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
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
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
Resolving the role of dryland flooding in the global carbon cycle. Aquatic sources of carbon dioxide and methane are globally significant, but unknown for flooded drylands. The aim of this project is to use an innovative combination of well-integrated methodologies to determine if flooded drylands release large amounts of carbon dioxide and methane. This project is significant because this release of carbon dioxide and methane has not previously been accounted for and may change the magnitude of ....Resolving the role of dryland flooding in the global carbon cycle. Aquatic sources of carbon dioxide and methane are globally significant, but unknown for flooded drylands. The aim of this project is to use an innovative combination of well-integrated methodologies to determine if flooded drylands release large amounts of carbon dioxide and methane. This project is significant because this release of carbon dioxide and methane has not previously been accounted for and may change the magnitude of the global terrestrial carbon dioxide sink and account of some of the planet’s missing sources of methane. The outcomes of this project will make a significant contribution to our understanding of the global carbon cycle and earth climate system, and inform future management of these systems.
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Mapping and Modelling the Ocean's Unseen Biodiversity. From the reef to the rainforest, Australia is famous for its unique biodiversity. Less well known is that Australia's coastline is predicted to be a global hotspot for biodiversity in marine microbes, the unseen life forces that maintain ocean health and productivity. This project aims to overcome historical technological and logistical hurdles by using cutting-edge sampling, genetic and modelling tools to provide the first models of microbi ....Mapping and Modelling the Ocean's Unseen Biodiversity. From the reef to the rainforest, Australia is famous for its unique biodiversity. Less well known is that Australia's coastline is predicted to be a global hotspot for biodiversity in marine microbes, the unseen life forces that maintain ocean health and productivity. This project aims to overcome historical technological and logistical hurdles by using cutting-edge sampling, genetic and modelling tools to provide the first models of microbial diversity patterns and organismal range in Australian marine systems. This is expected to be a crucial step for understanding the evolutionary and ecological processes that shape contemporary biodiversity.Read moreRead less
Marine urban development: how can ecology inform the design of multifunctional artificial structures? This project aims to experimentally manipulate the design of artificial structures to achieve multipurpose ecological objectives. Artificial structures such as buildings and roads have featured in terrestrial urban landscapes for many years, but have only more recently begun encroaching on aquatic environments. Most marine artificial structures lack the innovative design solutions required to mi ....Marine urban development: how can ecology inform the design of multifunctional artificial structures? This project aims to experimentally manipulate the design of artificial structures to achieve multipurpose ecological objectives. Artificial structures such as buildings and roads have featured in terrestrial urban landscapes for many years, but have only more recently begun encroaching on aquatic environments. Most marine artificial structures lack the innovative design solutions required to mitigate their ecological impacts and provide essential ecosystem services such as pollution abatement. This project will investigate the efficacy of these designs with both classical measures of diversity and structure and novel measures of ecosystem function. The project aims to provide essential information to inform the design of future marine urban developments.Read moreRead less
Mechanisms And Therapies In Cardiovascular Disease
Funder
National Health and Medical Research Council
Funding Amount
$8,360,700.00
Summary
Cardiovascular disease (CVD) claims 1 person every 10 min in Australia and causes 1 in 3 deaths worldwide. The molecular and cellular processes underlying atherosclerosis, vascular injury and thrombosis are highly complex and not well understood. A multifaceted approach is needed to effectively address these key challenges. This Program brings together world experts in these areas to interrogate gaps in our basic understanding of CVD, and to develop novel therapies for CVD patients by exploiting ....Cardiovascular disease (CVD) claims 1 person every 10 min in Australia and causes 1 in 3 deaths worldwide. The molecular and cellular processes underlying atherosclerosis, vascular injury and thrombosis are highly complex and not well understood. A multifaceted approach is needed to effectively address these key challenges. This Program brings together world experts in these areas to interrogate gaps in our basic understanding of CVD, and to develop novel therapies for CVD patients by exploiting new knowledge through integrated research.Read moreRead less
Estimating And Alleviating The Impacts Of Age-Related Sensory Decline
Funder
National Health and Medical Research Council
Funding Amount
$323,767.00
Summary
Sensory loss and dementia disproportionately affect older adults, often co-occur, and are the two leading contributors to disability burden among older Australians. This research will investigate the consequences that hearing and vision loss have for older adult health and wellbeing, informing strategies to reduce the disability burden of age-related sensory loss. These impacts include cognitive decline and dementia, mental health, quality of life, disability and independent living.
Structural And Functional Analysis Of A Cancer-linked Co-regulator Complex
Funder
National Health and Medical Research Council
Funding Amount
$729,571.00
Summary
We seek to understand the mechanisms by which genes are switched on and off throughout our lifetime. A number of multi-component protein machines are involved in this process but their make-up and mechanism of action is not understood. We will investigate the structure and function of one of these machines that has been strongly linked to cancer.