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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How do cells regulate redox environment at the subcellular level? Most organisms live in an aerobic environment that subjects their cells to reactive oxygen species. Reactive oxygen species have been proposed to lead to ageing, and in many diseases the balance between oxidising and reducing conditions (the redox environment) is perturbed. This research will identify how different cellular structures sense and maintain this redox homeostasis, not just in the whole cell, but within the different ....How do cells regulate redox environment at the subcellular level? Most organisms live in an aerobic environment that subjects their cells to reactive oxygen species. Reactive oxygen species have been proposed to lead to ageing, and in many diseases the balance between oxidising and reducing conditions (the redox environment) is perturbed. This research will identify how different cellular structures sense and maintain this redox homeostasis, not just in the whole cell, but within the different organelles in the cell. The work will help identify which cell compartments and processes are affected in different disease states and provide a fundamental understanding of how cells coordinate their different organelles to maintain the balance between oxidising and reducing conditions.Read moreRead less
A unified model of amino acid homeostasis. This project aims to develop a unified model of amino acid homeostasis in mammalian cells and apply it to brain cells. The model will be underpinned by a mathematical algorithm that allows predicting amino acid levels in the cytosol based on fundamental parameters such as transport and metabolism. This project should provide the significant benefit of enabling the prediction of essential functions such as cell growth and survival.
Defining the Regulatory Pool of Cholesterol in the Mammalian Cell. Heart disease remains the greatest killer of Australians and Alzheimer's disease represents a growing burden in our aging population. The information gained in this project will be invaluable in advancing our understanding of how cholesterol levels are controlled within the cell and will provide the groundwork for further research that can help to identify novel targets for new drugs to fight heart disease and Alzheimer's diseas ....Defining the Regulatory Pool of Cholesterol in the Mammalian Cell. Heart disease remains the greatest killer of Australians and Alzheimer's disease represents a growing burden in our aging population. The information gained in this project will be invaluable in advancing our understanding of how cholesterol levels are controlled within the cell and will provide the groundwork for further research that can help to identify novel targets for new drugs to fight heart disease and Alzheimer's disease.Read moreRead less
Symbiosomes and symbiosome membranes of corals and other cnidaria. Reef building corals and many other marine animals depend on symbiotic algae. Very little is known about the ways in which these organisms achieve effective communication with their endosymbionts, yet this is vital for understanding coral bleaching, a major present-day problem. In corals and their relatives, algae are housed in membrane-bounded vesicles, symbiosomes, which mediate the signal regulation that maintains an ongoin ....Symbiosomes and symbiosome membranes of corals and other cnidaria. Reef building corals and many other marine animals depend on symbiotic algae. Very little is known about the ways in which these organisms achieve effective communication with their endosymbionts, yet this is vital for understanding coral bleaching, a major present-day problem. In corals and their relatives, algae are housed in membrane-bounded vesicles, symbiosomes, which mediate the signal regulation that maintains an ongoing and healthy association at the cellular level. Unlike some terrestrial symbioses, little is known about the structure and function of the coral symbiosome. This study sets out to investigate this membrane at the cellular and molecular level.Read moreRead less
Is transport of miRNAs essential for plant development? This project will provide knowledge of how a new class of biologically active molecule (micro RNA) regulates expression of genes at sites in the plant that are critical for growth and development. MicroRNAs are believed to influence the size and shape of plants, how rapidly they grow and how well they produce and fill seeds. These molecules are part of a group of bioactive signals that move throughout the plant, functioning like hormones bu ....Is transport of miRNAs essential for plant development? This project will provide knowledge of how a new class of biologically active molecule (micro RNA) regulates expression of genes at sites in the plant that are critical for growth and development. MicroRNAs are believed to influence the size and shape of plants, how rapidly they grow and how well they produce and fill seeds. These molecules are part of a group of bioactive signals that move throughout the plant, functioning like hormones but directly influencing how well critical genes work. Their exploitation holds great promise for manipulating plant performance and enhancing crop yields. Read moreRead less
Navigating flux control through a branched metabolic pathway. This project aims to uncover control points and programmes in the mevalonate pathway, an important cellular metabolic pathway that produces cholesterol and isoprenoids. Knowledge of its regulation is largely restricted to just one enzyme (HMGCR). This project will determine how regulation of the later sterol-producing segment affects the early isoprenoid-segment of the mevalonate pathway; investigate how the two alternate routes to ch ....Navigating flux control through a branched metabolic pathway. This project aims to uncover control points and programmes in the mevalonate pathway, an important cellular metabolic pathway that produces cholesterol and isoprenoids. Knowledge of its regulation is largely restricted to just one enzyme (HMGCR). This project will determine how regulation of the later sterol-producing segment affects the early isoprenoid-segment of the mevalonate pathway; investigate how the two alternate routes to cholesterol synthesis operate and are regulated; and explore a co-ordinated and possibly co-operative transcriptional program. This project is expected to provide valuable knowledge of how cells control these critical lipids, which will ultimately inform better ways to treat diseases of cholesterol excess and defects in this pathway.Read moreRead less
Investigating the molecular function of alpha-Haemoglobin stabilising protein. The research described in this proposal will provide new insights into haemoglobin regulation and redox chemistry in erythrocytes. Deregulation of these processes gives rise to a number of debilitating diseases, including varieties of anaemia and thalassaemia-in Australia it is estimated that 3% of the population could be carriers of b-thalassaemia mutations. Given the contribution of free aHb to the pathology of b-th ....Investigating the molecular function of alpha-Haemoglobin stabilising protein. The research described in this proposal will provide new insights into haemoglobin regulation and redox chemistry in erythrocytes. Deregulation of these processes gives rise to a number of debilitating diseases, including varieties of anaemia and thalassaemia-in Australia it is estimated that 3% of the population could be carriers of b-thalassaemia mutations. Given the contribution of free aHb to the pathology of b-thalassaemia, understanding the specific aHb-binding factor, AHSP is a goal of national significance. In the long term, manipulation of AHSP function through gene therapy may have a direct role in the treatment of thalassaemia.Read moreRead less