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
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
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
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
The activation of T lymphocytes is essential part of our immune system to fend off harmful intruders. Our research aims to understand the process of T cell activation, in particular, the contribution of fats. We found that fats create a highly ordered patch at the T cell activation site. We want to understand how lipids and proteins work together to activate T cells, how this ordered regions function in T cell activation and whether dietary lipids alter these patches and thus T cell activation.
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
The role of turgor in hyphal extension of the Ascomycete Neurospora crassa. Cellular expansion is an absolute necessity during the growth and development of plants and fungi. This process relies heavily upon the accumulation of inorganic ions. Osmotically driven water influx then creates the hydrostatic pressure that underlies the increase in cell volume. Cellular expansion is normally asymmetric and localised in one small region, such as hyphal tip. How does the cell maintain the turgor that dr ....The role of turgor in hyphal extension of the Ascomycete Neurospora crassa. Cellular expansion is an absolute necessity during the growth and development of plants and fungi. This process relies heavily upon the accumulation of inorganic ions. Osmotically driven water influx then creates the hydrostatic pressure that underlies the increase in cell volume. Cellular expansion is normally asymmetric and localised in one small region, such as hyphal tip. How does the cell maintain the turgor that drives expansion? How is expansion controlled spatially? These questions will be addressed in this project by comprehensive study of ion transport processes in a model organism, Neurospora crassa, using osmotic sensitive and transport mutants.Read moreRead less
Regulation Of Voltage-Gated Potassium Channels: X-ray Structures Of Cytosolic Components Of The BK Nd Kv Families
Funder
National Health and Medical Research Council
Funding Amount
$235,500.00
Summary
This research will investigate aspects of ion channel gating (opening). Ion channels are specialised pores perforating cell membranes that facilitate transport of ions, or charged atoms, across its breadth. The flow of ions from one side to another is measurable as an electrical current. The pore, or channel, through which ions pass narrows in regions, creating an impasse, or gate , prohibiting passage. The gate is controlled by external factors, such as the binding of certain molecules (ligands ....This research will investigate aspects of ion channel gating (opening). Ion channels are specialised pores perforating cell membranes that facilitate transport of ions, or charged atoms, across its breadth. The flow of ions from one side to another is measurable as an electrical current. The pore, or channel, through which ions pass narrows in regions, creating an impasse, or gate , prohibiting passage. The gate is controlled by external factors, such as the binding of certain molecules (ligands), or, in the case of voltage-dependent ion channels, the application of a voltage to the membrane. Such perturbations widen the pore sufficiently to permit conduction. Voltage-gated potassium channels specifically transport potassium ions. They fall into multiple categories, and generally form large complexes with intracellular, as well as membrane-bound, portions. For some types, cues from intracellular chemical processes are known to regulate electrical excitability, using the intracellular domains to transfer information to the membrane. In others it is not clear if and how this might happen. Our efforts will focus on exploring this theme in two contrasting systems, Kv and BK channels. Kv channels open in response to voltage, whereas activation of BK channels requires both voltage and moderate levels of intracellular calcium. X-ray crystallography will be used to generate accurate three-dimensional images of selected potassium channel components, allowing us to visualise discrete steps in the regulation processes. Potassium channels are essential for life. They effect transmission of our nerve impulses, and are thus fundamental to central nervous system activity. This research will help us to understand the factors that control them.Read moreRead less
I am a cell biologist determining how the organization of the plasma membrane influences signal transduction processes; my long-term goal is to understand the spatial–temporal organization of cell signalling.