TNF Traffic And Secretion In Astrocytes And Microglial Cells: Unveilling New Targets For Ischemic Stroke
Funder
National Health and Medical Research Council
Funding Amount
$585,070.00
Summary
Neurodegenerative disorders share a similar pathway to disastrous neurotoxicity, which occurs through the release of cytokines such as tumour necrosis factor-a (TNF) from glial cells. TNF controls inflammation but its excessive secretion in the brain is highly detrimental. The mechanism of TNF secretion is unknown but strategies aimed at reducing it have therapeutic potential. This grant proposes to study TNF discharge to find new ways to reduce secretion and confer protection in a stroke model.
Stroke Induced Disturbances In Glymphatic Clearance: Implications For Brain Repair?
Funder
National Health and Medical Research Council
Funding Amount
$491,688.00
Summary
We have made a remarkable discovery that the ability of the brain to clear waste proteins is significantly impaired after stroke. This may have important implications for development of dementia and milder changes in thinking late after stroke. We already have some clues regarding potential mechanisms. In this project we will further investigate these mechanisms and their effects on the brain and develop our understanding of potential ways to reverse the clearance problem to develop treatments.
Microglial Paralysis In Post-stroke Neurodegeneration: Help Or Hindrance?
Funder
National Health and Medical Research Council
Funding Amount
$512,351.00
Summary
Dementia and cognitive decline may occur months or years after a stroke, associated with delayed loss of brain cells in different brain regions. We recently discovered that the cells responsible for protection and repair of brain, called microglia, become paralysed in these regions. We will use a live-imaging microscope to determine whether the microglial paralysis causes brain cell death. We will also determine if a commonly used stroke prevention drug can worsen the microglial paralysis.
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
Glutamate is one of the major neurotransmitters in the brain. It plays a very important role in most brain functions such as the ability to learn and the development of memory, but the lack of control of glutamate concentrations in the brain also underlies many pathological changes that cause neurological disorders such Alzheimer's disease, disability following a stroke, motor neurone disease and Parkinson's disease. These diseases place an enormous social and economic burden on society and in o ....Glutamate is one of the major neurotransmitters in the brain. It plays a very important role in most brain functions such as the ability to learn and the development of memory, but the lack of control of glutamate concentrations in the brain also underlies many pathological changes that cause neurological disorders such Alzheimer's disease, disability following a stroke, motor neurone disease and Parkinson's disease. These diseases place an enormous social and economic burden on society and in order to better understand and treat these diseases it is important to understand some of the fundamental biochemical processes that underlie both normal and pathogical functions of the key neurotransmitter glutamate. This project will investigate how the concentrations of glutamate are tightly regulated to maintain normal brain function and also to avoid the potentially pathological consequences when these control mechanisms fail.Read moreRead less