Identifying And Exploiting Novel Pharmacological Targets For Breast Cancer
Funder
National Health and Medical Research Council
Funding Amount
$431,000.00
Summary
Breast cancers are made up of different types of cancer cells, and not all cells contribute equally. A subset of cancer cells may be uniquely capable of driving tumor growth, rebuilding fatal tumors after therapy and establishing new tumors at distant sites. Identifying and exploiting the pathways that regulate the activity and survival of these cells will lead to better modes of treatment, and move towards a relapse-free future for breast cancer patients.
GABA(B) Receptor Modulation Of Gastrointestinal Function In Health And Disease By Alpha-Conotoxins
Funder
National Health and Medical Research Council
Funding Amount
$689,050.00
Summary
Chronic visceral pain is a common and debilitating condition arising from numerous diseases that affect our internal organs. There is a desperate need for more information about the mechanisms responsible for signalling chronic visceral pain to provide therapies and potentially find a cure for it. Our research focuses on ?-conotoxins (small peptides from marine cone snail venom) as novel potential therapeutic agents for the treatment of chronic visceral pain.
EPITHELIAL ION TRANSPORT DEFECTS IN CYSTIC FIBROSIS: PATHOPHYSIOLOGY AND TREATMENT
Funder
National Health and Medical Research Council
Funding Amount
$290,440.00
Summary
The thin layer of fluid covering the surface of the air passages acts to protect the airway surface from drying. This fluid also allows the hair-like projections, or cilia, on the top of the airway cells to beat more effectively. The volume and composition of this fluid is determined by the movement of salt and water across the mucous membranes of the air passages. The importance of this fluid is shown by the problems that occur in Cystic Fibrosis (CF), the most common lethal inherited disease a ....The thin layer of fluid covering the surface of the air passages acts to protect the airway surface from drying. This fluid also allows the hair-like projections, or cilia, on the top of the airway cells to beat more effectively. The volume and composition of this fluid is determined by the movement of salt and water across the mucous membranes of the air passages. The importance of this fluid is shown by the problems that occur in Cystic Fibrosis (CF), the most common lethal inherited disease affecting Australians. In CF, altered salt transport causes drying of the airway surface which impairs the working of the cilia. This leads to retention of mucous in the airway with repeated bacterial infections damaging the lungs. Simple tests have been designed to directly measure the movement of salt across the surface of the nasal passage using a fine soft rubber tube. Movement of mucous in the nose is measured using other simple techniques that are currently used diagnostically. Together, these tests in the nose provide vital information about how the surface of normal human airway moves salt, water and mucous. Any differences found in CF patients will then give us a good idea of the problems found in the CF lung. We will study the interactions between calcium, sodium and chloride in the fluid lining the airways, measuring changes in salt and mucous movement. A range of testing procedures will be used in human volunteers, anaesthetised mice and isolated tissues from sheep. We have already demonstrated important links between the fluid lining the airways and salt movement, and we expect that this may lead to the development of new treatments for Cystic Fibrosis. This therapy will focus on treating the lung problems of CF patients, the major cause of disability. We anticipate that this preventative therapy may offer real benefits in the fight to cure CF.Read moreRead less
Dissecting a hematopietic transcription factor complex. The development of mature active cells is a highly complex and coordinated process that is controlled largely by groups of interacting regulatory proteins. We are trying to understand, at a very detailed level, how a specific group of these proteins interact to regulate both normal blood cell development and the onset of childhood leukemias. Using this information we will try to develop reagents that can be used to inhibit these interaction ....Dissecting a hematopietic transcription factor complex. The development of mature active cells is a highly complex and coordinated process that is controlled largely by groups of interacting regulatory proteins. We are trying to understand, at a very detailed level, how a specific group of these proteins interact to regulate both normal blood cell development and the onset of childhood leukemias. Using this information we will try to develop reagents that can be used to inhibit these interactions and be used as lead compounds for treatments for disease.Read moreRead less
The role of the transcription factor Runx2 during mammary gland development and lactation. This proposal will further our understanding of mammary gland development and lactation and the mechanisms controlling mammary cell fate decisions such as differentiation. Regulation of cell fate lies at the core of most aspects of cell biology from normal development to dysfunction such as cancer. The knowledge gleamed from this project also has the potential to make economic gains for Australia by increa ....The role of the transcription factor Runx2 during mammary gland development and lactation. This proposal will further our understanding of mammary gland development and lactation and the mechanisms controlling mammary cell fate decisions such as differentiation. Regulation of cell fate lies at the core of most aspects of cell biology from normal development to dysfunction such as cancer. The knowledge gleamed from this project also has the potential to make economic gains for Australia by increasing the profitability and ensuring the sustainability of both the dairy and meat industries. Better understanding of the mechanisms controlling mammary epithelial cell differentiation should enable augmentation of lactation such as increasing milk protein content, using marker assisted selection (of targets such as Runx2) in cattle.Read moreRead less
Oxidative Damage and Cell Ageing. This research will benefit Australia by providing a fundamental understanding of how cells age. This will have immediate international impact at the scientific level and will inform strategies to reduce the rate of ageing and alleviation of age-related disorders. In the longer term the research may provide commercial and social outcomes by identifying antioxidant systems that will provide a genuine benefit in reducing ageing.
Cellular Responses to Oxidative Damage: Cell Aging. The aim of this project is to identify the mechanisms by which oxidative stress and free radical damage cause cell aging. This work will make a significant contribution to our understanding of the aging process in cells by identifying the major reactive oxygen species that contribute to cell aging, which defence systems and antioxidants provide the greatest degree of protection, what damage accumulates as cells age and which genetic systems ar ....Cellular Responses to Oxidative Damage: Cell Aging. The aim of this project is to identify the mechanisms by which oxidative stress and free radical damage cause cell aging. This work will make a significant contribution to our understanding of the aging process in cells by identifying the major reactive oxygen species that contribute to cell aging, which defence systems and antioxidants provide the greatest degree of protection, what damage accumulates as cells age and which genetic systems are activated as during the process.Read moreRead less
The effect of nitrogen monoxide on intracellular iron metabolism. We discovered that the crucial signalling molecule nitrogen monoxide (NO) mediates iron (Fe) and glutathione (GSH) release by the transporter MRP1 probably as an NO-Fe-GSH complex [DR(2006) PNAS USA 103:7670-5]. During our current ARC grant we have markedly extended these findings by showing that another molecule, GST Pi and MRP1 form part of a coordinated system that stores and transports NO as complexes of Fe and GSH, markedly e ....The effect of nitrogen monoxide on intracellular iron metabolism. We discovered that the crucial signalling molecule nitrogen monoxide (NO) mediates iron (Fe) and glutathione (GSH) release by the transporter MRP1 probably as an NO-Fe-GSH complex [DR(2006) PNAS USA 103:7670-5]. During our current ARC grant we have markedly extended these findings by showing that another molecule, GST Pi and MRP1 form part of a coordinated system that stores and transports NO as complexes of Fe and GSH, markedly extending NO half-life from milliseconds to hours. This has broad implications for understanding NO activity in many processes which have major vital health implications, including tumour cell killing by macrophages and blood pressure control.Read moreRead less
The Effect of Nitrogen Monoxide on Intracellular Iron Metabolism. For the first time, we discovered that nitric oxide (NO) is actively transported from cells by a protein that is known to also transport glutathione (GSH). This is important, as NO was thought to passively diffuse from cells. Active transport overcomes the problems of diffusion which is inefficient and non-targeted. Moreover, NO is released as a complex with iron and GSH which markedly increases its half-life. These findings have ....The Effect of Nitrogen Monoxide on Intracellular Iron Metabolism. For the first time, we discovered that nitric oxide (NO) is actively transported from cells by a protein that is known to also transport glutathione (GSH). This is important, as NO was thought to passively diffuse from cells. Active transport overcomes the problems of diffusion which is inefficient and non-targeted. Moreover, NO is released as a complex with iron and GSH which markedly increases its half-life. These findings have broad implications for understanding the activity of NO in many processes which have major health implications, including tumour cell killing by macrophages, blood pressure etc.Read moreRead less
The effect of nitrogen monoxide on intracellular iron metabolism. During our current ARC grant we discovered a novel relationship between energy metabolism and NO-mediated Fe efflux and showed that glutathione (GSH) is vital for this release mechanism (DR5,6). Intriguingly, this transport process is part of the cytotoxic effector machinery of activated macrophages against tumours, and requires further elucidation. We also showed that CO affects Fe metabolism by binding to Fe, and CO may modulate ....The effect of nitrogen monoxide on intracellular iron metabolism. During our current ARC grant we discovered a novel relationship between energy metabolism and NO-mediated Fe efflux and showed that glutathione (GSH) is vital for this release mechanism (DR5,6). Intriguingly, this transport process is part of the cytotoxic effector machinery of activated macrophages against tumours, and requires further elucidation. We also showed that CO affects Fe metabolism by binding to Fe, and CO may modulate NO's function. We will:-
(1) Examine if NO-mediated Fe release results in GSH efflux
(2) Identify the mechanism of NO-mediated Fe efflux.
(3) Assess the effect of inducing haem oxygenase 1 on Fe metabolism
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