Mitochondrial Iron Overload And Friedreich's Ataxia: The Role Of Frataxin In Iron And Haem Metabolism
Funder
National Health and Medical Research Council
Funding Amount
$285,990.00
Summary
Friedreich's ataxia (FA) is due to the lack of a protein known as frataxin. Recent studies using Baker's yeast have shown that the deletion of frataxin results in the accumulation of toxic iron in the mitochondrion. More recently, a variety of studies have shown that FA patients have iron loading within their cells. The iron build-up may cause severe damage. At present, the role of frataxin in mammalian mitochondrial iron metabolism is unknown. Our preliminary studies demonstrate that frataxin i ....Friedreich's ataxia (FA) is due to the lack of a protein known as frataxin. Recent studies using Baker's yeast have shown that the deletion of frataxin results in the accumulation of toxic iron in the mitochondrion. More recently, a variety of studies have shown that FA patients have iron loading within their cells. The iron build-up may cause severe damage. At present, the role of frataxin in mammalian mitochondrial iron metabolism is unknown. Our preliminary studies demonstrate that frataxin is down-regulated by either erythroid differentiation or the haem precursor protoporphyrin IX (Becker and Richardson, submitted). These data strongly suggest a role for frataxin in iron metabolism. In the present study we will continue to assess if frataxin plays a role in the way cells handle iron. Using a unique model of mitochondrial iron overload developed in my lab (Richardson et al. (1996) BLOOD 87:3477), we will extensively investigate the iron metabolism of the mitochondrion in order to determine the function of frataxin and its role in Friedreich's ataxia. In addition, we have developed a series of new drugs known as iron chelators that can enter the mitochondrion due to their high lipid solubility (Becker and Richardson 1999 J. Lab. Clin. Med. 134:510). These latter drugs are far more effective than the chelator currently used to treat iron overload, desferrioxamine (DFO). Indeed, our chelators have been designed to result in high iron chelation efficacy but low toxicity (see Becker and Richardson, 1999). This exciting research may be crucial in understanding the development of FA and in creating new therapies such as the use of iron chelators.Read moreRead less
Mitochondrial Iron Overload And Friedreich's Ataxia: The Role Of Frataxin In Iron And Haem Metabolism
Funder
National Health and Medical Research Council
Funding Amount
$606,000.00
Summary
Friedreich's ataxia (FA) is due to the lack of a protein known as frataxin. A variety of studies using Baker's yeast and conditional frataxin knockout (KO) mice have shown that deletion of frataxin leads to the accumulation of toxic iron in their mitochondrion. More recently, a variety of studies have shown that FA patients have iron-loading within their mitochondrion. Iron in the highly redox active environment of the mitochondrion could contribute to the generation of cytotoxic radicals that c ....Friedreich's ataxia (FA) is due to the lack of a protein known as frataxin. A variety of studies using Baker's yeast and conditional frataxin knockout (KO) mice have shown that deletion of frataxin leads to the accumulation of toxic iron in their mitochondrion. More recently, a variety of studies have shown that FA patients have iron-loading within their mitochondrion. Iron in the highly redox active environment of the mitochondrion could contribute to the generation of cytotoxic radicals that cause severe damage. Further, cells deficient in frataxin are sensitive to oxidant stress and Fe chelators rescue oxidant-mediated death of cells from FA patients. Indeed, free radical scavengers have shown to be of use in the treatment of this disease. Studies in DR's lab during this NHMRC grant have shown that frataxin is down-regulated by erythroid differentiation or the haem precursor, protoporphyrin IX (BLOOD 2002;99:3813-22). These data indicate a role for frataxin in Fe metabolism and the pathogenesis of FA. In this study we will continue to examine the role of frataxin in the way cells handle Fe using experimental models developed under the current NHMRC grant. These include transfected cell lines with low frataxin expression generated using an expression vector containing anti-sense frataxin cDNA. Further we obtained the frataxin conditional KO mouse and generated a breeding colony. These animals display many of the pathological features of FA and are the best current model of the disease. Indeed, they will be critical for assessing the role of frataxin in Fe metabolism and as a model to test the ability of Fe-binding drugs to prevent the pathology observed. We designed lipid-soluble chelators that can enter the mitochondrion to bind Fe (Biochim Biophys Acta 2001;1536:133-140) and these ligands will be tested to prevent disease progression in the KO mice. This exciting research is crucial for understanding the pathogenesis of FA and in creating new therapies.Read moreRead less
Rebuilding Southern Rock Lobster Stocks On The East Coast Of Tasmania: Informing Options For Management
Funder
Fisheries Research and Development Corporation
Funding Amount
$103,800.00
Summary
Rock lobster stocks off the east coast of Tasmania are in a depleted state and as a consequence a stock rebuilding strategy has been implemented. This has involved adopting a 200 tonnes east coast catch limit, comprising a catch cap for the commercial sector and a notional catch share for the recreational sector. While the commercial catch limit can be monitored and controlled directly, management of the recreational catch share is more problematic.
The recreational rock lobster fishery ....Rock lobster stocks off the east coast of Tasmania are in a depleted state and as a consequence a stock rebuilding strategy has been implemented. This has involved adopting a 200 tonnes east coast catch limit, comprising a catch cap for the commercial sector and a notional catch share for the recreational sector. While the commercial catch limit can be monitored and controlled directly, management of the recreational catch share is more problematic.
The recreational rock lobster fishery has been monitored for two decades, during which time there have been significant management changes and variability in stock abundance. The greatest changes have occurred in the east coast, which has traditionally attracted 60-70% of the state-wide recreational catch and effort. In an effort to restrict catches from that region there have been drastic reductions in bag and possession limits and a progressive reduction in season. Furthermore, major biotoxin events have resulted in closures of key areas during peak fishing periods.
High and varying levels of participation has made management of the recreational component of the fishery difficult. This situation is likely to be further exacerbated as stocks rebuild; higher catch rates are expected to attract increased effort and overall catches for the sector. For the commercial sector, the catch cap effectively represents a competitive or “Olympic” catch quota which, as catch rates improve, is likely to influence fleet dynamics and timing of catches as fishers ‘race’ to take the limited catch.
Understanding relationships between fisher behaviour, their expectations/aspirations, responses to changes in stock status and to management intervention is critical when implementing effective management strategies. This project aims to inform on the practical challenges to achieving the stock rebuilding objective and provide options to assist managers and both fishing sectors in achieving the ecological, social and economic goals for the fishery.
Objectives: 1. Determine the relationships between recreational fisher behaviour (effort and participation) and Rock Lobster catch rates and abundance 2. Assess fisher attitudes and compliance behaviour to management scenarios designed to achieve the east coast stock rebuilding objective 3. Model the effectiveness of alternative management scenarios in constraining recreational catches as stock rebuild 4. Model the impact on fleet dynamics, including economic implications, of the expected shift to an "Olympic" quota. 5. Evaluate the costs and benefits of short- and long-term management options for the east coast Rock Lobster fishery Read moreRead less
Temperature sensitivity of soil respiration and its components. This project aims to demonstrate how temperate evergreen forests could buffer against climate change. Soil respiration returns around half the carbon taken up by forests to the atmosphere. This project will characterise and quantify how microbes and roots in soils depend on temperature and substrate supply, and so predict how rising temperatures and drought will affect forests as natural carbon sequestration sinks. This project will ....Temperature sensitivity of soil respiration and its components. This project aims to demonstrate how temperate evergreen forests could buffer against climate change. Soil respiration returns around half the carbon taken up by forests to the atmosphere. This project will characterise and quantify how microbes and roots in soils depend on temperature and substrate supply, and so predict how rising temperatures and drought will affect forests as natural carbon sequestration sinks. This project will resolve the roles of environmental drivers of soil respiration across forests; integrate mechanistic understanding of differing plant and microbial responses to temperature within a common modelling framework; and evaluate the implications of this knowledge in predictions of climatic impacts on terrestrial carbon cycling.Read moreRead less
Discovery Indigenous Researchers Development - Grant ID: DI100100130
Funder
Australian Research Council
Funding Amount
$180,834.00
Summary
Developing predictive tools for rapid assessment of multiple impacts, including climate change, on the marine ecosystem of Torres Strait (Australia). This project will underpin Australia's long-term commitment to maintain environmental biodiversity and sustainability in the face of synergistic effects from multiple threats. We will describe the consequences of threats and stressors on marine processes, harvested resources, and ecosystem functioning by identifying vulnerable species and habitats. ....Developing predictive tools for rapid assessment of multiple impacts, including climate change, on the marine ecosystem of Torres Strait (Australia). This project will underpin Australia's long-term commitment to maintain environmental biodiversity and sustainability in the face of synergistic effects from multiple threats. We will describe the consequences of threats and stressors on marine processes, harvested resources, and ecosystem functioning by identifying vulnerable species and habitats. We will provide management advice on balancing cultural and ecosystem integrity, economic efficiency, and ecosystem resilience under scenarios of climate and environmental change. This information is of immediate use by Australian government agencies. The project will put Australian scientists at the forefront of research focused on the adaptation of marine ecosystems to synergistic effects.Read moreRead less
Linking phytoplankton to fisheries using zooplankton size spectra. This project aims to develop innovative numerical methods to understand the dynamics, carbon export, and trophic structure of zooplankton. The trophic links between phytoplankton, zooplankton and fisheries are unknown. The size- frequency distribution of zooplankton (size spectrum) is an innovative method for estimating their growth, predation and production as food for fish. Analysis of a global synthesis of zooplankton size dis ....Linking phytoplankton to fisheries using zooplankton size spectra. This project aims to develop innovative numerical methods to understand the dynamics, carbon export, and trophic structure of zooplankton. The trophic links between phytoplankton, zooplankton and fisheries are unknown. The size- frequency distribution of zooplankton (size spectrum) is an innovative method for estimating their growth, predation and production as food for fish. Analysis of a global synthesis of zooplankton size distributions from tropical to polar environments are expected to reveal these vital rates of pelagic ecosystems. The zooplankton rates will reveal, for the first time, the link between phytoplankton and fisheries, and will significantly improve ecosystem models and global assessments of environmental change.Read moreRead less
Platelets are key blood elements that are essential for the prevention of bleeding in response to injury or infection. Overactive or spontaneously active platelets cause thrombosis and blood clot formation. My laboratory has identified new physiological pathways of activation of platelet metalloproteinases, the enzymes that regulate surface levels of the prothrombotic platelet receptors. By understanding this mechanism of receptor regulation, we can uniquely target platelet receptors in people w ....Platelets are key blood elements that are essential for the prevention of bleeding in response to injury or infection. Overactive or spontaneously active platelets cause thrombosis and blood clot formation. My laboratory has identified new physiological pathways of activation of platelet metalloproteinases, the enzymes that regulate surface levels of the prothrombotic platelet receptors. By understanding this mechanism of receptor regulation, we can uniquely target platelet receptors in people with prothrombotic pathologies.Read moreRead less
Regulation Of Receptors That Control Platelet Function Under Shear Stress
Funder
National Health and Medical Research Council
Funding Amount
$507,273.00
Summary
Specialized human blood cells that control blood loss and clotting (platelets) are currently difficult to test in the clinical laboratory, meaning patients are at risk of excessive bleeding or serious clot formation during disease or treatment. The aim of this proposal is to use our new reagents and assays to develop more reliable methods for evaluating relative bleeding or clotting risk in individuals.
Autoimmune-based thrombocytopenia can be a life-threatening adverse event associated with viral load, surgery, drug therapies or the use of the anticoagulant, heparin. This grant will define mechanisms of anti-platelet antibody-dependent platelet activation and assess shedding of platelet-specific glycoprotein (GP)VI as an immediate consequence of this activation, provide a new strategy for evaluating risk of thrombosis in HIT.
The Role Of Duffy And PF4 In The Platelet Killing Of Malaria Parasites.
Funder
National Health and Medical Research Council
Funding Amount
$350,045.00
Summary
Platelets in the blood can kill the Plasmodium parasite, which lives inside red blood cells and causes malaria. Platelets bind parasite-infected red cells and release a molecule that is toxic to the parasite. This project will study why a red cell molecule called Duffy is also needed for this function of platelets. Most Africans carry a gene for Duffy that stops its expression in red cells, and may therefore be more susceptible to malaria because their platelets cannot kill the malaria parasite.