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
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE170100021
Funder
Australian Research Council
Funding Amount
$2,168,000.00
Summary
Australian Metabolic Phenotyping Centre (AMPC). This project aims to establish a centre for targeted and exploratory metabolic phenotyping. Metabolic phenotyping quantitatively measures the precursors, intermediates and products of metabolism interacting within a biological system. This project will use high-resolution spectrometry and spectroscopy to generate comprehensive, multi-parameter metabolite data sets for biological samples at the population level, at unprecedented throughput and low c ....Australian Metabolic Phenotyping Centre (AMPC). This project aims to establish a centre for targeted and exploratory metabolic phenotyping. Metabolic phenotyping quantitatively measures the precursors, intermediates and products of metabolism interacting within a biological system. This project will use high-resolution spectrometry and spectroscopy to generate comprehensive, multi-parameter metabolite data sets for biological samples at the population level, at unprecedented throughput and low cost, to address biological and biomedical research needs. This project is expected to make Australian scientists globally competitive in the life sciences including biological, clinical and biomedical, plant and crop sciences, analytical chemistry, toxicology, agriculture, wildlife conservation and sports science, and to drive advances in the data sciences for systems biology.Read moreRead less
Special Research Initiatives - Grant ID: SR1101002
Funder
Australian Research Council
Funding Amount
$21,000,000.00
Summary
Stem Cells Australia. Despite progress in stem cell research, scientists do not understand how stem cells “decide” what to become. Stem Cells Australia will draw upon strengths within Australia’s premier stem cell research universities and institutes. This collaboration between leading bioengineering, nanotechnology, stem cell and advanced molecular analysis experts, will fast-track efforts to deliver a fundamental understanding of the mechanisms of stem cell regulation and differentiation, and ....Stem Cells Australia. Despite progress in stem cell research, scientists do not understand how stem cells “decide” what to become. Stem Cells Australia will draw upon strengths within Australia’s premier stem cell research universities and institutes. This collaboration between leading bioengineering, nanotechnology, stem cell and advanced molecular analysis experts, will fast-track efforts to deliver a fundamental understanding of the mechanisms of stem cell regulation and differentiation, and the ability to control and influence this process. Stem Cells Australia will deliver new methods for stem cell propagation and manipulation, new translational technologies for therapeutic applications, and will prepare Australia’s future stem cell scientific leaders.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE180100157
Funder
Australian Research Council
Funding Amount
$600,000.00
Summary
Confocal and single molecule microscopes for systems microscopy. This project aims to establish Australia’s first system microscopy facility with dedicated live-cell confocal and single-molecule fluorescence microscopes. In systems microscopy, the imaging workflow is automated so that large and unbiased data sets of the spatiotemporal organisation of molecules and cells can be generated. Combined with statistical and bioinformatics analyses, image-derived data provides system-wide information th ....Confocal and single molecule microscopes for systems microscopy. This project aims to establish Australia’s first system microscopy facility with dedicated live-cell confocal and single-molecule fluorescence microscopes. In systems microscopy, the imaging workflow is automated so that large and unbiased data sets of the spatiotemporal organisation of molecules and cells can be generated. Combined with statistical and bioinformatics analyses, image-derived data provides system-wide information that is not easily obtainable with other approaches. The project will enable Australian researchers to image and analyse the full complexity of biological systems, potentially transforming cell biology, drug development and understanding the molecular basis of disease. It will also demonstrate how the capacity of microscopy facilities can be enhanced and bias in imaging data reduced by automating data acquisition and mining of image-based data.Read moreRead less
Targeting the undruggable: epitope mapping using Phylomers peptides to modulate activity of Transcription Factors. This project aims at expanding the pool of drug targets, by extending drug screening to protein-protein interaction networks. This project aims to assemble a novel technical platform to detect binding between proteins, using a combination of cell-free protein expression, AlphaScreen and single-molecule fluorescence. This pipeline has great potential to accelerate the exploration of ....Targeting the undruggable: epitope mapping using Phylomers peptides to modulate activity of Transcription Factors. This project aims at expanding the pool of drug targets, by extending drug screening to protein-protein interaction networks. This project aims to assemble a novel technical platform to detect binding between proteins, using a combination of cell-free protein expression, AlphaScreen and single-molecule fluorescence. This pipeline has great potential to accelerate the exploration of protein networks, and provides also a generic platform for drug screening on difficult targets. The project intends to screen Phylogica's libraries of peptides called Phylomers to discover tight binders to a Transcription Factor, Sox18. The objective of this project is to determine which Phylomers can disrupt specific interactions between Sox18 and its binding partners involved in lymphangiogenesis.Read moreRead less
A microfluidic array of phylomers for rapid discovery of peptide probes and biomarkers. This project, through an alliance with Phylogica, aims at exploiting a unique source of structural diversity for drug discovery, harvesting the creativity of nature in its most exotic places. The project will develop a novel approach to validate design and validate drug candidates, by gathering them on a single screening chip for a powerful discovery platform.
Industrial Transformation Training Centres - Grant ID: IC210100040
Funder
Australian Research Council
Funding Amount
$4,997,903.00
Summary
ARC Training Centre for Facilitated Advancement of Australia's Bioactives (FAAB). The Centre for Facilitated Advancement of Australia's Bioactives (FAAB) will transform the rapidly growing bioactive ingredients sector. It will apply advanced analytical methods to molecular characterisation of bioactive products derived from foods, food-waste, and cell-based biotechnologies. FAAB will determine modes of action for bioactives with potential lifestyle and nutritional benefits allowing for evidence- ....ARC Training Centre for Facilitated Advancement of Australia's Bioactives (FAAB). The Centre for Facilitated Advancement of Australia's Bioactives (FAAB) will transform the rapidly growing bioactive ingredients sector. It will apply advanced analytical methods to molecular characterisation of bioactive products derived from foods, food-waste, and cell-based biotechnologies. FAAB will determine modes of action for bioactives with potential lifestyle and nutritional benefits allowing for evidence-informed decision-making, and regulatory framework development. FAAB graduates will lead and deliver future national self-reliance to the Australian bioactives sector, increasing diversification and international competitiveness and development of regulation in a growing market. Read moreRead less
Mid-Career Industry Fellowships - Grant ID: IM230100154
Funder
Australian Research Council
Funding Amount
$1,049,904.00
Summary
Fungi Power: Designer Fungal Cell Factories for Advanced Biomanufacturing. This project aims to build an advanced biomanufacturing platform based on filamentous fungi in collaboration with industry. Using synthetic biology, the project expects to engineer superior fungal host strains customisable to the needs of the industry and to address their technological gaps. The expected outcomes include the development of cost-efficient and sustainable fungal-based bioprocesses for the companies to produ ....Fungi Power: Designer Fungal Cell Factories for Advanced Biomanufacturing. This project aims to build an advanced biomanufacturing platform based on filamentous fungi in collaboration with industry. Using synthetic biology, the project expects to engineer superior fungal host strains customisable to the needs of the industry and to address their technological gaps. The expected outcomes include the development of cost-efficient and sustainable fungal-based bioprocesses for the companies to produce products, such as fine chemicals, pharmaceutical actives and food ingredients. The project would provide significant benefits by enabling existing and emerging companies' commercial successes and competitiveness in global markets, creating new jobs and resulting in the growth of the bio-economy in Australia.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE110100174
Funder
Australian Research Council
Funding Amount
$800,000.00
Summary
Innovative synchrotron science - program for access to the Australian National Beamline Facility and cutting-edge beamlines at international synchrotrons. Synchrotron science dramatically affects the community through the innovative scientific, engineering and medical research outcomes it produces. This program for access to synchrotron beamlines is aimed at enhancing Australia's high international standing in synchrotron science and will have many flow-on effects in areas such as health and ind ....Innovative synchrotron science - program for access to the Australian National Beamline Facility and cutting-edge beamlines at international synchrotrons. Synchrotron science dramatically affects the community through the innovative scientific, engineering and medical research outcomes it produces. This program for access to synchrotron beamlines is aimed at enhancing Australia's high international standing in synchrotron science and will have many flow-on effects in areas such as health and industry.Read moreRead less
ARC Centre of Excellence in Synthetic Biology. The ARC Centre of Excellence in Synthetic Biology (CoESB) will provide the technical innovation critical for Australia to develop a vibrant bioeconomy building on the nation’s strengths in agriculture. For thousands of years we have used microbes to create bread, wine, cheese. Now, our Centre will pioneer new approaches to the design of synthetic microbes, enabling the development of custom-designed microbial communities, synthetic organelles and ne ....ARC Centre of Excellence in Synthetic Biology. The ARC Centre of Excellence in Synthetic Biology (CoESB) will provide the technical innovation critical for Australia to develop a vibrant bioeconomy building on the nation’s strengths in agriculture. For thousands of years we have used microbes to create bread, wine, cheese. Now, our Centre will pioneer new approaches to the design of synthetic microbes, enabling the development of custom-designed microbial communities, synthetic organelles and new to nature biological pathways and enzymes. CoESB will combine engineering with molecular biology to design and construct novel biological systems that can convert biomass from agriculture or waste streams to biofuel, bioplastics and other high-value chemicals.Read moreRead less