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
Investigating the activator function of the Bim protein. Apoptosis is a research area where Australia has had long standing success. The first observations of this important process were made by Prof John Kerr in the 60's and 70's. A molecular renaissance developed in the late 80's and has led to the current explosion in this area of research. Many of these recent studies have been conducted at the Walter and Eliza Hall Institute. Our scientific endeavour is aimed at broadening the understanding ....Investigating the activator function of the Bim protein. Apoptosis is a research area where Australia has had long standing success. The first observations of this important process were made by Prof John Kerr in the 60's and 70's. A molecular renaissance developed in the late 80's and has led to the current explosion in this area of research. Many of these recent studies have been conducted at the Walter and Eliza Hall Institute. Our scientific endeavour is aimed at broadening the understanding of the mechanisms of cell death using genetically modified mouse models. Insights gained through this project will have far reaching implications for the design of new drugs to combat cancer and degenerative diseases.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
Regulation of lipolysis: new players, new paradigms. The way in which fat is broken down is poorly understood. This research will determine how important proteins in fat breakdown are turned on and off. By understanding this relationship, effective pharmaceutical treatments will be developed that will enhance the capacity to burn fat and ultimately reduce the incidence of type 2 diabetes and cardiovascular disease, and ease the associated financial burden on the community and healthcare system. ....Regulation of lipolysis: new players, new paradigms. The way in which fat is broken down is poorly understood. This research will determine how important proteins in fat breakdown are turned on and off. By understanding this relationship, effective pharmaceutical treatments will be developed that will enhance the capacity to burn fat and ultimately reduce the incidence of type 2 diabetes and cardiovascular disease, and ease the associated financial burden on the community and healthcare system. Understanding fat breakdown is also important for developing new processing technologies in the food industry.Read moreRead less
Molecular basis of skeletal muscle lipoapoptosis. High levels of fat in cells are associated with obesity and type 2 diabetes, medical conditions that have increased dramatically in prevalence in Australia. High fat levels in cells also causes cell death. This research will determine the mechanisms by which excessive fat storage leads to cell death and whether this leads to insulin resistance and type 2 diabetes. By understanding this relationship, effective pharmaceutical treatments will be dev ....Molecular basis of skeletal muscle lipoapoptosis. High levels of fat in cells are associated with obesity and type 2 diabetes, medical conditions that have increased dramatically in prevalence in Australia. High fat levels in cells also causes cell death. This research will determine the mechanisms by which excessive fat storage leads to cell death and whether this leads to insulin resistance and type 2 diabetes. By understanding this relationship, effective pharmaceutical treatments will be developed that will ultimately reduce the incidence of type 2 diabetes, and ease the associated financial burden on the community and healthcare system.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
Augmenting the activity of glyoxalase-1 to increase dicarbonyl clearance . Reactive intermediates generated during our metabolism contribute to ageing. Glyoxalase-1 is a key defence enzyme against these toxic intermediates and therefore ageing itself. This project aims to investigate novel pathways how the expression and activity of glyoxalase-1 are regulated. This interdisciplinary project expects to generate new understanding by combining relevant cell and animal models, protein chemistry, epi ....Augmenting the activity of glyoxalase-1 to increase dicarbonyl clearance . Reactive intermediates generated during our metabolism contribute to ageing. Glyoxalase-1 is a key defence enzyme against these toxic intermediates and therefore ageing itself. This project aims to investigate novel pathways how the expression and activity of glyoxalase-1 are regulated. This interdisciplinary project expects to generate new understanding by combining relevant cell and animal models, protein chemistry, epigenetics and structural biology. It is expected that this work will improve understanding of this fundamental biological defence. This will allow us to identify the potential means to enhance the capacity of glyoxalase-1 to the future benefit of biological ageing.Read moreRead less