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The molecular basis of macropinocytosis in mammalian cells: the composition of endosome proteins and their function. Individual cells communicate with their immediate environment by the process of macropinocytosis, a process that involves the exchange of materials between the extracellular space and a specialised region of the cell termed endosomes. It is an important process in mammalian cells being essential to the correct functioning of many tissues. This project will advance understanding of ....The molecular basis of macropinocytosis in mammalian cells: the composition of endosome proteins and their function. Individual cells communicate with their immediate environment by the process of macropinocytosis, a process that involves the exchange of materials between the extracellular space and a specialised region of the cell termed endosomes. It is an important process in mammalian cells being essential to the correct functioning of many tissues. This project will advance understanding of macropinocytosis at a molecular level. The project is relevant to understanding the functioning of normal cells and the means by which some pathogens can enter cells and also understanding processes involved in tumour progression and metastasis.Read moreRead less
Investigation of a Phagocytic Synapse in the Uptake of Apoptotic Cells. Rapid clearance of cells that die by apoptosis is crucial for embryonic development, tissue turnover, and after inflammatory events. Specialised phagocytes engulf the apoptotic cell corpses in a way that minimises inflammation and prevents autoimmunity. Genetic studies have identified the key evolutionary receptors involved, but the molecular basis of this phagocytosis is still poorly understood. We have developed, and seek ....Investigation of a Phagocytic Synapse in the Uptake of Apoptotic Cells. Rapid clearance of cells that die by apoptosis is crucial for embryonic development, tissue turnover, and after inflammatory events. Specialised phagocytes engulf the apoptotic cell corpses in a way that minimises inflammation and prevents autoimmunity. Genetic studies have identified the key evolutionary receptors involved, but the molecular basis of this phagocytosis is still poorly understood. We have developed, and seek to establish, an integrated model that incorporates new findings to explain how the distinctive functions of specialised receptors can be orchestrated to achieve this function. A successful outcome to the project will provide new knowledge of value to human health.Read moreRead less
A structural investigation into the peptide-loading complex molecular machine. The proposed research program, using laboratory-based and synchrotron-based radiation, will provide fundamental insight into a process central to immunity, namely antigen presentation. Investigating the process of Antigen presentation is important, as it will further our understanding how a cell is "ear-marked" for being infected by viruses or bacteria. Such knowledge will increase Australia's international research ....A structural investigation into the peptide-loading complex molecular machine. The proposed research program, using laboratory-based and synchrotron-based radiation, will provide fundamental insight into a process central to immunity, namely antigen presentation. Investigating the process of Antigen presentation is important, as it will further our understanding how a cell is "ear-marked" for being infected by viruses or bacteria. Such knowledge will increase Australia's international research standing.Read moreRead less
Lipid raft and cyotoskeleton organization: How membrane domains give cells direction. For a large number of cells in our body it is imperative that they are able to orientate themselves relative to their environment, sense direction and translate incoming signals. To do so it is hypothesised that lipids on the cell surface are redistributed to form specialized domains. An asymmetric distribution of membrane domains can provide cells with a front and rear end and can further concentrate and co-or ....Lipid raft and cyotoskeleton organization: How membrane domains give cells direction. For a large number of cells in our body it is imperative that they are able to orientate themselves relative to their environment, sense direction and translate incoming signals. To do so it is hypothesised that lipids on the cell surface are redistributed to form specialized domains. An asymmetric distribution of membrane domains can provide cells with a front and rear end and can further concentrate and co-ordinate signalling molecules to a specific site. The project will determine the role of lipid domain in stabilizing cell shape and their remodelling during cell migration, the digestion of foreign particles and the formation of cell-cell contacts.Read moreRead less
Proteins form up to 25% of our diet. The first step in protein absorption is the digestion of protein into smaller units called peptides and amino acids. Both components are subsequently taken up by specialised cells in the wall of the intestine. In this project we plan to study how protein absorption occurs at the surface of these intestinal cells and investigate why this process fails in malabsorption syndromes, where the uptake of amino acids is impaired.
This proposal concerns the biochemical investigation of a protein called GABA receptor which is a known target for various anti-anxiety drugs (anxiolytics), anti-convulsants, sedatives, depressants, anti-epilespy drugs, alcohol and anaesthetics. This work is expected to lead to the determination of the three-dimensional shape of the protein which will provide essential information about how the protein works and lay the foundation for the design and development of new drugs to control epilepsy, ....This proposal concerns the biochemical investigation of a protein called GABA receptor which is a known target for various anti-anxiety drugs (anxiolytics), anti-convulsants, sedatives, depressants, anti-epilespy drugs, alcohol and anaesthetics. This work is expected to lead to the determination of the three-dimensional shape of the protein which will provide essential information about how the protein works and lay the foundation for the design and development of new drugs to control epilepsy, act as general anaesthetics, relieve anxiety and induce sleep.Read moreRead less
Membrane excitability and cellular calcium regulation in the peripheral nervous system under different (patho)-physiological conditions and in inflammatory disease. Studies of cytokine action on neurons and muscle give new insights into functional responses of the nervous system to systemic inflammation and sepsis. In some countries, sepsis is the third most frequent cause of death following heart attack. Elucidating the pathomechanisms allows to develop therapeutic strategies. Electrophysiology ....Membrane excitability and cellular calcium regulation in the peripheral nervous system under different (patho)-physiological conditions and in inflammatory disease. Studies of cytokine action on neurons and muscle give new insights into functional responses of the nervous system to systemic inflammation and sepsis. In some countries, sepsis is the third most frequent cause of death following heart attack. Elucidating the pathomechanisms allows to develop therapeutic strategies. Electrophysiology, Ca2+ regulation and optical membrane potentiometry allow us to monitor early changes in disease on a (sub)cellular level. Experiments on Ca2+ regulation and ion channel function in muscle with different cholesterol membrane contents will help to understand pathomechanisms in high cholesterol diseases, e.g. obesity, on the membrane level long before cardiovascular effects become prominent.Read moreRead less
An X-ray crystallographic investigation into co-receptors on T-lymphocytes. T lymphocytes are an indispensable cellular component of the immune system. The normal process of T cell selection in the thymus, and the ability of mature T cells to respond to foreign antigens are governed by receptor recognition and co-receptor mediated events. The co-receptors encompass a wide spectrum of structurally diverse proteins that are involved in adhesion, co-ligation and signal transduction. This proposa ....An X-ray crystallographic investigation into co-receptors on T-lymphocytes. T lymphocytes are an indispensable cellular component of the immune system. The normal process of T cell selection in the thymus, and the ability of mature T cells to respond to foreign antigens are governed by receptor recognition and co-receptor mediated events. The co-receptors encompass a wide spectrum of structurally diverse proteins that are involved in adhesion, co-ligation and signal transduction. This proposal aims to investigate, using X-ray crystallography as the primary research tool, co- receptors located on T-lymphocytes. This work will gain fundamental insights into co-receptor function.Read moreRead less
The functional organisation of the trans-Golgi network: From cultured cells to physiological systems. This research will result in a better understanding of the secretory pathway of all eukaryotic cells, a process of broad biological and biomedical significance. It will impact on cell biology in the broadest sense, from membrane biogenesis to lipid domain organization, as well as membrane transport, protein structure and protein targeting. Furthermore, this work will utilize and develop fronti ....The functional organisation of the trans-Golgi network: From cultured cells to physiological systems. This research will result in a better understanding of the secretory pathway of all eukaryotic cells, a process of broad biological and biomedical significance. It will impact on cell biology in the broadest sense, from membrane biogenesis to lipid domain organization, as well as membrane transport, protein structure and protein targeting. Furthermore, this work will utilize and develop frontier technologies of live cell imaging and RNA interference as a genetic tool to investigate functions of a protein family. By training post-graduate students and post-doctoral staff, it will contribute to the expertise of cell biology in Australia. International collaborations will enhance connections between Australia and overseas research.Read moreRead less
Molecular microscopy: protein and membrane dynamics in resting and activated T cells. The aim of this research, to understand the molecular organization and dynamics of the plasma membrane that underlie the signal transduction events, is at the very heart of understanding cell communication. T cell recognition and activation initiates an adaptive immune response to invading pathogens and structurally altered proteins that can be found in cancers. By providing functional insights into the molecul ....Molecular microscopy: protein and membrane dynamics in resting and activated T cells. The aim of this research, to understand the molecular organization and dynamics of the plasma membrane that underlie the signal transduction events, is at the very heart of understanding cell communication. T cell recognition and activation initiates an adaptive immune response to invading pathogens and structurally altered proteins that can be found in cancers. By providing functional insights into the molecular mechanism of T cell activation, we will not only provide fundamental knowledge of receptor signalling but also specific details of T cell receptort triggering that may lead to the development of new therapeutic strategies to control T cell activation.Read moreRead less