NADPH Oxidase In Pathological Angiogenesis In Solid Tumours And Retina
Funder
National Health and Medical Research Council
Funding Amount
$581,989.00
Summary
Understanding blood vessel growth has profound clinical implications for many diseases. Blocking vessel growth is a promising strategy for treatment of cancer and eye complications accompanying diabetes, whereas treatments to stimulate new vessel growth will treat ischemic disorders ie. heart attack and stroke. Here we investigate whether targeting an enzyme that grows blood vessels has potential for making drugs to stop tumor growth or eye damage that occurs with diabetes and premature births.
Iron is essential for the growth of all cells. Generally, cancer cells have a high iron requirement due to their rapid rate of proliferation. This makes them susceptible to the action of drugs called iron chelators that deplete cell iron. A wide variety of studies, including clinical trials in leukemia and neuroblastoma patients, have shown that the clinically used chelator, desferrioxamine (DFO), can have potent anti-tumour activity. Indeed, in an important clinical trial, a marked decrease in ....Iron is essential for the growth of all cells. Generally, cancer cells have a high iron requirement due to their rapid rate of proliferation. This makes them susceptible to the action of drugs called iron chelators that deplete cell iron. A wide variety of studies, including clinical trials in leukemia and neuroblastoma patients, have shown that the clinically used chelator, desferrioxamine (DFO), can have potent anti-tumour activity. Indeed, in an important clinical trial, a marked decrease in tumour burden was observed while there were no significant side effects, demonstrating an appreciable therapeutic index. However, DFO suffers from serious problems, including that it requires long infusions and does not readily penetrate cells. Further, in some cancer patients, DFO has shown little activity. Considering these results, we have developed a new group of chelators that show far greater activity than DFO at inhibiting cancer cell growth. These studies have been published in high quality journals such as BLOOD (Richardson et al. 1995, 1997, 1999) and form the basis for the current study. In this study we will examine how these iron-binding drugs work to inhibit the growth of cancer cells compared to their normal counterparts. These studies are important for the rational design of even more effective chelators. Recent studies in my lab have shown that our new chelators have far greater activity than a drug currently used to treat leukemia, known as hydroxyurea (HU). Our studies also show that the chelators act by a variety of mechanisms, explaining their greater activity than HU. Furthermore, we have shown that these chelators show significant anti-tumour activity in mice. The potential of this form of therapy has been confirmed by the entrance of the chelator, Triapine, into clinical trials (Vion Pharmaceuticals, USA). Our chelators are more effective than Triapine, thus, the present project is crucial for developing novel anti-tumour therapies.Read moreRead less
Development Of Novel Anti-epileptic Drugs Targeting Vesicular Endocytosis
Funder
National Health and Medical Research Council
Funding Amount
$202,950.00
Summary
Our team developed a drug program targeting a novel mechanism for epilepsy treatment, neuronal synaptic vesicle endocytosis. This project will develop the most promising series of drugs. Preclinical development is advanced, lacking only efficacy data across models predictive of the spectrum of human epilepsies to enable candidate selection for clinical trials. The program will advance a totally new concept for the treatment of epilepsy.
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
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
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
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