Investigations of signals involved in redox-regulation of carbon storage. This project seeks molecular understanding of signals optimising storage processes in plants in response to nutrient supply and environmental stress. Discovering regulatory signals that control carbon storage and yield will maintain Australia's international reputation in this field of research and may provide technical opportunities to improve crops in healthy or stressful environments. This is an issue of increasing impo ....Investigations of signals involved in redox-regulation of carbon storage. This project seeks molecular understanding of signals optimising storage processes in plants in response to nutrient supply and environmental stress. Discovering regulatory signals that control carbon storage and yield will maintain Australia's international reputation in this field of research and may provide technical opportunities to improve crops in healthy or stressful environments. This is an issue of increasing importance especially in the context of global warming. Read 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
Understanding Sphingolipid Mediators Of Insulin Resistance
Funder
National Health and Medical Research Council
Funding Amount
$643,447.00
Summary
Sphingolipids are a class of lipid metabolites that have a variety of functions within cells. It has been known for some time that an accumulation of excess lipid, including certain sphingolipids, can adversely impact insulin action and glucose metabolism in cells. In this project we will a combination of strategies to test the hypothesis that the sphingolipid profile can be manipulated to have favourable effects on metabolism.
Is transport of miRNAs essential for plant development? This project will provide knowledge of how a new class of biologically active molecule (micro RNA) regulates expression of genes at sites in the plant that are critical for growth and development. MicroRNAs are believed to influence the size and shape of plants, how rapidly they grow and how well they produce and fill seeds. These molecules are part of a group of bioactive signals that move throughout the plant, functioning like hormones bu ....Is transport of miRNAs essential for plant development? This project will provide knowledge of how a new class of biologically active molecule (micro RNA) regulates expression of genes at sites in the plant that are critical for growth and development. MicroRNAs are believed to influence the size and shape of plants, how rapidly they grow and how well they produce and fill seeds. These molecules are part of a group of bioactive signals that move throughout the plant, functioning like hormones but directly influencing how well critical genes work. Their exploitation holds great promise for manipulating plant performance and enhancing crop yields. Read moreRead less
Integration of Cellular Gene Regulation Processes. This research program aims to identify specific transcriptional regulatory networks in yeast, to determine how some of these networks interact with each other and within these networks to identify the roles of genes whose functions are currently unknown. It will identify systems regulating genes concerned with one-carbon metabolism, cellular responses to oxidative stress and developmental changes associated with meiosis. It will provide a fra ....Integration of Cellular Gene Regulation Processes. This research program aims to identify specific transcriptional regulatory networks in yeast, to determine how some of these networks interact with each other and within these networks to identify the roles of genes whose functions are currently unknown. It will identify systems regulating genes concerned with one-carbon metabolism, cellular responses to oxidative stress and developmental changes associated with meiosis. It will provide a framework to test regulatory network models and to analyse the molecular basis of interactions between control systems. This research will eventually provide the ability to predict how cells respond to drugs and other environmental stimuli.Read moreRead less
Navigating flux control through a branched metabolic pathway. This project aims to uncover control points and programmes in the mevalonate pathway, an important cellular metabolic pathway that produces cholesterol and isoprenoids. Knowledge of its regulation is largely restricted to just one enzyme (HMGCR). This project will determine how regulation of the later sterol-producing segment affects the early isoprenoid-segment of the mevalonate pathway; investigate how the two alternate routes to ch ....Navigating flux control through a branched metabolic pathway. This project aims to uncover control points and programmes in the mevalonate pathway, an important cellular metabolic pathway that produces cholesterol and isoprenoids. Knowledge of its regulation is largely restricted to just one enzyme (HMGCR). This project will determine how regulation of the later sterol-producing segment affects the early isoprenoid-segment of the mevalonate pathway; investigate how the two alternate routes to cholesterol synthesis operate and are regulated; and explore a co-ordinated and possibly co-operative transcriptional program. This project is expected to provide valuable knowledge of how cells control these critical lipids, which will ultimately inform better ways to treat diseases of cholesterol excess and defects in this pathway.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0560987
Funder
Australian Research Council
Funding Amount
$156,697.00
Summary
Robust High Resolution Gene and Protein Expression Analysis Facilities in WA. Biological research is playing an increasingly important role in keeping agriculture internationally competitive and helping to unravel the basic mechanisms underpinning plant and animal health. This collaborative research equipment will greatly enhance and extend our existing functional genomic facilities in WA, allowing robust pre-fractionation of samples for directed proteomic analysis within complex systems and al ....Robust High Resolution Gene and Protein Expression Analysis Facilities in WA. Biological research is playing an increasingly important role in keeping agriculture internationally competitive and helping to unravel the basic mechanisms underpinning plant and animal health. This collaborative research equipment will greatly enhance and extend our existing functional genomic facilities in WA, allowing robust pre-fractionation of samples for directed proteomic analysis within complex systems and allowing accurate and sensitive measurement of gene expression. Both of these are critical for analysis of low abundance components involved in signalling and regulatory functions in biological samples.Read moreRead less
Nanoprobe and Microprobe Spectroscopic Techniques in Drug Design, Probing Mechanisms of Diseases, and Bioinorganic Chemistry. Nanoprobe and microprobe spectroscopic techniques offer unparalleled opportunities to probe the structures and distributions of drugs, carcinogens, and biomolecules in cultured cells and tissues. Such techniques represent new frontiers in understanding in vivo metabolic processes at the molecular level, as well as providing unprecedented information on the metabolism and ....Nanoprobe and Microprobe Spectroscopic Techniques in Drug Design, Probing Mechanisms of Diseases, and Bioinorganic Chemistry. Nanoprobe and microprobe spectroscopic techniques offer unparalleled opportunities to probe the structures and distributions of drugs, carcinogens, and biomolecules in cultured cells and tissues. Such techniques represent new frontiers in understanding in vivo metabolic processes at the molecular level, as well as providing unprecedented information on the metabolism and distributions of pharmaceuticals and toxins involved in the treatment and cause of diseases, such as cancer. This project is aimed at pushing the boundaries of nanoprobe and microprobe (X-ray absorption, SRIXE, PIXE, Raman and two-photon fluorescence) techniques for such applications.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0453722
Funder
Australian Research Council
Funding Amount
$385,240.00
Summary
Collaborative Genomics, Proteomics and Metabolomics Facility for Western Australia. Plant and animal agriculture in Western Australia contributes $6billion per annum to the nation. Biotechnology is playing an increasingly important role in keeping agriculture internationally competitive, and requires investment in platform technologies to underpin basic and applied research. This collaborative project will provide state-of-the-art equipment and extend existing joint facilities that will enable ....Collaborative Genomics, Proteomics and Metabolomics Facility for Western Australia. Plant and animal agriculture in Western Australia contributes $6billion per annum to the nation. Biotechnology is playing an increasingly important role in keeping agriculture internationally competitive, and requires investment in platform technologies to underpin basic and applied research. This collaborative project will provide state-of-the-art equipment and extend existing joint facilities that will enable WA researchers to carry out high quality research on genomics, proteomics and the metabolic functioning of plants and animals. This will generate new knowledge, provide advanced training and help ensure that Australian R&D in agricultural biotechnology stays at the forefront and benefits the nation.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