Discovery Early Career Researcher Award - Grant ID: DE120102556
Funder
Australian Research Council
Funding Amount
$375,000.00
Summary
The influence of crosstalk between protein post-translational modifications on the propagation of molecular signals. The ability of a cell to respond appropriately to its surroundings is a result of interactions between proteins and chemical modifiers termed post-translational modifications (PTM). This project will show how PTM interactions (competition/ cooperation) influence cellular outcomes in response to changes in the environment.
Developing orthogonal synthetic signaling cascades. This project proposes a generic approach for the construction of molecular switches based on artificially autoinhibited proteases. The bottom-up design of protein-based signaling networks is a key goal of synthetic biology. Yet, this remains elusive due to our inability to tailor-make signal transducers and receptors that can be readily compiled into defined signaling networks. Using structure-guided design and directed protein evolution, a set ....Developing orthogonal synthetic signaling cascades. This project proposes a generic approach for the construction of molecular switches based on artificially autoinhibited proteases. The bottom-up design of protein-based signaling networks is a key goal of synthetic biology. Yet, this remains elusive due to our inability to tailor-make signal transducers and receptors that can be readily compiled into defined signaling networks. Using structure-guided design and directed protein evolution, a set of protease-based signal transducers and ligand activated allosteric receptors will be created. The developed components are intended to be used to construct artificial signaling networks in mammalian cells that are orthogonal to the endogenous signaling cascades.Read moreRead less
Dynamic regulation of cell signalling scaffolds. This project aims to determine how cells utilise scaffold-type signalling proteins to orchestrate, over time, diverse cellular responses critical for normal development and physiology. The project expects to generate fundamental new knowledge in cell and synthetic biology with broad relevance that will foster establishment of new international linkages and networks. This research should benefit the biotechnology sector by identifying strategies fo ....Dynamic regulation of cell signalling scaffolds. This project aims to determine how cells utilise scaffold-type signalling proteins to orchestrate, over time, diverse cellular responses critical for normal development and physiology. The project expects to generate fundamental new knowledge in cell and synthetic biology with broad relevance that will foster establishment of new international linkages and networks. This research should benefit the biotechnology sector by identifying strategies for engineering scaffolds with desired biological outputs, with applications in areas such as large-scale cell production, immunotherapy, wound healing and regenerative medicine.Read moreRead less
The importance of exosomal membrane composition in intercellular signaling. Exosomes, microvesicles secreted by cells, are powerful signaling organelles. This project will explore the similarities and differences between the exosomal and host cell membrane. Membrane molecules exclusively present in exosomes may have important signaling implications and can aid in the uptake/fusion of exosomes by/with target cells.
Unravelling a canonical mitochondrial stress response pathway. Stress has a major impact on all life forms and is considered one of the key determinants of healthy ageing. This project aims to unravel a highly novel pathway through which many different forms of stress converge to induce a conserved stress response in mammalian cells. Major outcomes include rewriting the textbook on how stress is sensed by cells and how cells respond to this stress and will provide novel approaches and technologi ....Unravelling a canonical mitochondrial stress response pathway. Stress has a major impact on all life forms and is considered one of the key determinants of healthy ageing. This project aims to unravel a highly novel pathway through which many different forms of stress converge to induce a conserved stress response in mammalian cells. Major outcomes include rewriting the textbook on how stress is sensed by cells and how cells respond to this stress and will provide novel approaches and technologies for studying stress in a broad range of organisms and systems. This project will benefit all efforts to understand stress and aid efforts by others to ameliorate stress-mediated health defects across the animal kingdomRead moreRead less
Mechanisms of memory function involving site-specific tau phosphorylation. This project aims to understand the molecular principles that facilitate encoding, maintenance and retrieval of memories in the brain. To store memories in brain circuits, electrical and chemical signals are crucial. Brain cells can integrate signals into biochemical modifications of intracellular proteins. The nature of the protein modifications that represent memory within brain cells is unknown. This project uses innov ....Mechanisms of memory function involving site-specific tau phosphorylation. This project aims to understand the molecular principles that facilitate encoding, maintenance and retrieval of memories in the brain. To store memories in brain circuits, electrical and chemical signals are crucial. Brain cells can integrate signals into biochemical modifications of intracellular proteins. The nature of the protein modifications that represent memory within brain cells is unknown. This project uses innovative genome editing, mathematical modelling and proteomic approaches, to study how biochemical modifications of a key protein called tau help encode and retrieve memories. These molecular insights will make a significant advance in the current understanding of a brain function that is essential to all human activities.Read moreRead less
Uncovering New Mechanisms of Metabolite-Sensing and Signaling. This project aims to understand how cells sense changes in metabolic activity, to ensure energy demands are matched with nutrient supply. Our proposal will fill critical gaps in our understanding of the molecular mechanisms underlying metabolic sensing. This will generate new knowledge with far reaching potential for Australian industries that rely on the propagation and utilization of living organisms, including agriculture, biotech ....Uncovering New Mechanisms of Metabolite-Sensing and Signaling. This project aims to understand how cells sense changes in metabolic activity, to ensure energy demands are matched with nutrient supply. Our proposal will fill critical gaps in our understanding of the molecular mechanisms underlying metabolic sensing. This will generate new knowledge with far reaching potential for Australian industries that rely on the propagation and utilization of living organisms, including agriculture, biotechnology and brewing, as well as knowledge relevant to sporting performance and the metabolic dimensions of ageing. This project will support advanced training of early career researchers and PhD students, which will expand Australian research capabilities and contribute to a producing a highly skilled workforce.Read moreRead less
Novel regulatory mechanisms for the protein kinase Akt. This project aims to investigate unique feedback/feedforward regulatory behaviour of the protein kinase Akt by combining novel mathematical modelling with innovative lab methods for assessing Akt function in live cells. The project aspires to generate new knowledge that advances signal transduction research and provide computational and lab tools that provide an important resource for other researchers. The project will provide significant ....Novel regulatory mechanisms for the protein kinase Akt. This project aims to investigate unique feedback/feedforward regulatory behaviour of the protein kinase Akt by combining novel mathematical modelling with innovative lab methods for assessing Akt function in live cells. The project aspires to generate new knowledge that advances signal transduction research and provide computational and lab tools that provide an important resource for other researchers. The project will provide significant benefits such as transforming efforts to design Akt therapeutics and enabling other researchers to make new discoveries.Read moreRead less
Molecular control of memory traces. This project aims to understand how particular molecules help encode memories in the brain for future retrieval. Individual memories are encoded in brain cells through an unknown physical process. This project uses innovative approaches to manipulate memory-containing cells and will provide a new detailed explanation of memory. Outcomes of this work will significantly advance the current understanding of how memories are physically generated and maintained, wh ....Molecular control of memory traces. This project aims to understand how particular molecules help encode memories in the brain for future retrieval. Individual memories are encoded in brain cells through an unknown physical process. This project uses innovative approaches to manipulate memory-containing cells and will provide a new detailed explanation of memory. Outcomes of this work will significantly advance the current understanding of how memories are physically generated and maintained, which is an essential component of human and animal life. This research provides significant benefits in understanding the biology behind memory and in maintaining memory capacity in ageing.
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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