The Sulphate Anion Protects Against Stroke: Characterisation Of Neuroprotective Potential And Mechanism Of Action.
Funder
National Health and Medical Research Council
Funding Amount
$189,170.00
Summary
Stroke-cerebral ischaemia affects approximately 40,000 - 50,000 Australians every year and is Australia's leading single cause of disability and second greatest cause of death after heart disease. About 25% of people who suffer a stroke die within one month while most survivors are disabled because of impaired speech, memory, thought processes, vision, balance, or motor control of the limbs (paralysis). The direct and indirect cost of stroke to the Australian community is over $2 billion annuall ....Stroke-cerebral ischaemia affects approximately 40,000 - 50,000 Australians every year and is Australia's leading single cause of disability and second greatest cause of death after heart disease. About 25% of people who suffer a stroke die within one month while most survivors are disabled because of impaired speech, memory, thought processes, vision, balance, or motor control of the limbs (paralysis). The direct and indirect cost of stroke to the Australian community is over $2 billion annually. Hence preventing or reducing brain damage following stroke is of fundamental clinical, social and economic significance. A stroke occurs when there is a reduced blood supply to the entire brain (Global ischaemia; eg. cardiac arrest, heart bypass surgery, closed head injury) or when there is a reduced blood supply to a specific region of the brain, usually as a result of a blockage in a brain artery (thrombo-embolic stroke or focal ischaemia). Despite decades of research, there is no totally satisfactory clinical treatment to reduce brain damage following stroke; the search for new treatments is paramount. We have shown that sodium sulphate can prevent brain damage in rat models of focal and global ischaemia. Importantly we demonstrated that sodium sulphate could prevent brain damage when given up to 8 hours after the stroke was induced in the global model. Delayed treatment following stroke is of clinical significance, since most patients do not receive medical attention until several hours after initial stroke symptoms. It is not known how sodium sulphate protects the brain from stroke. This project has three main aims: 1. To determine the how well sodium sulphate treatment protects the brain in rats following stroke. 2. To determine if sodium sulphate treatment can reduce brain damage in the rat model of focal ischaemia when given 4 - 8 hours after the stroke. 3. To determine how sodium sulphate protects the brain from stroke.Read moreRead less
Identification And Characterisation Of Novel Hydroxylases And Their Substrates Involved In Cellular Hypoxic Response.
Funder
National Health and Medical Research Council
Funding Amount
$239,250.00
Summary
The human body is able to sense and respond to changes in oxygen levels. Under low oxygen (hypoxia) individual cells switch on a number of different genes required to increase red blood cell production and blood flow, and decrease oxygen consumption. This may be under environmental situations such as high altitude, but is also an important part of many human diseases, such as heart attack and stroke (where a clot stops blood flow and oxygen delivery) or cancer (where tumours require oxygen for g ....The human body is able to sense and respond to changes in oxygen levels. Under low oxygen (hypoxia) individual cells switch on a number of different genes required to increase red blood cell production and blood flow, and decrease oxygen consumption. This may be under environmental situations such as high altitude, but is also an important part of many human diseases, such as heart attack and stroke (where a clot stops blood flow and oxygen delivery) or cancer (where tumours require oxygen for growth). We have known for sometime that a few key proteins are activated by hypoxia, such as the HIF proteins, and these act as a master switch to turn on numerous other genes. However, the actual oxygen sensors have remained a mystery. Recent research by others and myself has identified a number of the oxygen sensors, which are hydroxylase enzymes that require oxygen. Under normal conditions with ample oxygen they modify the HIF proteins and keep them inactive, but when oxygen is limiting they can't modify the HIFs and the unmodified HIF is active. So far four different oxygen sensors have been identified, but there is strong evidence for more sensors, and they are likely to modify more targets than just the HIFs. This project aims to identify new oxygen sensing hydroxylases and novel targets, and determine what they each do. I already have some preliminary information as to what some of the other oxygen sensors might be and also some of their likely targets. This work should greatly enhance our understanding of how the body responds to hypoxia, both under normal conditions and during disease. These oxygen sensors might also be very useful drug targets. For example, drugs that inhibit these enzymes should increase the activity of the HIF proteins and facilitate a more rapid response by the body to a heart attack or stroke, and thus limit the damage, whereas drugs that activate the enzymes would inhibit the HIFs and be useful in limiting tumour growth.Read moreRead less
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
Adenosine A1 And A3 Receptor Mediated Cardioprotection In Ischaemic Myocardium
Funder
National Health and Medical Research Council
Funding Amount
$265,698.00
Summary
Damage to the heart from coronary vascular disease causes significant morbidity and mortality in Australia. Indeed, ischaemic injury represents the single greatest cause of premature death. Moreover, due to the increasing age of our population the problem is growing - coronary artery disease affects 50% of those older than 65, contributing to an increased incidence of angina pectoris, myocardial infarction, arrhythmia, congestive heart failure, and sudden death. Protective strategies have been, ....Damage to the heart from coronary vascular disease causes significant morbidity and mortality in Australia. Indeed, ischaemic injury represents the single greatest cause of premature death. Moreover, due to the increasing age of our population the problem is growing - coronary artery disease affects 50% of those older than 65, contributing to an increased incidence of angina pectoris, myocardial infarction, arrhythmia, congestive heart failure, and sudden death. Protective strategies have been, and continue to be, developed to reduce the extent of tissue damage and minimise prolonged reductions in heart function. The success of these interventions has been mixed. This research project takes the novel approach of identifying the true roles of two receptors present in the heart (the adenosine A1 and A3 receptors) which may play a crucial role in enhancing tolerance of the heart to disease and injury. We currently do not fully understand the roles of these receptors, although preliminary findings suggest they can exert powerful protective effects during disease conditions. From a fundamental viewpoint, identifying the roles of these two receptors will significantly advance our understanding of the mechanisms of injury and protection in the heart. From a therapeutic viewpoint, this study will take us closer to the potential use of adenosine receptor-based therapy in protecting the heart from ischaemic injury.Read moreRead less
The aim of this project is to improve our understanding of the role that increased eye pressure (intraocular pressure or IOP) plays in the development of glaucoma-related nerve death and associated vision loss. Despite being the second leading cause of vision loss in Australia, our understanding of the factors that damage nerves in the eye (the ganglion cells that carry visual information to the brain) in glaucoma remains incomplete. For example, elevated eye pressure is a well-established risk ....The aim of this project is to improve our understanding of the role that increased eye pressure (intraocular pressure or IOP) plays in the development of glaucoma-related nerve death and associated vision loss. Despite being the second leading cause of vision loss in Australia, our understanding of the factors that damage nerves in the eye (the ganglion cells that carry visual information to the brain) in glaucoma remains incomplete. For example, elevated eye pressure is a well-established risk factor for glaucoma, but as many as half of those with glaucoma do not have high eye pressure. Clinical data suggests that pressure fluctuations (or spikes), which go unnoticed in routine clinical check ups, may be involved in glaucoma onset and progression. To date there has been no direct evidence to support this contention. This project aims to use a novel experimental model of pressure elevation in rodents to consider this possibility. By measuring the eye's electrical response to a flash of light it is possible to sensitively assess how pressure spikes, that are known to occur with regularity in humans, might affect the health of retinal ganglion cells. Anatomical measures will also be used to establish the sequence of events that cause cellular damage. This knowledge is an important public health issue, because it will improve understanding of the risk factors for the development of glaucoma. The results may lead to improvements in detection and treatment strategies such as closer monitoring for pressure spikes and more aggressive treatment for those who show greater variability in their eye pressures.Read moreRead less
The Importance Of P38 MAPK Signalling In Aging-Related Ischaemic Intolerance And Failed Cardioprotection
Funder
National Health and Medical Research Council
Funding Amount
$496,302.00
Summary
Ischaemic heart disease is the leading cause of death in Australia, and will rise in coming years with the aging of our population. Our research shows aged hearts become less resistant to damage during ischaemia-heart attack, and insensitive to normally beneficial therapies. This project will identify molecular changes responsible for these changes. By understanding how age impairs the hearts defences, it may be possible to improve therapy of ischaemic heart disease in older patients.
Effects Of Hypoxia And Reactive Oxygen Species On Neuronal Excitability Of Intrinsic Cardiac Ganglia
Funder
National Health and Medical Research Council
Funding Amount
$70,000.00
Summary
Neural control of the heart is mediated by intrinsic cardiac neurones which respond to chemical substances such as neurotransmitters released from nerve fibres innervating the heart and vasoactive substances released into the coronary ciruculation. Prolonged periods of myocardial ischaemia (hypoxia) and post ischaemic reperfusion (oxygen-derived free radicals) influence the electrical activity of the intrinsic cardiac nervous system. The involvement of membrane electrical phenomena in general, a ....Neural control of the heart is mediated by intrinsic cardiac neurones which respond to chemical substances such as neurotransmitters released from nerve fibres innervating the heart and vasoactive substances released into the coronary ciruculation. Prolonged periods of myocardial ischaemia (hypoxia) and post ischaemic reperfusion (oxygen-derived free radicals) influence the electrical activity of the intrinsic cardiac nervous system. The involvement of membrane electrical phenomena in general, and ion-selective pores (ion channels) in particular, and the action of hypoxia and oxygen-derived free readicals on their function will be studied in isolated neurones dissociated from neonatal and adult rat intrinsic cardiac ganglia. The characterization of ion channels modulated by hypoxia and reactive oxygen species will be monitored using electrical and fluorescence techniques. The opening of ion channels in the cell membrane by changes in either voltage or the intracellular calcium ion concentration leads to an electrical response. The goal of the research is to elucidate the mechanisms underlying the effects of ischaemia and ischaemia-reperfusion on neuronal excitability in mammalian cardiac ganglia, thus regulation of the heart rate. Development of therapeutic strategies to prevent ischaemia and reperfusion injuries in coronary heart disease and improvement of cardiac protection during surgery are potential outcomes of this research.Read moreRead less
A Novel Marker Of Distressed Neurons In The Hypoxic Brain: Regulation, Function And Potential Clinical Utility.
Funder
National Health and Medical Research Council
Funding Amount
$526,878.00
Summary
The brain is easily damaged by lack of oxygen (hypoxia). We have recently identified a novel protein called GLAST1b which is expressed in distressed neurons. This protein is a glutamate transporter. Glutamate is implicated as a toxic agent hypoxia. This study will investigate what regulates the expression of GLAST1b, what the consequences of expression are, and whether this marker can be developed as a diagnostic tool for identifying the presence of, and distribution of brain damage.
The Effect Of Ischaemia And Reperfusion On Sarcoplasmic Reticulum Calcium Handling In The Heart
Funder
National Health and Medical Research Council
Funding Amount
$236,208.00
Summary
Ischaemic heart disease is one of the most common causes of premature death in our society. Ischaemia occurs when the blood flow to the heart is obstructed so that oxygen cannot get to the muscle cells and metabolic waste products cannot be washed away. During ischaemia the concentration of free calcium within a cardiac muscle cell increases, and when blood flow is returned to the muscle this calcium concentration can increase further to very high levels. It is this change in calcium that is res ....Ischaemic heart disease is one of the most common causes of premature death in our society. Ischaemia occurs when the blood flow to the heart is obstructed so that oxygen cannot get to the muscle cells and metabolic waste products cannot be washed away. During ischaemia the concentration of free calcium within a cardiac muscle cell increases, and when blood flow is returned to the muscle this calcium concentration can increase further to very high levels. It is this change in calcium that is responsible for the reduced muscle force and abnormal cardiac rhythm that are the main cause of death. Cardiac muscle cells contain an intracellular compartment called the sarcoplasmic reticulum (SR). Under normal conditions the SR stores large amounts of calcium in order to maintain a low concentration of calcium free within the cell. However, even in a resting cell, calcium can escape from the SR through channels in SR membrane. We are using a state-of-the-art microscope to visualize these tiny packets of calcium, termed calcium sparks, as they travel through the SR membrane. If the number of calcium sparks increases, the amount of calcium being released from the SR also increases. We are studying what happens to calcium sparks, and therefore SR calcium release, during ischaemic heart disease. We are also examining the effect of ischaemic heart disease on the concentration of calcium within the SR and the activity of the transporters that pump calcium back into the SR. We hope to show that a change in the way the SR regulates calcium contributes to ischaemic damage. Understanding how changes in SR function alter muscle force and cardiac rhythm will help in the development of drugs to protect against ischaemic damage.Read moreRead less