One of the current challenges in public health is to translate the progress from the Human Genome Project into reduced morbidity and mortality from disease. Once genetic defects are characterised, knowledge about the variability in severity of disease in mutation carriers, is important from a public health perspective. Hereditary Haemochromatosis (HH) is a common genetic disorder of iron overload that results in a wide spectrum of disease, varying from non-specific symptoms to severe damage to l ....One of the current challenges in public health is to translate the progress from the Human Genome Project into reduced morbidity and mortality from disease. Once genetic defects are characterised, knowledge about the variability in severity of disease in mutation carriers, is important from a public health perspective. Hereditary Haemochromatosis (HH) is a common genetic disorder of iron overload that results in a wide spectrum of disease, varying from non-specific symptoms to severe damage to liver, heart, pancreas and joints from iron deposition. It is easily treatable by regular blood donation, and population-based screening for HH has therefore been advocated. In this study we aim to address gaps in the existing data on HH regarding dietary and lifestyle factors that contribute to the variable clinical picture of HH. The study will be based on the Melbourne Collaborative Cohort Study, a cohort of 31,500 men and women who have been followed for approximately 10 years. Information on dietary and lifestyle factors was collected at initial enrollment, along with a blood specimen. We will test all non-Southern European participants (31,176) for the common HH mutations in the HFE gene and then select a subgroup of 1150 people, including all people with the main genetic defect as well as a comparison group, for further clinical followup. Participants will have genetic counselling and informed consent will be obtained. Participants will complete a short questionnaire and give a blood sample for measurement of iron overload, liver function, and other relevant blood tests, then undergo a brief clinical examination. Results of all tests will be given at a followup visit by genetic counsellor or physician. This study will provide important data on natural history of HH risk factors that influence variability in clinical presentation and the association of HFE mutations with chronic diseases and all cause mortality.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
$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
Development Of Iron Complexes For The Treatment Of FriedreichÍs Ataxia & The Role Of Frataxin In Iron Metabolism
Funder
National Health and Medical Research Council
Funding Amount
$616,143.00
Summary
Friedreich's ataxia (FA) is a neuro- & cardio-degenerative disease where there is an accumulation of toxic iron (Fe) in the mitochondrion. Work from our current NHMRC grant showed iron plays a significant role in FA pathology In fact, the CIs dissected the mechanisms of mitochondrial iron-loading & have published 8 papers in high impact journals with 3 papers in PNAS USA in the last 2 yrs Understanding of this process has led to the design of rationalised drugs for FA This work in this Renewal c ....Friedreich's ataxia (FA) is a neuro- & cardio-degenerative disease where there is an accumulation of toxic iron (Fe) in the mitochondrion. Work from our current NHMRC grant showed iron plays a significant role in FA pathology In fact, the CIs dissected the mechanisms of mitochondrial iron-loading & have published 8 papers in high impact journals with 3 papers in PNAS USA in the last 2 yrs Understanding of this process has led to the design of rationalised drugs for FA This work in this Renewal could lead to novel therapies for FARead moreRead less
Examination Of The Molecular Pharmacology Of Anthracyclines Induced Via Their Interaction With Iron
Funder
National Health and Medical Research Council
Funding Amount
$618,401.00
Summary
Anthracyclines are highly effective anti-cancer drugs, but their use is limited by toxic effects on the heart. This is thought to be due to these drugs directly binding iron (Fe). Indeed, we showed that anthracyclines induced marked changes in the way heart cells utilise Fe (DR1-3, 38; Mol. Pharmacol. 2002, 2003, 2004, 2005). We were the first to show that anthracyclines prevent Fe release from the criticial Fe storage protein ferritin. This prevents the use of Fe for vital processes eg. DNA and ....Anthracyclines are highly effective anti-cancer drugs, but their use is limited by toxic effects on the heart. This is thought to be due to these drugs directly binding iron (Fe). Indeed, we showed that anthracyclines induced marked changes in the way heart cells utilise Fe (DR1-3, 38; Mol. Pharmacol. 2002, 2003, 2004, 2005). We were the first to show that anthracyclines prevent Fe release from the criticial Fe storage protein ferritin. This prevents the use of Fe for vital processes eg. DNA and haem synthesis. Hence, this effect probably contributes to the cytotoxic activity of anthracyclines on the heart. We showed that novel drugs developed in my lab that bind Fe called chelators show high activity in animals (DR4) and prevent anthracycline-mediated Fe accumulation in ferritin. Importantly, Fe chelators have been shown to inhibit anthracycline-mediated cardiotoxicity. Indeed, the clinically used cardioprotective agent, ICRF-187, is actually an Fe chelator (5, DR6). However, ICRF-187 is not totally successful in terms of its cardioprotective effects and can cause myelosuppression (5, DR6). While the clinically used chelator, desferrioxamine (DFO), can prevent anthracycline-mediated cardiotoxicity, its poor membrane permeability limits its effectiveness. Our chelators are highly permeable and overcome the disadvantages of DFO (DR4). Thus, they are vital to examine for preventing anthracycline-mediated cardiotoxicity. In this proposal we will examine the changes in Fe metabolism induced by anthracyclines and test the hypothesis that novel Fe chelators may prevent the cardiotoxicity of these agents. We also aim to be the first to assess if preparation of anthracyclines which cannot bind iron prevents their cardiotoxicity. This will be done by preparing metal complexes of these drugs which prevent Fe-binding eg. anthracycline-zinc complexes. These studies are important for the development of less cardiotoxic forms of these very useful anti-tumour agents.Read moreRead less
Development Of Iron Chelators For The Treatment Of Friedreichs Ataxia And The Role Of Frataxin In Iron Metabolism
Funder
National Health and Medical Research Council
Funding Amount
$550,987.00
Summary
Friedreich's ataxia (FA) is a neuro- and cardio-degenerative disease where there is an accumulation of toxic Fe in the mitochondrion. Excitingly, work from our current NHMRC grant showed iron plays a significant role in FA pathology. Importantly, we developed new drugs (Fe chelators) which rescue the cardiac pathology of FA in an animal model. Studies will now assess if our drugs prevent the neurodegeneration of FA in another animal model. This work could lead to novel therapies for FA.
Investigating The Cellular Response To Iron-Depletion: The Trilogy Of ASK1, Thioredoxin And Ribonucleotide Reductase
Funder
National Health and Medical Research Council
Funding Amount
$552,572.00
Summary
Iron is crucial for many essential biological processes. Recently, we demonstrated that iron-depletion can affects important signalling pathways (e.g., JNK and p38) that play important roles in growth arrest and apoptosis. This study is designed to investigate the cellular and molecular effects of iron depletion which currently remains unclear. The research is crucial for understanding: (1) the effects of iron deficiency and (2) for understanding the effects of iron chelators that are used for t ....Iron is crucial for many essential biological processes. Recently, we demonstrated that iron-depletion can affects important signalling pathways (e.g., JNK and p38) that play important roles in growth arrest and apoptosis. This study is designed to investigate the cellular and molecular effects of iron depletion which currently remains unclear. The research is crucial for understanding: (1) the effects of iron deficiency and (2) for understanding the effects of iron chelators that are used for treating various diseases.Read moreRead less
Tectonothermal and mineralization history of banded iron formations of the north Pilbara Craton. Iron ore is Australia's largest single export commodity, accounting for 8% ($12.8 billion) of total merchandise exports in 2006. Most of that value comes from the Pilbara region of Australia. Discovery rates of new deposits have declined over the past two decades, while many mines are nearing the end of production. Exploration expenditure has also declined. There is therefore an urgent need to reinvi ....Tectonothermal and mineralization history of banded iron formations of the north Pilbara Craton. Iron ore is Australia's largest single export commodity, accounting for 8% ($12.8 billion) of total merchandise exports in 2006. Most of that value comes from the Pilbara region of Australia. Discovery rates of new deposits have declined over the past two decades, while many mines are nearing the end of production. Exploration expenditure has also declined. There is therefore an urgent need to reinvigorate exploration to maintain an industry that underpins much of Australia's regional wealth. Outcomes of the project will provide exploration with improved geological tools with which to develop superior exploration models and thereby better direct exploration strategies.Read moreRead less
Industrial Transformation Research Hubs - Grant ID: IH140100035
Funder
Australian Research Council
Funding Amount
$5,000,000.00
Summary
ARC Research Hub for Computational Particle Technology. ARC Research Hub for Computational Particle Technology. This research hub aims to develop and apply advanced theories and mathematical models to design and optimise particulate and multiphase processes that are widely used in the minerals and metallurgical industries. This should be achieved through detailed analysis of the fundamentals governing fluid flow, heat and mass transfer at different time and length scales, facilitated by various ....ARC Research Hub for Computational Particle Technology. ARC Research Hub for Computational Particle Technology. This research hub aims to develop and apply advanced theories and mathematical models to design and optimise particulate and multiphase processes that are widely used in the minerals and metallurgical industries. This should be achieved through detailed analysis of the fundamentals governing fluid flow, heat and mass transfer at different time and length scales, facilitated by various novel research techniques. Research outcomes including theories, computer models and simulation techniques, as well as well-trained young researchers, should have a significant impact across a range of industries of vital importance to Australia’s economic and technological future, including the minerals, metallurgical, materials, chemical, energy, pharmaceutical and environment sectors.Read moreRead less
Pharmacology Of Potential Anti-Tumour Agents: Iron Chelators Of The BpT Class
Funder
National Health and Medical Research Council
Funding Amount
$585,455.00
Summary
Pharmacology of Potential Anti-Tumour Agents: Iron Chelators of the BpT Class Cancer cells have a high iron requirement for DNA synthesis and many clinical trials showed Fe chelators are effective anti-cancer drugs. Their potential to act as anti-tumour agents has been confirmed by the entrance of Triapine into widespread NCI clinical trials. In this NHMRC Renewal, we will perform pharmacological and preclinical studies to promote the development of BpT chelators as novel anti-tumour agents.
Improved control of dioxin emissions during iron ore sintering. This project aims to develop an innovative assessment of dioxin formation through analysis and speciation of its precursors (Cl and Cu). Iron ore sintering is the industrial process with the highest emissions of dioxins and furans to the environment in Australia, which are amongst the most toxic substances produced by man. The aim of this project is to conduct critical investigations required for control of dioxin emissions during i ....Improved control of dioxin emissions during iron ore sintering. This project aims to develop an innovative assessment of dioxin formation through analysis and speciation of its precursors (Cl and Cu). Iron ore sintering is the industrial process with the highest emissions of dioxins and furans to the environment in Australia, which are amongst the most toxic substances produced by man. The aim of this project is to conduct critical investigations required for control of dioxin emissions during iron ore sintering. The expected outcome of this project is the development of control mechanisms for the process conditions responsible for dioxin formation. This should provide significant benefits, such as assisting the Australian iron ore industry to address the environmental requirements of their international trade partners and sustain their iron ore exports.Read moreRead less