Mechanisms Of Cell Death In Focal Cerebral Ischaemia
Funder
National Health and Medical Research Council
Funding Amount
$229,624.00
Summary
Stroke most commonly results from interruption to a major artery in the brain. If not rapidly reversed the reduction in blood flow leads to the death of many cells in the brain tissue. There is currently considerable interest in developing treatments to be used in the early stages of stroke that can reduce cell death. As the extent of cell death is the major determinant of the long-term disabilities from stroke, such treatments are likely to provide considerable benenfits for affected individual ....Stroke most commonly results from interruption to a major artery in the brain. If not rapidly reversed the reduction in blood flow leads to the death of many cells in the brain tissue. There is currently considerable interest in developing treatments to be used in the early stages of stroke that can reduce cell death. As the extent of cell death is the major determinant of the long-term disabilities from stroke, such treatments are likely to provide considerable benenfits for affected individuals. Our study will investigate mechanisms underlying the death of brain cells in an animal model of stroke and in cells treated in culture. These studies will specifically focus on the role in cell death of alterations in mitochondria, a part of the cell that provides the energy needed for their normal function. The proposed investigations will identify molecular events that contribute to the mitochondrial dysfunction and examine the importance of these changes in brain tissue damage. The findings should contribute to the identication of new therapeutic approaches aimed at ameliorating the consequences of stroke.Read moreRead less
Characterisation Of Antioxidant Pathways Involving Gpx-1: Implications For Neural Ischemic Reperfusion Injury.
Funder
National Health and Medical Research Council
Funding Amount
$458,250.00
Summary
Neural damage following stroke can be grouped into two stages. The first occurs immediately following the ischemic insult and results in the rapid loss of neural cell viability; the second stage (which usually results in severe neural dysfunction) occurs over many hours following reperfusion. There is however, a window of opportunity shortly following the ischemia-reperfusion where damage to the brain can be minimized if appropriate therapeutic intervention was available. However, our ability to ....Neural damage following stroke can be grouped into two stages. The first occurs immediately following the ischemic insult and results in the rapid loss of neural cell viability; the second stage (which usually results in severe neural dysfunction) occurs over many hours following reperfusion. There is however, a window of opportunity shortly following the ischemia-reperfusion where damage to the brain can be minimized if appropriate therapeutic intervention was available. However, our ability to identify novel targets and devise strategies for the treatment of stroke relies on our understanding of (a) the molecular processes that are initiated following brain ischemia and (b) the delayed molecular events that follow reperfusion and hypoperfusion and result in extensive neuronal loss. A major component that accompanies stroke is the generation of oxidative stress. Reactive oxygen species (ROS) are thought to make a significant contribution to neuronal cell injury and death during both the early and late stages following ischemia. Therefore the molecular pathways that are involved in ROS generation are prime targets for the development of improved therapies. It has already been established by us that the antioxidant enzyme, glutathione peroxidase-1 (Gpx-1) is essential in protecting neurons from ischemic injury-death. A clearer understanding of how Gpx-1 confers this protection in vivo would make an important contribution towards the design of improved treatments. In this proposal, we plan to determine the role of Gpx-1 in an in vivo model of stroke to: (1) demonstrate in a broader sense the functional importance of this antioxidant enzyme in neuronal survival and (2) to demonstrate in a more specific manner, the impact of this enzyme on two signaling molecules, PI3kinase (PI3K) and NFkB (both of which are redox sensitive and play important roles in neuronal cell viability) and their relevance to ischemic cell injury and death.Read moreRead less
NOVEL THERAPIES FOR ALZHEIMER'S DISEASE BASED ON A-BETA - METAL INTERACTIONS
Funder
National Health and Medical Research Council
Funding Amount
$461,443.00
Summary
The genetic data clearly show that the amyloid protein (A-beta) is central to the brain damage which occurs in Alzheimer's disease (AD). However exogenous or environmental factors involved in regulating its toxic actions are not understood. We have shown that the metals zinc and copper have dramatic effects on the properties of A-beta and that chemicals which alter the amounts of these metals in the brain may be useful in treating the disease. In this project we are investigating the ability of ....The genetic data clearly show that the amyloid protein (A-beta) is central to the brain damage which occurs in Alzheimer's disease (AD). However exogenous or environmental factors involved in regulating its toxic actions are not understood. We have shown that the metals zinc and copper have dramatic effects on the properties of A-beta and that chemicals which alter the amounts of these metals in the brain may be useful in treating the disease. In this project we are investigating the ability of one such compound to affect the metabolism of A-beta in a mouse model of AD.Read moreRead less
The Role Of Oxidative Stress In The Patho-aetiology Of Prion Disorders Using Infected Cell Culture And Animal Models
Funder
National Health and Medical Research Council
Funding Amount
$112,014.00
Summary
The transmissible spongiform encephalopathies (TSE; also known as prion diseases) are a biologically unique and fascinating group of invariably fatal diseases which primarily affect the brains of both humans and animals. In humans, sporadic Creutzfeldt-Jakob disease (CJD) is the most common form, while in animals it is the recent epidemic of bovine spongiform encephalopathy (mad cow disease), and its probable transmission to humans as new variant CJD, which has drawn so much attention to this gr ....The transmissible spongiform encephalopathies (TSE; also known as prion diseases) are a biologically unique and fascinating group of invariably fatal diseases which primarily affect the brains of both humans and animals. In humans, sporadic Creutzfeldt-Jakob disease (CJD) is the most common form, while in animals it is the recent epidemic of bovine spongiform encephalopathy (mad cow disease), and its probable transmission to humans as new variant CJD, which has drawn so much attention to this group of disorders. The preponderance of scientific evidence now supports the belief that infectivity in TSEs relates predominantly (probably exclusively) to a protein (called the prion protein; PrP) which is normally found on the cell surface of a number of types of brain cells, including neurons. Transmissibility, and hence infectivity, is more correctly associated with a malfolded version of PrP into an abnormal shape which gives the mutant protein significantly different biological and biochemical properties, including relative resistance to breakdown by enzymes that metabolise proteins (proteases) and enhanced tendency to aggregate. However, the precise steps involved in this transformation to the abnormal infectious form of PrP are not known. Similarly, our understanding of how different folding and accumulation of this protein brings about disease is not clear. Nevertheless, as with other neurological diseases (eg Alzheimer's disease) which are a consequence of unexplained spontaneous premature degeneration of parts of the brain (neurodegenerative diseases), oxidative stress is increasingly believed to play a role. Oxidative stress is a generic term used to describe the enhanced production within a cell of small, very harmful, oxygen containing molecules which under normal circumstances can be successfully detoxified. This project involves a detailed study of the role of oxidative stress in the causation of prion diseases using both mouse and cell culture models.Read moreRead less
By the time a patient first presents with symptoms of Parkinson's disease at the clinic, a large proportion (60-70%) of the cells in a specific part of the brain have been destroyed. This degeneration progresses until, within a few years, most of the cells have died. This project investigates the mechanisms involved in the continued death of cells and a possible new therapy that interrupts the progression. If the aims of this proposal are met, the drug could rapidly go to clinical trial.
Deciphering The Neuroprotective Mechanism Of Parkinsons Disease-Associated Protein Kinase PINK1
Funder
National Health and Medical Research Council
Funding Amount
$547,994.00
Summary
Parkinson's disease is caused by premature death of nerve cells that control body movements. The enzyme PINK1 protects against nerve cell death by chemically modifying specific cellular proteins that maintain cell survival. We aim at identifying these proteins and investigating how PINK1-catalysed modification modulates their ability to maintain nerve cell survival. The study will benefit development of drugs that protect against nerve cell death for treatment and prevention of the disease.
Central Control Of Stress-induced Changes In Immune Function.
Funder
National Health and Medical Research Council
Funding Amount
$411,724.00
Summary
LONG-TERM STRESS CAN ALTER OUR BRAIN'S ATTEMPTS TO FIGHT INFECTION Long-term stress is often blamed for causing illness but precisely how this occurs is now only beginning to be realised. It is especially disturbing that long-term stress can increase one's susceptibility to infections. Stress can alter the way our brain can help deal with assaults by bacteria and viruses. Normally, at the start of an infection, we release a hormone called cortisol from our adrenal glands. A low level of cortisol ....LONG-TERM STRESS CAN ALTER OUR BRAIN'S ATTEMPTS TO FIGHT INFECTION Long-term stress is often blamed for causing illness but precisely how this occurs is now only beginning to be realised. It is especially disturbing that long-term stress can increase one's susceptibility to infections. Stress can alter the way our brain can help deal with assaults by bacteria and viruses. Normally, at the start of an infection, we release a hormone called cortisol from our adrenal glands. A low level of cortisol in our body is beneficial because it can prevent the infection from taking hold in our body and spreading. However if we are chronically stressed our brains tell the adrenal glands to secrete excessive amounts of cortisol over long periods of time and this imbalance can actually hinder the ability of one's immune system to fight an infection. The unfortunate consequence is that the infection is more likely to win the battle and spread to cause further havoc. The present study will identify which areas of the brain are important in driving the secretion of cortisol during infection and how long-term stress can influence those areas. Because we might be exposed to long-term psychological stress that is repeated regularly or irregularly we will determine which pattern of stress has the greatest effect. An investigation into how the brain operates during long-term stress and infection will help us develop ways to prevent stress from disrupting our immune systems.Read moreRead less