Lipid Rafts, Amyloid Neurotoxicity And Alzheimer's Disease
Funder
National Health and Medical Research Council
Funding Amount
$318,267.00
Summary
Alzheimer's disease is the major cause of dementia in the elderly. Individuals with Alzheimer's disease exhibit a slow decline in cognition which usually results in prolonged institutionalisation. This creates an enormous burden on society. The project aims to identify mechanisms which cause Alzheimer's disease. Specifically, it will examine how a component of the brain, known as the amyloid protein, contributes to nerve cell degeneration. It is hoped that by identifying these mechanisms, new ta ....Alzheimer's disease is the major cause of dementia in the elderly. Individuals with Alzheimer's disease exhibit a slow decline in cognition which usually results in prolonged institutionalisation. This creates an enormous burden on society. The project aims to identify mechanisms which cause Alzheimer's disease. Specifically, it will examine how a component of the brain, known as the amyloid protein, contributes to nerve cell degeneration. It is hoped that by identifying these mechanisms, new targets for drug development will be found.Read moreRead less
Is EphA4 The Major Molecular Regulator Of Axonal Regeneration?
Funder
National Health and Medical Research Council
Funding Amount
$491,000.00
Summary
Spinal cord injury affects a substantial number of Australians each year. Around half the number of spinal cord injury cases result in quadriplegia, with loss of function to a varying degree in the upper as well as the lower limbs. The limited degree of repair of spinal axons following injury means that such paralysis is usually permanent. Although the inability to walk is a serious issue, the limited function of the arms and hands results in a loss of independence which is a major factor contri ....Spinal cord injury affects a substantial number of Australians each year. Around half the number of spinal cord injury cases result in quadriplegia, with loss of function to a varying degree in the upper as well as the lower limbs. The limited degree of repair of spinal axons following injury means that such paralysis is usually permanent. Although the inability to walk is a serious issue, the limited function of the arms and hands results in a loss of independence which is a major factor contribuing to the enormous personal, financial, and community costs of this problem, estimated to cost the Australian community $200 million a year. In recent years advanced anatomical and molecular approaches to the problem of repair of the central nervous system have provided great insights into the neuronal and glial reactions to neural damage that appear to govern the success or failure of neural regeneration. Our preliminary data indicate that a receptor tyrosine kinase, EphA4, which is important for axonal pathfinding in the developing nervous system, is a potent inhibitor of neural regeneration following spinal cord injury. In this project we will determine the mechanisms by which EphA4 exerts its inhibitory effects, and examine the effect of neutralizing EphA4 signalling on neural regeneration. Success in achieving this result will lead to the development of a therapeutic intervention that we will test in mouse models.Read moreRead less
Within the nervous system, neurons communicate through the release of neurotransmitter chemicals across connections between individual neurons (synapses). Before their release, neurotransmitters are stored inside nerve endings, within small membranous spheres called synaptic vesicles. Neuronal cell shape and the neuron's ability to migrate to different regions of the brain during development affect the way that the adult brain functions. Alterations in any of these brain functions may lead to di ....Within the nervous system, neurons communicate through the release of neurotransmitter chemicals across connections between individual neurons (synapses). Before their release, neurotransmitters are stored inside nerve endings, within small membranous spheres called synaptic vesicles. Neuronal cell shape and the neuron's ability to migrate to different regions of the brain during development affect the way that the adult brain functions. Alterations in any of these brain functions may lead to diseases affecting normal mental function. Ral is a small GTPase enzyme found in brain, and particularly in neurons. Small GTPases are responsible for regulating cell functions by acting as switches, turning biochemical processes on and off inside the cell. Within neurons, Ral is found on the surface of synaptic vesicles, implicating it in the regulation of neurotransmitter release. Other Ral functions have been demonstrated in non-neuronal cells that may be of particular significance in neuronal cells. However, no studies have previously investigated Ral function in the nervous system. The research proposed aims to establish what role RalA performs within neuronal cells, and by what biochemical mechanism it performs this role. Techniques of molecular biology, biochemistry and microscopy will be used to establish these functions. This research will lead to increased knowledge of the significance of this protein to cellular, and particularly neuronal cell function. This forms the basis for the understanding normal neuronal function, and for the identification of factors causing diseases of the nervous system. In time, such research aids in the development of specific therapies for sufferers of such diseases of the nervous system.Read moreRead less
Roles Of Peripherally Derived BDNF In Regeneration Of Spinal Cord And The Mechanisms
Funder
National Health and Medical Research Council
Funding Amount
$472,770.00
Summary
Injury to the brain and spinal cord often leads to permanent disability due to lack of regeneration. The mechanism why central nerve does not regenerate is not known. Neurotrophic factors are powerful molecules which can overcome effects of inhibitory factors on regeneration. This project aims to investigate how neurotrophic factors override the effects of inhibitory factors and how to improve the regeneration by increasing the production of neurotrophic factors within nerves. Successful complet ....Injury to the brain and spinal cord often leads to permanent disability due to lack of regeneration. The mechanism why central nerve does not regenerate is not known. Neurotrophic factors are powerful molecules which can overcome effects of inhibitory factors on regeneration. This project aims to investigate how neurotrophic factors override the effects of inhibitory factors and how to improve the regeneration by increasing the production of neurotrophic factors within nerves. Successful completion of this project will help understanding the mechanism of how neurotrophic factors work on regeneration and developing the effective way to improve regeneration of the injured spinal cord.Read moreRead less
Sialyltransferase In The Bipolar And Schizophrenic Brain: Examining The Role Of A Novel Generalised Susceptibility Gene
Funder
National Health and Medical Research Council
Funding Amount
$512,627.00
Summary
Bipolar disorder and schizophrenia are two major psychiatric conditions affecting over 800,000 Australians. We have identified a new gene which contributes to increased risk to developing both bipolar disorder and schizophrenia. We will investigate the function of this gene in normal brain development, and how this function is disrupted in individuals with bipolar disorder and schizophrenia. Understanding the biological cause will help us define better treatments for these severe mental illnesse ....Bipolar disorder and schizophrenia are two major psychiatric conditions affecting over 800,000 Australians. We have identified a new gene which contributes to increased risk to developing both bipolar disorder and schizophrenia. We will investigate the function of this gene in normal brain development, and how this function is disrupted in individuals with bipolar disorder and schizophrenia. Understanding the biological cause will help us define better treatments for these severe mental illnesses.Read moreRead less
Identifying Genetic Pathways Underlying The Development Of Distinct Neuronal Subtypes Among Midbrain Dopamine Neurons.
Funder
National Health and Medical Research Council
Funding Amount
$462,709.00
Summary
There is an urgent need in the field of Parkinson's disease (PD) research to develop new strategies aimed at halting progression of the disease (neuroprotection) and alleviaing the symptoms (restorative therapy). This project employs a novel and innovative design to identify genes expressed specifically by the cell type most effected in PD and therefore provide new genetic targets for neuroprotective and resorative therapy.
Sez-6 Signalling Mechanisms And Function In The Developing Neocortex
Funder
National Health and Medical Research Council
Funding Amount
$501,815.00
Summary
Over the course of evolution, the mammalian brain cortex has become disproportionately large with respect to other brain regions. The dramatic increase in processing power resulting from the increased neuronal number and connectivity in the cortex has enabled us to acquire functions that make us human, such as the use of language. In spite of the enormous difference in size between the brains of humans and those of mice, studies on cortical development in mice are relevant to humans since the or ....Over the course of evolution, the mammalian brain cortex has become disproportionately large with respect to other brain regions. The dramatic increase in processing power resulting from the increased neuronal number and connectivity in the cortex has enabled us to acquire functions that make us human, such as the use of language. In spite of the enormous difference in size between the brains of humans and those of mice, studies on cortical development in mice are relevant to humans since the organization of the cortex (thickness, layer patterning and regional specialization) is very similar in these two organisms, and indeed, in all mammals. A complex series of developmental events is required to produce a normal brain cortex. Malformations in the cortex occurring in human neurological disorders, including epilepsy and mental retardation, result from mutations in genes regulating crucial developmental processes. Failure of developing nerve cells to make the correct connections can result in these, or other, debilitating neurological conditions. We have evidence that a brain protein called Seizure-related gene 6 (Sez-6) regulates normal connectivity and function of neurons in the mature cortex. We will determine the molecular pathways used for signalling of Sez-6 and also investigate in detail the formation of connections between cortical neurons early in development and how these connections become aberrant in the absence of Sez-6 function.Read moreRead less
The Use Of Soluble Antagonists Of EphA4 In Spinal Cord Injuries
Funder
National Health and Medical Research Council
Funding Amount
$622,361.00
Summary
Permanent and limited recovery of function following spinal cord injury is a direct result of the lack of nerve regrowth through the injury. Our preliminary data suggest that antagonising the effects of EphA4, a protein involved in brain development, leads to substantial functional recovery simultaneous with nerve regrowth. In addition to designing new, more effective blockers of EphA4, we will study the signalling pathways that EphA4 activates to inhibit nerve regrowth.
Inside our cells is a complex traffic system. The vehicles are vesicles that come in different shapes and sizes and travel to specific destinations in the cell to deliver cargo such as: surface growth factor receptors that are to have their signalling terminated, proteins and lipids destined for the cell wall for growth or development (like neurite outgrowth) and proteins and hormones destined for secretion (like neurotransmitter release). More than 100 human genetic disorders map to defects in ....Inside our cells is a complex traffic system. The vehicles are vesicles that come in different shapes and sizes and travel to specific destinations in the cell to deliver cargo such as: surface growth factor receptors that are to have their signalling terminated, proteins and lipids destined for the cell wall for growth or development (like neurite outgrowth) and proteins and hormones destined for secretion (like neurotransmitter release). More than 100 human genetic disorders map to defects in one of the components of this system. Proteins called small GTPases provide order for this traffic and allow specific cargo to reach specific destinations. They regulate cell functions by acting as switches, turning biochemical processes on and off inside the cell. Ral is a small GTPase enzyme found in brain and broadly distributed in other cells. We have discovered that Ral is part of a large signalling complex. When activated Ral stimulates effectors, either the exocyst or RalBP1. In turn, mild oxidative stress controls a Ral inhibitor protein called ERp57. The research proposed aims to establish the functional role for the Ral signalling complex in cells. We will determine with which vesicle trafficking events Ral is associated, which effector it utilises in that pathway, and how that effector directs the traffic. We will also map the steps that may lead to inactivation of Ral via ERp57 in cells, and propose that this is mediated by mild oxidative stress. Techniques of molecular biology, biochemistry, molecular biology, proteomics and microscopy will be used to establish these functions. The research will lead to increased knowledge of the significance of this protein to cellular and particularly neuronal cell function. This forms the basis for understanding normal cell function and for identification of further factors causing diseases of vesicle transport. In time, such research aids in the development of specific therapies for sufferers of such diseases.Read moreRead less