Arachidonic Acid Modulation Of Glutamate Transporters
Funder
National Health and Medical Research Council
Funding Amount
$286,980.00
Summary
Neurotransmitter transporters play a key role in regulating the dynamics of neurotransmission and are also the targets for a number of very important drugs. Glutamate is the predominant neurotransmitter responsible for fast excitatory neurotransmission and glutamate transporters are responsible for controlling glutamate concentrations to maintain normal neurotransmission. The failure of glutamate transporters has been implicated as playing a key role in brain damage following a stoke and also fo ....Neurotransmitter transporters play a key role in regulating the dynamics of neurotransmission and are also the targets for a number of very important drugs. Glutamate is the predominant neurotransmitter responsible for fast excitatory neurotransmission and glutamate transporters are responsible for controlling glutamate concentrations to maintain normal neurotransmission. The failure of glutamate transporters has been implicated as playing a key role in brain damage following a stoke and also for long term neurological disorders such as Alzheimer's disease. In this project we shall investigate a novel mechanism for regulating the activity of glutamate transporters and explore the possibility of pharmacologically manipulating glutamate transporters. This work may lead to the development of novel compounds that improve transporter function and reduce the pathological consequences of impaired transporter function. Such compounds may have therapeutic potential as neuroprotectants in the treatment of neurological disorders such ischaemic brain damage or neurodegenerative disorders such Alzheimer's disease.Read moreRead less
The Influence Of Gender And Steroid Hormones On Cerebrovascular NADPH Oxidase During Health And Disease
Funder
National Health and Medical Research Council
Funding Amount
$390,974.00
Summary
My research addresses several major questions regarding the regulation of brain blood flow and mechanisms that may contribute to stroke. There is confusion as to whether giving menopausal women hormone replacement worsens the effect of having a stroke. I propose that female hormones may lower blood flow to the brain after menopause and therefore cause more damage to the brain after stroke.
Pharmacological Modulation Of Microglial Responses After Transient Forebrain Ischaemia In Rats
Funder
National Health and Medical Research Council
Funding Amount
$170,906.00
Summary
A stroke is caused by an acute blockade of blood flow to a brain region and is normally caused by a clot in the artery that supplies blood to that region. Within minutes, the region of the brain that is receiving no blood flow, dies and so the functions controlled by that region cease. If this region controls key functions such as breathing then the patient dies and this occurs in about one third of patients. However, in the majority of patients, the blockage affects parts of the brain controlli ....A stroke is caused by an acute blockade of blood flow to a brain region and is normally caused by a clot in the artery that supplies blood to that region. Within minutes, the region of the brain that is receiving no blood flow, dies and so the functions controlled by that region cease. If this region controls key functions such as breathing then the patient dies and this occurs in about one third of patients. However, in the majority of patients, the blockage affects parts of the brain controlling movement of limbs or speech and so these patients suffer permanent disabilities. Not surprisingly, stroke is the most common life-threatening neurological disease and the major cause of disability in adults over 45. Apart from the profound effect stroke has on the patient and the family, the annual cost of disability to the Australian community is approx $ 1 billion. If the disability could be minimised by reducing institutionalization then the cost saving would be great. Research is being carried out to define how nerves die when they have insufficient blood supply and progress has been made in understanding the biochemical basis of this process. Such knowledge opens the way for the design of novel drugs to delay nerve death. Our laboratory has been successful in designing a novel drug, AM-36 that minimises nerve death in the forebrain of rats that have had the blood supply to the forebrain interrupted for 3 to 5 hours. A recent report has shown that a stroke in the forebrain can lead to nerve damage in the spinal cord and this could contribute to impaired walking in stroke patients. This is an unexpected finding and this project seeks to define how and when nerves in the spine die after a stroke in the forebrain. Such information should then lead to the rational design of drugs to minimise the death of nerves in the spinal cord as well as in the forebrain.Read moreRead less
Molecular Pharmacology And Physiology Of Glycine Transport
Funder
National Health and Medical Research Council
Funding Amount
$170,274.00
Summary
The simple amino acid glycine plays an important role in many metabolic events in the body and in the mammalian central nervous system glycine has additional functions as a neurotransmitter. In the spinal cord and brain stem, glycine acts as an inhibitory neurotransmitter through activation of glycine receptors. In the brain, glycine may also act as an excitatory neurotransmitter through its action as a co-activator with glutamate at the NMDA subtype of glutamate receptors. This project will add ....The simple amino acid glycine plays an important role in many metabolic events in the body and in the mammalian central nervous system glycine has additional functions as a neurotransmitter. In the spinal cord and brain stem, glycine acts as an inhibitory neurotransmitter through activation of glycine receptors. In the brain, glycine may also act as an excitatory neurotransmitter through its action as a co-activator with glutamate at the NMDA subtype of glutamate receptors. This project will address the issue as to whether glycine transporters have the capacity to regulate glycine concentrations within excitatory synapses and thereby play an active role in regulating neurotransmission. This work will form the basis for understanding the role that glycine plays in normal brain functions, such as learning and memory, and also under pathological conditions following a stroke. This work will also serve as a basis for assessing the therapeutic potential of manipulating glycine concentrations in the treatment of neurological disorders, such as schizophrenia.Read moreRead less
HYPOXIA AND THE TRANSCRIPTIONAL REGULATION OF CYP GENES IN CELLS
Funder
National Health and Medical Research Council
Funding Amount
$211,527.00
Summary
Hypoxia, or oxygen deprivation caused by the decreased supply of blood to cells, is a component of ischaemic injury of the cardiovascular system (as in angina or atherosclerosis) and numerous other organs (e.g. in cancer and chemical-mediated injury). It is now known that the content of certain proteins that activate specialised target genes is increased rapidly in cells in response to oxygen deprivation. Some of the most important of these proteins are hypoxia-inducible factor-1 (or HIF-1) and ....Hypoxia, or oxygen deprivation caused by the decreased supply of blood to cells, is a component of ischaemic injury of the cardiovascular system (as in angina or atherosclerosis) and numerous other organs (e.g. in cancer and chemical-mediated injury). It is now known that the content of certain proteins that activate specialised target genes is increased rapidly in cells in response to oxygen deprivation. Some of the most important of these proteins are hypoxia-inducible factor-1 (or HIF-1) and activator protein-1 (or AP-1). We have identified a novel target gene that is activated in hypoxia. This gene produces an enzyme, termed cytochrome P450 2J2, that acts on fatty acids which are present in cell membranes and converts them into molecules that control the flow of potassium and calcium ions into cells. Alterations in the flow of such ions into cells have been observed previously in hypoxia but the mechanism of this effect is unclear. Thus, cytochrome P450 2J2 is switched on in hypoxia and generates fatty acid metabolites that control protective ion fluxes in cells.Read moreRead less
Alternate Signalling Pathways Regulating The Human Arachidonate Epoxygenase CYP2J2 In Response To Stress Stimuli
Funder
National Health and Medical Research Council
Funding Amount
$369,000.00
Summary
Hypoxia, or oxygen deprivation, is caused by the decreased supply of blood to cells and is a component of ischaemic injury to the cardiovascular system (e.g. stroke, atherosclerosis) and numerous other organs (e.g. cancer and chemical mediated injury). It is now known that an important group of proteins that switch on specialised target genes in response to hypoxia is Activator-Protein-1 (AP-1). We have found that cytochrome P450 2J2 (CYP2J2), which is an enzyme that forms beneficial fatty acid ....Hypoxia, or oxygen deprivation, is caused by the decreased supply of blood to cells and is a component of ischaemic injury to the cardiovascular system (e.g. stroke, atherosclerosis) and numerous other organs (e.g. cancer and chemical mediated injury). It is now known that an important group of proteins that switch on specialised target genes in response to hypoxia is Activator-Protein-1 (AP-1). We have found that cytochrome P450 2J2 (CYP2J2), which is an enzyme that forms beneficial fatty acid products inside cells, is decreased in hypoxia and that this is due to increased activity of AP-1. We know that similar stressful stimuli can also result in a loss of CYP2J2. Again, AP-1 is involved but we have further evidence for the role of another pathway. This project will explore how these pathways operate individually and together to decrease CYP2J2. Studying the regulation of human genes is difficult because we can not readily monitor their levels in cells in either healthy or sick individuals. So we will make transgenic mouse models to study human CYP2J2 regulation, which will provide information on the human situation. In this project we will identify which factors switch off the CYP2J2 transgene and will analyse the signalling pathways within cells that control this response. The importance of these studies is that they will help us to design pharmacological strategies to prevent the loss of CYP2J2 in cells that are stressed. Such agents may be effective in the treatment of ischaemic injury seen in stroke and atherosclerosis. If we can maintain CYP2J2 levels we may be able to maintain the beneficial fatty acid levels in cells and have a novel therapeutic approach for keeping cells alive.Read moreRead less
Does NADPH Oxidase Link Gender, Hormone Replacement Therapy And Outcome After Stroke?
Funder
National Health and Medical Research Council
Funding Amount
$481,439.00
Summary
This project will assess whether the reduction of a novel mechanism to open brain arteries (i.e. via activation of 'Nox' proteins and generation of oxygen radicals) is a possible explanation of why hormone replacement therapy (HRT) increases the risk of stroke in postmenopausal women. We will compare brain artery function of normal mice with those deficient in certain Nox genes in models of menopause, HRT and stroke. This knowledge should lead to safer stroke therapies in women and men.
Pharmacological Strategies To Prevent Damage To White Matter In The Central Nervous System After Ischaemia
Funder
National Health and Medical Research Council
Funding Amount
$150,770.00
Summary
A stroke is caused by an acute blockade of blood flow to a brain region and in most cases, is caused by a clot in the artery that supplies the oxygenated blood and nutrients such as glucose to that region. Within minutes, the region of the brain that is deprived of blood flow will die and so the functions controlled by that region are lost. In the majority of stroke patients, the middle cerebral artery is blocked and this affects parts of the brain controlling movement of limbs or speech and so ....A stroke is caused by an acute blockade of blood flow to a brain region and in most cases, is caused by a clot in the artery that supplies the oxygenated blood and nutrients such as glucose to that region. Within minutes, the region of the brain that is deprived of blood flow will die and so the functions controlled by that region are lost. In the majority of stroke patients, the middle cerebral artery is blocked and this affects parts of the brain controlling movement of limbs or speech and so these patients suffer permanent disabilities. Not surprisingly, stroke is the most common life-threatening neurological disease and the major cause of disbility in adults over 45 years of age. Apart from the profound effect that stroke has on the patient and family, the annual cost of disability to the Australian community is approximately $ 1 billion. If the disability could be reduced, this could reduce the need for institutionalisation of patients and then the cost saving would be great. So our research is directed towards designing drugs to minimise the disability after stroke. Research in the past has focussed on designing drugs to minimise damage to the grey matter in brain but it is becoming apparent that the white matter in brain is very important for transmitting information and also needs to be protected. We will study the biochemical changes in white matter after a stroke in a rat model and use this information to design in a rational way, novel drugs to minimise damage to white matter (axons), thereby reducing the degree of disability after a stroke.Read moreRead less
Voltage Dependent Calcium Channels And Vascular Function: Do Microdomains Determine Function?
Funder
National Health and Medical Research Council
Funding Amount
$597,682.00
Summary
Blood flow depends on arterial diameter which can change with contraction of muscle in the vessel wall. Calcium influx through one type of channel in the muscle cells has been considered critical, but drugs targeting these channels have not succeeded in treating the arterial spasm which occurs after stroke and head injury. Our study will investigate the existence and role of other calcium channels in brain arteries. Knowledge gained will likely lead to development of new drug targets for stroke.
Metabotropic Glutamate Receptors: Pharmacological Studies Of Receptor Subtypes In Neuronal Injury.
Funder
National Health and Medical Research Council
Funding Amount
$145,770.00
Summary
Glutamate is the major transmitter of excitatory information in the mammalian brain. Disruption of glutamate-mediated signaling between brain cells results in high extracellular levels of glutamate which is toxic to neurones. A recently discovered family of signal transducers, the metabotropic glutamate receptors, has been found to be localized on neurones and is switched on by these toxic glutamate levels. The roles of these metabotropic glutamate receptors in neurotoxicity is essentially unexp ....Glutamate is the major transmitter of excitatory information in the mammalian brain. Disruption of glutamate-mediated signaling between brain cells results in high extracellular levels of glutamate which is toxic to neurones. A recently discovered family of signal transducers, the metabotropic glutamate receptors, has been found to be localized on neurones and is switched on by these toxic glutamate levels. The roles of these metabotropic glutamate receptors in neurotoxicity is essentially unexplored and is the topic under investigation in this project. How their activation affects cellular signaling switch on will be investigated to gain an understanding of the roles metabotropic glutamate receptors play in acute brain injury (eg stroke) and chronic neurodegenerative conditions (eg Huntington's chorea and Alzheimer's disease).Read moreRead less