Mixing the jigsaw pieces of natural products: new molecules-new properties. This project aims to examine the capacity of exploiting the bacterial biosynthetic machinery to fast-track access to analogues of natural products. Due to increased drug resistance, new reservoirs of natural products are needed for evaluation as future drugs. Desferrioxamine B will be used as a model natural product to establish the biosynthesis of new analogues in bacterial culture supplemented with unsaturated, fluorin ....Mixing the jigsaw pieces of natural products: new molecules-new properties. This project aims to examine the capacity of exploiting the bacterial biosynthetic machinery to fast-track access to analogues of natural products. Due to increased drug resistance, new reservoirs of natural products are needed for evaluation as future drugs. Desferrioxamine B will be used as a model natural product to establish the biosynthesis of new analogues in bacterial culture supplemented with unsaturated, fluorinated or deuterated building blocks. The intended outcomes are to deliver advances in methods for generating structurally diverse pools of natural products, new label-free probes, knowledge of natural product biosynthesis, and excellence in training research students in frontier methods in chemical biology and drug discovery.Read moreRead less
Resurrecting Ancient Proteins to Unlock New Catalytic Activity. This project aims to study the proteins that nature uses to make penicillin and related antibiotics, and their prehistoric ancestors. By doing so, the project expects to deepen understanding of these important processes, open up ways to make new antibiotics, and generate new knowledge about protein evolution. Intended outcomes include new biocatalysts based on the ancient ones, new antibiotic compounds active against resistant bacte ....Resurrecting Ancient Proteins to Unlock New Catalytic Activity. This project aims to study the proteins that nature uses to make penicillin and related antibiotics, and their prehistoric ancestors. By doing so, the project expects to deepen understanding of these important processes, open up ways to make new antibiotics, and generate new knowledge about protein evolution. Intended outcomes include new biocatalysts based on the ancient ones, new antibiotic compounds active against resistant bacteria, and a richer understanding of how these proteins have evolved over the last 4 billion years. This promises significant benefits in the form of new ways to address the challenge posed by antimicrobial resistance to antibiotics, which is a serious threat to the continued effectiveness of current antibiotics.Read moreRead less
Expanding access to modified proteins via a novel semi-synthetic platform. This project aims to address a critical knowledge gap in understanding how post-translational modifications modulate the structure and activity of proteins. By developing an innovative semi-synthetic platform to produce pure proteins inaccessible by existing methods, the project will reveal how natural protein modifications influence structure and function. Expected outcomes include the delivery of breakthrough technologi ....Expanding access to modified proteins via a novel semi-synthetic platform. This project aims to address a critical knowledge gap in understanding how post-translational modifications modulate the structure and activity of proteins. By developing an innovative semi-synthetic platform to produce pure proteins inaccessible by existing methods, the project will reveal how natural protein modifications influence structure and function. Expected outcomes include the delivery of breakthrough technologies for accessing modified proteins for a range of applications in academia and industry, as well as the generation of new knowledge in the fields of chemistry and biology. The project will lead to the training of interdisciplinary early career researchers and has the potential to benefit Australia’s biotechnology sector.Read moreRead less
The macrophage nucleus - its form and function during migration in vivo. As cells migrate through tissues, they encounter complex, 3-dimensional environments that provide cues to guide them and present obstacles in their path. This project focuses on macrophages, a large immune cell capable of both amoeboid and mesenchymal modes of migration. The nucleus is the largest organelle and its bulk and stiffness must be managed as migrating cells travel through constrictions. The project uses specialis ....The macrophage nucleus - its form and function during migration in vivo. As cells migrate through tissues, they encounter complex, 3-dimensional environments that provide cues to guide them and present obstacles in their path. This project focuses on macrophages, a large immune cell capable of both amoeboid and mesenchymal modes of migration. The nucleus is the largest organelle and its bulk and stiffness must be managed as migrating cells travel through constrictions. The project uses specialised high-end microscopy and genetic methods to examine how the nucleus of migrating zebrafish macrophages deforms, repositions and is restructured during migration in living tissues, and how this influences macrophage locomotion. The goal is to provide fundamental insights into the cell biology of macrophage migration.Read moreRead less
CRISPR-based pathway activation for bioactive molecule discovery in fungi. Fungi produce an incredible array of unique bioactive molecules, many of which have contributed greatly to humanity (e.g. the antibiotic penicillin, which has saved millions of lives since its discovery). DNA sequencing has revealed many fungi contain the genetic instructions to produce new molecules that have not been seen previously. However, these genes are “switched off" by default and cannot be accessed. This project ....CRISPR-based pathway activation for bioactive molecule discovery in fungi. Fungi produce an incredible array of unique bioactive molecules, many of which have contributed greatly to humanity (e.g. the antibiotic penicillin, which has saved millions of lives since its discovery). DNA sequencing has revealed many fungi contain the genetic instructions to produce new molecules that have not been seen previously. However, these genes are “switched off" by default and cannot be accessed. This project will develop innovative new methods to "hot-wire" these genes, allowing them to turn on and produce a treasure trove of new bioactive molecules. The outcomes of this project will transform our abilities to tap into the hidden potential of fungi to generate new lead molecules for the agricultural and medical industries.Read moreRead less
Characterisation of the beneficial vs toxic forms of selenium in the diet. This project aims to examine how dietary selenium is converted into essential proteins and beneficial compounds that mitigate against a broad range of human diseases; or alternatively, into toxic molecules. Cutting-edge methodologies should resolve significant unknowns in selenium metabolism, to provide definitive dietary guidelines and to explore how selenium can treat and protect against disease. Expected outcomes from ....Characterisation of the beneficial vs toxic forms of selenium in the diet. This project aims to examine how dietary selenium is converted into essential proteins and beneficial compounds that mitigate against a broad range of human diseases; or alternatively, into toxic molecules. Cutting-edge methodologies should resolve significant unknowns in selenium metabolism, to provide definitive dietary guidelines and to explore how selenium can treat and protect against disease. Expected outcomes from this national and international collaboration include expert training for young biochemical researchers and refinements to novel analytical techniques. Results should benefit the food and agricultural sectors to provide tailored products locally and for export, as well as enhanced health opportunities for all Australians.Read moreRead less
Sugar transporters in coral symbiosis and origin of parasitism. We aim to identify how symbiotic algae feed sugar to their coral hosts. Corals need this algal sugar to exist, but no one knows how it is transferred, so understanding this crucial mechanism is hugely significant. The first benefit of this research will be a fundamental understanding about how two organisms (algae and coral) cooperate to build habitats like the Great Barrier Reef. We also aim to explore whether coral/algal coopera ....Sugar transporters in coral symbiosis and origin of parasitism. We aim to identify how symbiotic algae feed sugar to their coral hosts. Corals need this algal sugar to exist, but no one knows how it is transferred, so understanding this crucial mechanism is hugely significant. The first benefit of this research will be a fundamental understanding about how two organisms (algae and coral) cooperate to build habitats like the Great Barrier Reef. We also aim to explore whether coral/algal cooperation paved the way for the origin of parasitism. The second key outcome will be to identify the precise molecular mechanism that allowed parasitism to arise. This will benefit us through understanding the origins of important diseases such as human malaria and related infections of livestock and wildlife.
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Chemical staples and chemical probes to dissect dynamins cellular roles. Modulation of protein structure drives cellular function. Dynamin GTPase forms at least two macromolecular structures with different cellular functions. The drivers behind these different structures is unknown. In this project we will leverage our discoveries, and planned enhancements, of chemical biology probes that will modulate dynamin activity by inhibiting at three distinct sites, and one site that stimulates dynamin a ....Chemical staples and chemical probes to dissect dynamins cellular roles. Modulation of protein structure drives cellular function. Dynamin GTPase forms at least two macromolecular structures with different cellular functions. The drivers behind these different structures is unknown. In this project we will leverage our discoveries, and planned enhancements, of chemical biology probes that will modulate dynamin activity by inhibiting at three distinct sites, and one site that stimulates dynamin activity. It is known that Dynamin helices and rings are believed responsible for at least three in cell biological functions: in hormone, neutral and receptor internalisation; cellular mitosis and in actin dynamics. Prior to this work we have lacked the tools to understand the role of shape modulation of protein function.Read moreRead less
Migration-Dependent Signalling in Macrophages . The project aims to investigate a mechanism of communication used by immune cells to guide each other towards sites of damage. The project will characterise newly revealed cell signalling membrane trails left behind by migrating cells, utilising biochemistry, innovative imaging and microscopy and a transparent zebrafish model to view cell migration through living tissues. Expected outcomes include new fundamental knowledge in the area of immune cel ....Migration-Dependent Signalling in Macrophages . The project aims to investigate a mechanism of communication used by immune cells to guide each other towards sites of damage. The project will characterise newly revealed cell signalling membrane trails left behind by migrating cells, utilising biochemistry, innovative imaging and microscopy and a transparent zebrafish model to view cell migration through living tissues. Expected outcomes include new fundamental knowledge in the area of immune cell migration with relevance to the basic biology of inflammation, repair and regeneration and new innovations for cell imaging. Significant benefits are expected to arise from this new knowledge and from advanced skills training and improved national capabilities in bio-imaging and analysis.Read moreRead less
Shear stimulated Brillouin microscopy for cell mechanobiology. This project aims to develop novel technology for non-contact imaging of micro-mechanical properties in cells and tissues to answer fundamental questions of cell mechnanobiology. Based on principles of Brillouin light scattering, the project takes advantage of a radio-frequency lock-in detection scheme. The project will result in a real-time, high-sensitivity, non-contact 3D imaging solution for spatial characterisation of cell's loc ....Shear stimulated Brillouin microscopy for cell mechanobiology. This project aims to develop novel technology for non-contact imaging of micro-mechanical properties in cells and tissues to answer fundamental questions of cell mechnanobiology. Based on principles of Brillouin light scattering, the project takes advantage of a radio-frequency lock-in detection scheme. The project will result in a real-time, high-sensitivity, non-contact 3D imaging solution for spatial characterisation of cell's local stiffness and compressibility. This will underpin the advancement of knowledge in the area of cell mechanobiology and the investigation of diseases, where microscale changes in cell mechanical properties lead to cell dysfunction and apoptosis.Read moreRead less