The impact of Hyaluronic Acid on growth factor signalling and angiogenesis. Blood vessel development is controlled by growth factor signalling. Vessels are attracted by and migrate along growth factor gradients, and this is controlled by the extracellular matrix (ECM). From the zebrafish model, we have identified a novel gene that modulates the ECM, impacting growth factor signalling and vessel development. The project will explore by what mechanism this gene impacts signalling. It will comprehe ....The impact of Hyaluronic Acid on growth factor signalling and angiogenesis. Blood vessel development is controlled by growth factor signalling. Vessels are attracted by and migrate along growth factor gradients, and this is controlled by the extracellular matrix (ECM). From the zebrafish model, we have identified a novel gene that modulates the ECM, impacting growth factor signalling and vessel development. The project will explore by what mechanism this gene impacts signalling. It will comprehensively define where in the embryo it is required and investigate what cofactors it interacts with to perform its function. Using genetic zebrafish and mouse models as well as cell culture models we will investigate the fundamental biology of this gene.Read moreRead less
Pyroptotic macrophages posthumously sculpt immune responses. The life of an organism relies on the timely birth and death of its cells. Importantly, it is crucial for cells to die not only at the right time, but also in an appropriate manner. This proposal investigates a cell death pathway that triggers potent immune responses. This proposal seeks to reveal precisely how cell death sculpts immune responses. Expected outcomes include new insights into how immune cells die, and how they instruct i ....Pyroptotic macrophages posthumously sculpt immune responses. The life of an organism relies on the timely birth and death of its cells. Importantly, it is crucial for cells to die not only at the right time, but also in an appropriate manner. This proposal investigates a cell death pathway that triggers potent immune responses. This proposal seeks to reveal precisely how cell death sculpts immune responses. Expected outcomes include new insights into how immune cells die, and how they instruct immune responses from beyond the grave. Project benefits include a fundamental understanding of how cell death signalling sculpts tissue immune responses, and knowledge of how to manipulate cell death responses for future basic research and commercial applications beyond this project.Read moreRead less
Nuclear alarmins escalate tissue immune responses. Humans and other animals are constantly exposed to potential threats, including microbes on and near the body. Animals can live with such dangers because these everyday encounters are made harmless by the immune system. It is unclear how cells distinguish low-danger threats from high-danger threats. This proposal seeks to reveal how immune cells identify increasing levels of threat and appropriately escalate their responses. Expected outcomes in ....Nuclear alarmins escalate tissue immune responses. Humans and other animals are constantly exposed to potential threats, including microbes on and near the body. Animals can live with such dangers because these everyday encounters are made harmless by the immune system. It is unclear how cells distinguish low-danger threats from high-danger threats. This proposal seeks to reveal how immune cells identify increasing levels of threat and appropriately escalate their responses. Expected outcomes include new insights into how immune cells and tissues respond according to the posing threat. Project benefits include understanding how to manipulate danger responses for future basic research and commercial applications, and fundamental understanding of how animals flourish in a dangerous world.Read moreRead less
Making muscle: molecular dissection of membrane domain formation. For a muscle to contract efficiently in response to an electrical signal it requires the formation of an extensive system of hollow membranous tubules through which the signal can be propagated. This proposal addresses the molecular mechanisms involved in the formation of this tubule system in skeletal muscle. This project will develop cell biology in a whole organism rather than a cell culture system and provide a new framework f ....Making muscle: molecular dissection of membrane domain formation. For a muscle to contract efficiently in response to an electrical signal it requires the formation of an extensive system of hollow membranous tubules through which the signal can be propagated. This proposal addresses the molecular mechanisms involved in the formation of this tubule system in skeletal muscle. This project will develop cell biology in a whole organism rather than a cell culture system and provide a new framework for Australian and international cell biologists. It will generate new knowledge, train young Australian scientists, help build international collaborative networks and engage the public outside the research community.Read moreRead less
The core inflammasome as a model for caspase activation. This project aims to change the paradigm for the structure of the active inflammasome. Inflammasomes activate caspases, enzymes central to cell death and inflammatory processes. The current concept of inflammasomes is that caspases are recruited into a single massive protein complex seen as a “speck” in the cell. This project proposes the speck is a terminal stage, after the major enzymatic activity is over. This project aims to purify sma ....The core inflammasome as a model for caspase activation. This project aims to change the paradigm for the structure of the active inflammasome. Inflammasomes activate caspases, enzymes central to cell death and inflammatory processes. The current concept of inflammasomes is that caspases are recruited into a single massive protein complex seen as a “speck” in the cell. This project proposes the speck is a terminal stage, after the major enzymatic activity is over. This project aims to purify smaller early stage inflammasome complexes, for structural analysis. The outcome will be a clearer understanding of processes of caspase activation and inflammasome formation. This will provide significant benefits, such as improve our understanding of processes of cell death and innate immunity, and train students.Read moreRead less
New guardians of the mucosa: Molecular characterisation of M cell biology. We aim to completely define the cellular and molecular biology of gut and lung M cells for the first time. We will elucidate how they develop, are regulated and function at a molecular level, and how M cells maintain normal gut and lung tissues and induce immune responses to protect against microbial challenges. In the future, the new insights will be essential pre-requisites for the development of mucosal-based intervent ....New guardians of the mucosa: Molecular characterisation of M cell biology. We aim to completely define the cellular and molecular biology of gut and lung M cells for the first time. We will elucidate how they develop, are regulated and function at a molecular level, and how M cells maintain normal gut and lung tissues and induce immune responses to protect against microbial challenges. In the future, the new insights will be essential pre-requisites for the development of mucosal-based interventions and vaccines that protect the gut and lung from infectious and inflammatory issues. The harnessing of effective immune responses to control such challenges, are of enormous fundamental and long-standing biological interest, and are amongst the most important areas of current scientific research.Read moreRead less
Decoding the spatiotemporal control of DNA replication and repair. DNA replication is the fundamental mechanism of genetic inheritance and essential for all cellular life. This project aims to inform our understanding of how human cells coordinate the DNA replication machinery in time and space to accurately copy the human genome. By applying multiple innovative approaches and employing an interdisciplinary research team, this project is anticipated to generate new knowledge that explains how th ....Decoding the spatiotemporal control of DNA replication and repair. DNA replication is the fundamental mechanism of genetic inheritance and essential for all cellular life. This project aims to inform our understanding of how human cells coordinate the DNA replication machinery in time and space to accurately copy the human genome. By applying multiple innovative approaches and employing an interdisciplinary research team, this project is anticipated to generate new knowledge that explains how the human genome is replicated. This knowledge is expected to generate research publications of high quality and provide economic benefits, such as unlocking new potentially patentable DNA technologies. Read moreRead less
What drives the Anterior Expansion of the Central Nervous System? A striking and highly conserved feature of the central nervous system is that the brain is larger than the spinal cord. Despite the manifest implications this has for nervous system function, the underlying drivers are largely unknown. This project aims to investigate the mechanisms controlling anterior expansion of the central nervous system, and will generate new knowledge in the areas of nervous system development and evolution ....What drives the Anterior Expansion of the Central Nervous System? A striking and highly conserved feature of the central nervous system is that the brain is larger than the spinal cord. Despite the manifest implications this has for nervous system function, the underlying drivers are largely unknown. This project aims to investigate the mechanisms controlling anterior expansion of the central nervous system, and will generate new knowledge in the areas of nervous system development and evolution. This project aims to impact on our understanding of nervous system function, develop bioinformatics tools with broad utility within the biosciences field, strengthen Australia’s international standing in the developmental neuroscience, and enhance the capacity for interdisciplinary international collaborations.Read moreRead less
A macrophage-centric holistic view of postnatal development. The immediate postnatal period in mammals is crucial for survival, long term health and productivity. It is also a time when animals are especially susceptible to infectious disease. This project aims to investigate how cells of the innate immune system called macrophages control somatic growth and development of mature organ function in the early postnatal period. The project aims to build upon investment in new animal models and a no ....A macrophage-centric holistic view of postnatal development. The immediate postnatal period in mammals is crucial for survival, long term health and productivity. It is also a time when animals are especially susceptible to infectious disease. This project aims to investigate how cells of the innate immune system called macrophages control somatic growth and development of mature organ function in the early postnatal period. The project aims to build upon investment in new animal models and a novel discovery to generate significant new knowledge that challenges current concepts of mammalian growth control. The outcomes will enhance Australia's international reputation in the fields of physiology, immunology and developmental biology and may translate to improvements in health in animals and humans. Read moreRead less