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
LIM-homeodomain interactions in neuronal development. The loss of central nervous system function, through accident or disease, is devastating for affected individuals and their families. Our current inability to stimulate the regeneration of nervous tissue is a result of the lack of detailed knowledge of the complex processes that must take place, at the molecular and cellular levels, during neuronal development. We are determining how a group of cellular proteins that have key roles in motor n ....LIM-homeodomain interactions in neuronal development. The loss of central nervous system function, through accident or disease, is devastating for affected individuals and their families. Our current inability to stimulate the regeneration of nervous tissue is a result of the lack of detailed knowledge of the complex processes that must take place, at the molecular and cellular levels, during neuronal development. We are determining how a group of cellular proteins that have key roles in motor neuron development interact with each other and with DNA. With this information we are developing reagents that can be used to further probe central nervous system function and may ultimately be used to regenerate damaged nerves.Read moreRead less
The Dynamics of Plant Cell Division-Discovering the Mechanisms of Organelle Inheritance. This project seeks to understand molecular mechanisms responsible for organelle partitioning in dividing plant cells. Understanding these mechanisms will contribute new knowledge relevant to plant biotechnology (eg chloroplast transformation, cytoplasmic male sterility, plant development and totipotency) and thus to Australian agriculture broadly. This project will enhance Australian research capacity in the ....The Dynamics of Plant Cell Division-Discovering the Mechanisms of Organelle Inheritance. This project seeks to understand molecular mechanisms responsible for organelle partitioning in dividing plant cells. Understanding these mechanisms will contribute new knowledge relevant to plant biotechnology (eg chloroplast transformation, cytoplasmic male sterility, plant development and totipotency) and thus to Australian agriculture broadly. This project will enhance Australian research capacity in the fields of organelle inheritance and plant cytoskeletal dynamics and thus will maintain Australia's leading reputation in these fields. In addition, the project will maintain a high quality and productive research environment capable of providing excellent research training for new scientists in this field. 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
Re-uniting marsupials and eutherians by embryonic micromanipulation. The unique responsibility for transmitting life from generation to generation normally depends on the gametes. This project will use new reproductive technologies to investigate the properties of the oocyte in reprogramming somatic cell nuclei, and will use the nuclei of both marsupial and eutherian somatic cells to test this. We will also use both marsupial and eutherian genes to insert into the oocyte to create the first tra ....Re-uniting marsupials and eutherians by embryonic micromanipulation. The unique responsibility for transmitting life from generation to generation normally depends on the gametes. This project will use new reproductive technologies to investigate the properties of the oocyte in reprogramming somatic cell nuclei, and will use the nuclei of both marsupial and eutherian somatic cells to test this. We will also use both marsupial and eutherian genes to insert into the oocyte to create the first transgenic marsupials. We will also investigate the ability of spermatozoa from species of increasing genetic distance to ferttilise marsupial eggs using intracytoplasmic sperm injection (ICSI).Read moreRead less
The role of turgor in hyphal extension of the Ascomycete Neurospora crassa. Cellular expansion is an absolute necessity during the growth and development of plants and fungi. This process relies heavily upon the accumulation of inorganic ions. Osmotically driven water influx then creates the hydrostatic pressure that underlies the increase in cell volume. Cellular expansion is normally asymmetric and localised in one small region, such as hyphal tip. How does the cell maintain the turgor that dr ....The role of turgor in hyphal extension of the Ascomycete Neurospora crassa. Cellular expansion is an absolute necessity during the growth and development of plants and fungi. This process relies heavily upon the accumulation of inorganic ions. Osmotically driven water influx then creates the hydrostatic pressure that underlies the increase in cell volume. Cellular expansion is normally asymmetric and localised in one small region, such as hyphal tip. How does the cell maintain the turgor that drives expansion? How is expansion controlled spatially? These questions will be addressed in this project by comprehensive study of ion transport processes in a model organism, Neurospora crassa, using osmotic sensitive and transport mutants.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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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
Mechanisms of cell death regulation by the Bcl-2 protein family. Through the proposed study, the expected outcome is a better understanding of the important process of how the Bcl-2 family of proteins interact with each to control cell death. Furthermore, as dysfunctional apoptosis signalling contributes to diseases such as autoimmune conditions, neurodegenerative disorders and cancer, a detailed and sound understanding of how the cell death machinery operates should enable the design of more ef ....Mechanisms of cell death regulation by the Bcl-2 protein family. Through the proposed study, the expected outcome is a better understanding of the important process of how the Bcl-2 family of proteins interact with each to control cell death. Furthermore, as dysfunctional apoptosis signalling contributes to diseases such as autoimmune conditions, neurodegenerative disorders and cancer, a detailed and sound understanding of how the cell death machinery operates should enable the design of more effective and importantly, safer therapies against these pathologies.Read moreRead less