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
Chemical principles underpinning a spermostatic-microbiostatic agent capable of preventing pregnancy and the spread of sexually transmitted disease. This project explores the development of a method for simultaneously controlling fertility while preventing the spread of sexually transmitted diseases. A novel aspect of the approach, that will dramatically influence product development, is that the active principles will only be generated on contact with seminal plasma.
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0561041
Funder
Australian Research Council
Funding Amount
$347,358.00
Summary
A New Generation Biosensor and Fluorescence Facility for Proteomics. The complete DNA sequence (the genome) is now known for many organisms and advances are being made to identify the complement of messenger RNA (the transcriptome) and the resultant collection of proteins (the proteome). The genome is largely fixed while the transcriptome and proteome differ between cell types in an organism and constantly vary to adapt the cell to changing conditions. The mediators of these variations are prote ....A New Generation Biosensor and Fluorescence Facility for Proteomics. The complete DNA sequence (the genome) is now known for many organisms and advances are being made to identify the complement of messenger RNA (the transcriptome) and the resultant collection of proteins (the proteome). The genome is largely fixed while the transcriptome and proteome differ between cell types in an organism and constantly vary to adapt the cell to changing conditions. The mediators of these variations are proteins, interacting with each other and with signal molecules. The next frontier in molecular biology is to identify and quantify these protein interactions. Our two institutions have a very large cohort of biologists whose research on proteins would be greatly facilitated by the Biacore 3000 and the ISS K2.Read moreRead less
Chemical and Biochemical Characterisation of Novel Iron Chelators with Therapeutic Potential. Iron is essential for life, but iron-overload is a potentially fatal condition. There is no natural mechanism to excrete iron in humans, so patients suffering from iron-overload disorders are treated with the chelator Desferal to enable iron excretion typically from an early age. Desferal is orally ineffective and must be given by subcutaneous infusion (12-24h, 5-6 days/week) resulting in poor patient c ....Chemical and Biochemical Characterisation of Novel Iron Chelators with Therapeutic Potential. Iron is essential for life, but iron-overload is a potentially fatal condition. There is no natural mechanism to excrete iron in humans, so patients suffering from iron-overload disorders are treated with the chelator Desferal to enable iron excretion typically from an early age. Desferal is orally ineffective and must be given by subcutaneous infusion (12-24h, 5-6 days/week) resulting in poor patient compliance. We will conduct critical chemical and biological experiments with a new series of potentially orally active iron chelators identified in our lab. The results from this project will be vital for the development of these compounds as pharmaceuticals.Read moreRead less
Molecular Regulation Of Metabolism And Body Composition By Ski Via Crosstalk With Nuclear Hormone Receptor Signalling.
Funder
National Health and Medical Research Council
Funding Amount
$558,441.00
Summary
Obesity is a common and burdensome health problem in the community which leads to diabetes and heart disease. A number of factors, including hormones play important roles in determing risk of obesity. This study proposes to investigate whether the Ski gene which is a regulatory factor for many hormones affects metabolism in transgenic mouse models of altered Ski function. The proposed studies may identify Ski as a target for therapy for obesity and improvement in sketal muscle metabolism.
Peopling educational policy: realising the new Australian English and mathematics curricula. Implementation of Australian curricula in English and mathematics provides an opportunity for school systems to re-examine practice. This project will identify resources and teacher learning opportunities needed to facilitate implementation of these curricula and use findings to develop interventions identified as likely to optimise implementation.
Improving student outcomes: coaching teachers in the power of feedback. This project aims to investigate how student outcomes can be augmented through coaching teachers in effective feedback practice. The project addresses a critical problem of stagnating levels of student achievement in Australian schools with the innovative research design combining evidence-based, pedagogies of feedback, formative assessment and instructional coaching to improve teacher practice and ultimately raise student a ....Improving student outcomes: coaching teachers in the power of feedback. This project aims to investigate how student outcomes can be augmented through coaching teachers in effective feedback practice. The project addresses a critical problem of stagnating levels of student achievement in Australian schools with the innovative research design combining evidence-based, pedagogies of feedback, formative assessment and instructional coaching to improve teacher practice and ultimately raise student achievement levels. The project aims to guide policy implementation in pedagogy to raise the quality of teaching standards and to improve learning outcomes for Australian students. Ultimately, outcomes from the research will help close the gap for low achieving students, and challenge and extend those who may already be meeting required benchmarks. Read moreRead less
Multiliteracies for addressing disadvantage in senior school science. Multiliteracies for addressing disadvantage in senior school science. This project aims to develop discipline-specific pedagogies in senior physics, chemistry and biology to improve disadvantaged students’ engagement and achievement. Many students from disadvantaged backgrounds fail to develop the linguistic precision and symbolic representational dexterity needed to comprehend and communicate senior school science concepts. T ....Multiliteracies for addressing disadvantage in senior school science. Multiliteracies for addressing disadvantage in senior school science. This project aims to develop discipline-specific pedagogies in senior physics, chemistry and biology to improve disadvantaged students’ engagement and achievement. Many students from disadvantaged backgrounds fail to develop the linguistic precision and symbolic representational dexterity needed to comprehend and communicate senior school science concepts. These pedagogies will ‘infuse’ multiliteracies in senior school science to improve access to science-based pathways for these students, and enable them to understand progressively more complex scientific concepts and demonstrate this in examinations. This project is expected to improve student retention, arrest declining enrolments in senior school science, and increase young people working in science.Read moreRead less
The online future of Science and Engineering education: The essential elements of laboratory-based learning for remote-access implementation. Laboratory classes are a critical part of science and engineering degree programs, but there has been little research into what actually takes place within them. Remote laboratories, in which students control equipment via the internet, are one potential solution for accommodating rising numbers of students, but the interfaces must be developed to effectiv ....The online future of Science and Engineering education: The essential elements of laboratory-based learning for remote-access implementation. Laboratory classes are a critical part of science and engineering degree programs, but there has been little research into what actually takes place within them. Remote laboratories, in which students control equipment via the internet, are one potential solution for accommodating rising numbers of students, but the interfaces must be developed to effectively support student learning. This project will investigate how students interact with equipment, each other, and with laboratory demonstrators in order to determine the crucial components of effective laboratory learning experiences. It will identify and characterise the interactions of students in laboratory classes, and develop mechanisms to support these interactions remotely.Read moreRead less
Out-of-field Teaching: Sustaining Quality Practices Across Subjects. Teaching out-of-field (teaching a subject without qualifications) is a rising concern internationally, and is linked to attrition, stress, and reduced student learning outcomes. With a comparatively high percentage of out-of-field teachers, Australia is exposed to significant social, economic and educational costs. Through the development of longitudinal case studies, this project investigates the changing landscape of teacher ....Out-of-field Teaching: Sustaining Quality Practices Across Subjects. Teaching out-of-field (teaching a subject without qualifications) is a rising concern internationally, and is linked to attrition, stress, and reduced student learning outcomes. With a comparatively high percentage of out-of-field teachers, Australia is exposed to significant social, economic and educational costs. Through the development of longitudinal case studies, this project investigates the changing landscape of teacher perceptions and practices over three years, within school institutional cultures relating to teacher assignment, support, and out-of-field mathematics and science teaching. Outcomes of the project will aim to inform the development of system and school policy and practice, in dealing with this internationally pervasive issue.Read moreRead less