Understanding how reproduction and sexual conflict drive sex-dependent longevity and ageing. The biological study of longevity and ageing has two important fronts: understanding how evolution shapes lifespan and ageing, and the mechanistic study of how molecules, genes, hormones, tissues and cells interact during ageing. The evolutionary study of ageing is considered one of the success stories of the emerging field of evolutionary medicine, yet we desperately need greater integration of the evol ....Understanding how reproduction and sexual conflict drive sex-dependent longevity and ageing. The biological study of longevity and ageing has two important fronts: understanding how evolution shapes lifespan and ageing, and the mechanistic study of how molecules, genes, hormones, tissues and cells interact during ageing. The evolutionary study of ageing is considered one of the success stories of the emerging field of evolutionary medicine, yet we desperately need greater integration of the evolutionary and mechanistic spheres. This project addresses why males and females have different lifespans and age differently in a way that bridges evolutionary and mechanistic study, and will build Australia's research capacity to study ageing at both levels. Read moreRead less
To be cooperative or selfish: individual decisions in a model society. Understanding the basis of cooperative behaviour is a major challenge to biological and social science. Our ability to deal with problems such as global warming and the rapid loss of biodiversity, will depend upon an unprecedented level of cooperation between individuals and countries. Our work will use an animal model that shares a number of key characteristics with the societies of our early human ancestors to explore, thro ....To be cooperative or selfish: individual decisions in a model society. Understanding the basis of cooperative behaviour is a major challenge to biological and social science. Our ability to deal with problems such as global warming and the rapid loss of biodiversity, will depend upon an unprecedented level of cooperation between individuals and countries. Our work will use an animal model that shares a number of key characteristics with the societies of our early human ancestors to explore, through experiments and detailed molecular analysis, the basis of cooperative interactions between individuals. This work will uncover the key principles that drive the evolution of cooperation in society and will help us to understand the basis of one the most important components of human nature.Read moreRead less
Intra-genomic conflict and the evolution of sexually selected traits. The dynamics of sexual selection may prevent the simultaneous optimization of traits shared by the sexes, or of different traits within each sex. This proposal focuses on the consequences of these conflicts for phenotypic and genomic evolution. First, I will compare selection acting on a sexually dimorphic trait in males and females. Second, I will use artificial selection to create a novel sexually dimorphic trait, and track ....Intra-genomic conflict and the evolution of sexually selected traits. The dynamics of sexual selection may prevent the simultaneous optimization of traits shared by the sexes, or of different traits within each sex. This proposal focuses on the consequences of these conflicts for phenotypic and genomic evolution. First, I will compare selection acting on a sexually dimorphic trait in males and females. Second, I will use artificial selection to create a novel sexually dimorphic trait, and track the evolutionary response. Third, I will investigate the link between two important fitness traits: body size and ageing rate. This work will enhance important on-going research in the laboratory of Robert Brooks (UNSW).Read moreRead less
From developmental stability to organismic senility: Hox genes and telomere impact on life history evolution. Australia benefits from training researchers and technicians in new, break-through biotechnology and from applying this knowledge to relevant, cutting-edge questions in highly publicized research fields. This project contains both these ingredients. Our model species (a lizard) has a relatively high level of offspring malformations (ca 15%), which makes it much more likely to detect thei ....From developmental stability to organismic senility: Hox genes and telomere impact on life history evolution. Australia benefits from training researchers and technicians in new, break-through biotechnology and from applying this knowledge to relevant, cutting-edge questions in highly publicized research fields. This project contains both these ingredients. Our model species (a lizard) has a relatively high level of offspring malformations (ca 15%), which makes it much more likely to detect their underlying genetic mechanism. Furthermore, we can also assess how these animals survive and reproduce in relation to how quickly they age, which can be measured by assessing the shortening of telomeres per unit time. Thus, this collaboration provides an opportunity to train Australian researchers and in that process generate very high profile research.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
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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