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
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.
New Lead-Free Brass Solutions for Drinking Water Applications. The aim of this Linkage Project is to provide viable material solutions to address the health problem of Lead-contamination in drinking water arising from Leaded-brass plumbing products and the impact Lead-removal from brass will have on the brass industry. In order to achieve this, this project engages leading multidisciplinary researchers along with Australian and international industry partners from across the brass industry suppl ....New Lead-Free Brass Solutions for Drinking Water Applications. The aim of this Linkage Project is to provide viable material solutions to address the health problem of Lead-contamination in drinking water arising from Leaded-brass plumbing products and the impact Lead-removal from brass will have on the brass industry. In order to achieve this, this project engages leading multidisciplinary researchers along with Australian and international industry partners from across the brass industry supply and sales network. This project seeks to identify and harness the key material-product attributes required to develop and implement new, lead-free alloy alternatives that meet health-compliance, production and commercial viability, that offer benefits across the industry network and health benefits to society.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE140100003
Funder
Australian Research Council
Funding Amount
$280,000.00
Summary
Flexible forming facility for low cost light weight applications. Flexible forming facility for low-cost light-weight applications: This project will establish Australia’s first flexible roll forming facility. The facility will be unique in the world, being specifically designed to roll form the most advanced high strength alloys into complex three-dimensional shapes and investigate their material behaviour under a wide range of loading conditions. This technology represents a step change in com ....Flexible forming facility for low cost light weight applications. Flexible forming facility for low-cost light-weight applications: This project will establish Australia’s first flexible roll forming facility. The facility will be unique in the world, being specifically designed to roll form the most advanced high strength alloys into complex three-dimensional shapes and investigate their material behaviour under a wide range of loading conditions. This technology represents a step change in commercial processing and has the capacity to form materials with high strength and limited ductility. This will lead to the development of new techniques for the manufacture of new advanced materials including advanced high strength steels, composites, nano structured metals and light metal alloys for automotive and aerospace applications.Read moreRead less
ARC Centre of Excellence - in Ore Deposits. Australia's minerals industry faces a two-fold challenge - to find new ore deposits and to mine them with maximum efficiency and minimal environmental impact. Those challenges demand a new generation of focused ore deposit research, tailored specifically for the Australian context. The Centre of Excellence in Ore Deposits will provide the foundation of fundamental research required by a successful, efficient and sustainable Australian minerals industry ....ARC Centre of Excellence - in Ore Deposits. Australia's minerals industry faces a two-fold challenge - to find new ore deposits and to mine them with maximum efficiency and minimal environmental impact. Those challenges demand a new generation of focused ore deposit research, tailored specifically for the Australian context. The Centre of Excellence in Ore Deposits will provide the foundation of fundamental research required by a successful, efficient and sustainable Australian minerals industry. The Centre will also play a leading role in the undergraduate and postgraduate training of future geoscientists. The concentration of internationally recognised researchers in the Centre will ensure it maintains its premier position in the international ore deposit research arena.Read moreRead less
Design of tuneable microstructures for additive manufacturing. The project intends to develop methods to tune the microstructure of materials in additive manufacturing so that components can be manufactured with maximum productivity and properties. Additive manufacturing is leading the mass customisation of manufacturing. Designed tunable microstructures enable structure and properties to be tailored for specific applications. One of the greatest challenges, however, is how to control the scale ....Design of tuneable microstructures for additive manufacturing. The project intends to develop methods to tune the microstructure of materials in additive manufacturing so that components can be manufactured with maximum productivity and properties. Additive manufacturing is leading the mass customisation of manufacturing. Designed tunable microstructures enable structure and properties to be tailored for specific applications. One of the greatest challenges, however, is how to control the scale and morphology of the microstructure. This project aims to use the interdependence model of grain refinement to control and design grain sizes. The project first plans to investigate the near-rapid solidification conditions in aluminium alloys. It then plans to re-design the harder-to-manufacture titanium alloys to improve grain size control.Read moreRead less
Industrial Transformation Training Centres - Grant ID: IC180100005
Funder
Australian Research Council
Funding Amount
$4,889,410.00
Summary
ARC Training Centre in Surface Engineering for Advanced Materials. The ARC Training Centre in Surface Engineering for Advanced Materials aims to provide pathways for job creation and a high quality workforce in manufacturing. Surface engineering for advanced materials is a core need in all manufacturing sectors and controls the efficiency, productivity and sustainability of Australian industry. This Centre will integrate industry-university cooperation for applied training within an industrial s ....ARC Training Centre in Surface Engineering for Advanced Materials. The ARC Training Centre in Surface Engineering for Advanced Materials aims to provide pathways for job creation and a high quality workforce in manufacturing. Surface engineering for advanced materials is a core need in all manufacturing sectors and controls the efficiency, productivity and sustainability of Australian industry. This Centre will integrate industry-university cooperation for applied training within an industrial setting and will cover a spectrum of applications ranging from thin films to thick coatings and additive layered materials. The Centre will pursue outcomes that are reflected in terms of industry-fit researchers and deliver commercial benefits for industry.Read moreRead less
Nature's mechanisms for leaching and remobilising metals. This project aims to understand the chemical and physical processes that govern reactive transport and metal scavenging in rocky environments. Much of Australia's mineral wealth is the result of the interaction of warm fluids with rocks deep in the Earth over geological timescales. The formation of ore deposits is governed by the physical chemistry of mineral dissolution and crystallisation, and by fluid flow through porous rocks and frac ....Nature's mechanisms for leaching and remobilising metals. This project aims to understand the chemical and physical processes that govern reactive transport and metal scavenging in rocky environments. Much of Australia's mineral wealth is the result of the interaction of warm fluids with rocks deep in the Earth over geological timescales. The formation of ore deposits is governed by the physical chemistry of mineral dissolution and crystallisation, and by fluid flow through porous rocks and fractures. This project integrates innovation in geology, chemistry, and mineral engineering, and will deliver mineral-scale reaction models that will increase efficiency of in-situ mining and leaching technologies. Knowledge generated can be applied to improve mineral exploration, mining, and processing, contributing to unlocking billions of dollars’ worth of resources tied up in low grade, mineralogically complex ores.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE180100070
Funder
Australian Research Council
Funding Amount
$966,283.00
Summary
Cutting-edge electron probe microanalysis driving Western Australia’s resource geosciences. This project aims to provide a new generation electron microprobe, with advances in trace element mapping and cathodoluminescence analysis to enable superior characterisation of a wide range of materials. The overwhelming demand for electron probe microanalysis from research groups in Western Australia requires renewal of over-subscribed, ageing facilities to drive innovation and alleviate bottlenecks in ....Cutting-edge electron probe microanalysis driving Western Australia’s resource geosciences. This project aims to provide a new generation electron microprobe, with advances in trace element mapping and cathodoluminescence analysis to enable superior characterisation of a wide range of materials. The overwhelming demand for electron probe microanalysis from research groups in Western Australia requires renewal of over-subscribed, ageing facilities to drive innovation and alleviate bottlenecks in advanced geosciences multi-capability workflows. The electron probe will drive underpinning geoscience, resources science and economic geology, as well as support a broad range of disciplines and diverse fields, such as nanotechnology, microelectronics and aquatic sciences.Read moreRead less
Experimental constraints on the genesis of gold-rich ore deposits. The project will provide a new set of tools to explore for gold-rich ore deposits in Australia and globally. By integrating geochemical studies with cutting-edge experiments carried out at three Australian universities in strategic partnership with industry, the outcomes of this project will provide much needed knowledge to predict the locations of large gold-rich deposits that are concealed beneath vast expanses of the Australia ....Experimental constraints on the genesis of gold-rich ore deposits. The project will provide a new set of tools to explore for gold-rich ore deposits in Australia and globally. By integrating geochemical studies with cutting-edge experiments carried out at three Australian universities in strategic partnership with industry, the outcomes of this project will provide much needed knowledge to predict the locations of large gold-rich deposits that are concealed beneath vast expanses of the Australian continent. The new results will translate into smarter exploration practice, significantly enhancing success in targeting ore deposits that are rich in high-value metal and display the smallest have a small environmental footprint, to underpin the sustainability of our nation into the future.
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