinders University. We are interested in the toxic effects of both a-synuclein and its metabolites, their mechanisms and ways to block them.
Neuronal Membranes And Connections In Dementia: Targets For Intervention
Funder
National Health and Medical Research Council
Funding Amount
$720,144.00
Summary
This research aims to understand why some people with Mild Cognitive Impairment (MCI) progress to dementia, whilst others do not. The fact that some people’s cognitive abilities can improve provides an opportunity to study the mechanisms that protect their brain cells from the degeneration associated with dementia. Understanding the cellular changes will lead to therapies that can be tested in the lab for individuals.
Metabolism And Neurotoxicity Of Hemin And Hemin-derived Iron
Funder
National Health and Medical Research Council
Funding Amount
$346,400.00
Summary
Stroke is a leading cause of death and disability in industrialised countries. Much of the brain damage that follows a hemorrhagic stroke is attributable to the presence of free iron which mediates oxidative stress in brain cells. This iron originates from hemin, which in turn is derived from the hemoglobin in extravasated blood cells. The fact that iron is freed from hemin in the post-stroke period makes it an attractive therapeutic target. However, remarkably little is known about the metaboli ....Stroke is a leading cause of death and disability in industrialised countries. Much of the brain damage that follows a hemorrhagic stroke is attributable to the presence of free iron which mediates oxidative stress in brain cells. This iron originates from hemin, which in turn is derived from the hemoglobin in extravasated blood cells. The fact that iron is freed from hemin in the post-stroke period makes it an attractive therapeutic target. However, remarkably little is known about the metabolism of hemin by the different types of brain cells. The present project investigates the metabolism and neurotoxicity of hemin in brain cells and will examine the capacity of potential therapeutic agents to protect brain cells from hemin toxicity. The data obtained from this project will advance our understanding of the uptake and metabolism of hemin by the four main types of brain cell, and the factors that are likely to be involved in the neurotoxicity of hemin-derived iron following hemorrhagic stroke. The study will also provide data concerning the relative effectiveness of potential therapeutic agents, and information concerning the cell types, time points and aspects of hemin metabolism that are most effectively targeted by these agents. Such advances will guide the development of therapeutic approaches that are directed at minimising the brain damage which results from hemin-derived iron in humans.Read moreRead less
Subcellular recruitment of a RhoA ubiquitination complex by Rnd proteins. This study addresses a novel molecular mechanism through which members of the Rnd family of GTP-binding proteins regulate the morphology and migration of immature nerve cells of the developing nervous system. This study has broad implications for the understanding of cell migration during embryo development, as well as in health and disease.
Assessing the mechanisms and dynamics of myelination in the brain. This project is expected to refine our understanding of brain plasticity by revealing how myelin plasticity optimises brain function in response to experience. Using a multidisciplinary approach incorporating animal studies, mathematical modelling and computational neuroscience, the project seeks to redefine our understanding of myelin remodelling using an entirely new integrated cell-to-system approach. The expected outcome is f ....Assessing the mechanisms and dynamics of myelination in the brain. This project is expected to refine our understanding of brain plasticity by revealing how myelin plasticity optimises brain function in response to experience. Using a multidisciplinary approach incorporating animal studies, mathematical modelling and computational neuroscience, the project seeks to redefine our understanding of myelin remodelling using an entirely new integrated cell-to-system approach. The expected outcome is fundamental knowledge revealing how myelination is dynamically regulated by neural activity throughout life. This may transform current understanding of neuroplasticity that could aid in the future development of strategies to improve brain health.Read moreRead less
Astrocyte Regulation Of Ammonia And Glutamate In Neonatal Hypoxia-Ischaemia
Funder
National Health and Medical Research Council
Funding Amount
$523,804.00
Summary
Lack of oxygen is a common problem for newborn infants, ocurring during events such as a difficult labour, and can lead to brain damage. We have discovered that a protein in the brain which normally removes ammonia (a toxic product of metabolism) is rapidly lost after a brief period of low oxygen. We propose that a build up of ammonia in the brain may be a key damaging event in hypoxia-related brain injury, and that it will be ameniable to therapeutic intervention.
Microtubule structure in nervous system repair. This Project aims to investigate the role of structural and functional cellular components known as microtubules in nervous system regeneration. This Project aims to use innovative approaches in confocal and electron microscopy, genetics, and cell biology, with the expectation of generating new knowledge into nervous system repair. Expected outcomes of this Project include a comprehensive description of how microtubules are rearranged following ner ....Microtubule structure in nervous system repair. This Project aims to investigate the role of structural and functional cellular components known as microtubules in nervous system regeneration. This Project aims to use innovative approaches in confocal and electron microscopy, genetics, and cell biology, with the expectation of generating new knowledge into nervous system repair. Expected outcomes of this Project include a comprehensive description of how microtubules are rearranged following nervous system injury and the importance of microtubule modifying proteins in promoting regeneration. This should provide significant benefits in our understanding of the cellular mechanisms behind nervous system repair, and offer new approaches for promoting regeneration after injury.Read moreRead less
Molecules and mechanisms regulating axonal degeneration and regeneration in Caenorhabditis elegans neurons. Understanding the molecular mechanisms underlying nerve degeneration and regeneration is essential to tackle and provide treatment for neurodegenerative diseases and injury of the nervous system. This project aims to discover, using a genetic approach and a simple animal model system, the molecules regulating these crucial biological processes.