The role of phosphoinositides in endosomal maturation dynamics. This project aims to investigate the regulation of an intracellular compartment within a cell called endosomes, which plays critical roles in cellular homeostasis, signalling and pathogen entry. New knowledge is expected to be generated in understanding endosome maturation and the signalling events that drive this process using a unique, multidisciplinary approach combining state of the art imaging techniques and high throughput pro ....The role of phosphoinositides in endosomal maturation dynamics. This project aims to investigate the regulation of an intracellular compartment within a cell called endosomes, which plays critical roles in cellular homeostasis, signalling and pathogen entry. New knowledge is expected to be generated in understanding endosome maturation and the signalling events that drive this process using a unique, multidisciplinary approach combining state of the art imaging techniques and high throughput protein analysis. The anticipated outcomes will be to define the molecular steps that govern the membrane-bound machinery on endosomes that directs endosomal maturation. This should provide significant benefits in delineating a process that is linked to almost all aspects of cell life.Read moreRead less
Manipulation of mitochondrial function by Legionella pneumophila. . The intracellular bacterial pathogen Legionella pneumophila co-evolved with eukaryotic hosts and has developed sophisticated mechanisms to manipulate human cell function – mitochondria in particular – by secreting >300 effector proteins through a specialised Type-IV system into the host cell. This research aims to understand the function of effector proteins targeted to mitochondria; delivering important new knowledge in host-pa ....Manipulation of mitochondrial function by Legionella pneumophila. . The intracellular bacterial pathogen Legionella pneumophila co-evolved with eukaryotic hosts and has developed sophisticated mechanisms to manipulate human cell function – mitochondria in particular – by secreting >300 effector proteins through a specialised Type-IV system into the host cell. This research aims to understand the function of effector proteins targeted to mitochondria; delivering important new knowledge in host-pathogen and mitochondrial biology and advanced cell biology tools. With most of the effector proteins yet to be characterised, benefits from the project will be to reveal specifically how these target mitochondria, and more broadly, how bacterial pathogens manipulate organelles for their survival.Read moreRead less
Organising Intracellular Compartments by Formation of Transport Carriers. This project aims to investigate the cellular components which generate carriers that transport material between compartments within the cell. The process of sorting proteins and sending them to the right place is a fundamental mechanism critical to understand how individual proteins function as the move around within cells. The generated knowledge about how cells organise themselves through the movement of proteins betwee ....Organising Intracellular Compartments by Formation of Transport Carriers. This project aims to investigate the cellular components which generate carriers that transport material between compartments within the cell. The process of sorting proteins and sending them to the right place is a fundamental mechanism critical to understand how individual proteins function as the move around within cells. The generated knowledge about how cells organise themselves through the movement of proteins between endosomal intracellular compartments will provide significant benefits by enhancing our capacity to understand this conserved cellular pathway which ensures the integrity of all cellular processes including signalling, communication, homeostasis and development.Read moreRead less
Fyn-STEP-Tau axis: the nanoscale mechanisms of synaptic plasticity. This project investigates how brain cells use their molecular machinery to communicate with one another. At the heart of this process lies the synapses, the contact points that connect brain cells. This project will employ an innovative combination of quantitative microscopy techniques, gene knockout mouse models, and advanced computational and mathematical analyses to generate new knowledge on how a crucial set of proteins orga ....Fyn-STEP-Tau axis: the nanoscale mechanisms of synaptic plasticity. This project investigates how brain cells use their molecular machinery to communicate with one another. At the heart of this process lies the synapses, the contact points that connect brain cells. This project will employ an innovative combination of quantitative microscopy techniques, gene knockout mouse models, and advanced computational and mathematical analyses to generate new knowledge on how a crucial set of proteins organises in space and time to regulate synaptic connectivity. This will provide significant benefits, including molecular-level insight into the inner workings of the brain and interdisciplinary training for students. The expected outcomes include a deeper understanding of brain functions, such as learning and memory.Read moreRead less
Regulation of activity-induced glutamate receptor trafficking in neurons. Neurons communicate via synapses, where chemicals (such as glutamate) are released to transmit neuronal signals. This proposal is aimed at understanding the molecular mechanisms of neuronal communication and adaptive plasticity, which are essential for normal brain function. The proposed research will combine biophysical, biochemical, molecular and cell biological assays to elucidate the role of a calcium binding protein i ....Regulation of activity-induced glutamate receptor trafficking in neurons. Neurons communicate via synapses, where chemicals (such as glutamate) are released to transmit neuronal signals. This proposal is aimed at understanding the molecular mechanisms of neuronal communication and adaptive plasticity, which are essential for normal brain function. The proposed research will combine biophysical, biochemical, molecular and cell biological assays to elucidate the role of a calcium binding protein in controlling glutamate receptor trafficking in neurons. The outcomes will enhance our understanding of how neural plasticity is generated and maintained, knowledge that is critical for our understanding of cellular correlates of information, sensory and motor processing, as well as learning, memory and cognition. Read moreRead less
Unveiling the nanoscale organisation and dynamics of synaptic vesicle pools. This project aims to uncover the role of key molecules in allowing brain cells to actively communicate with each other. Communication between neurons relies on the fusion of synaptic vesicles containing neurotransmitters with the presynaptic plasma membrane. The addition of vesicular membrane is transient as the vesicles quickly reform from the plasma membrane and refill with neurotransmitter ready for subsequent rounds ....Unveiling the nanoscale organisation and dynamics of synaptic vesicle pools. This project aims to uncover the role of key molecules in allowing brain cells to actively communicate with each other. Communication between neurons relies on the fusion of synaptic vesicles containing neurotransmitters with the presynaptic plasma membrane. The addition of vesicular membrane is transient as the vesicles quickly reform from the plasma membrane and refill with neurotransmitter ready for subsequent rounds of fusion. This recycling process ensures that neurons communicate efficiently, however the underpinning mechanism is unknown. This project aims to use a recently developed single synaptic vesicle super-resolution tracking method to establish how Myosin-VI and Synapsin-IIa orchestrate this recycling in central and peripheral neurons. It will explain how neurons manage to preserve their ability to communicate.Read moreRead less
Mapping the integration of T cell fate control across time and space. This project aims to apply new methods to determine how coordination of signalling complexes impacts upon the fate of cells of the adaptive immune system. It expects to determine how the context of signallng orchestrates cell fates such as differentiation, death and proliferation. The project is expected to yield an experimental and analytical platform for further investigations into a broad range of biological questions, and ....Mapping the integration of T cell fate control across time and space. This project aims to apply new methods to determine how coordination of signalling complexes impacts upon the fate of cells of the adaptive immune system. It expects to determine how the context of signallng orchestrates cell fates such as differentiation, death and proliferation. The project is expected to yield an experimental and analytical platform for further investigations into a broad range of biological questions, and to provide new knowledge of this fundamental problem. This platform should support further work that ultimately provides new models for tissue and immune cell regeneration, and new manufacturing platforms for therapies for humans and livestock, among other benefits.Read moreRead less
Structure of the essential Commander protein trafficking complex. This project aims to provide a fundamental understanding of the structure and function of Commander, a large protein complex that controls export and recycling of internalised receptors. Commander is highly conserved throughout evolution and is essential for maintaining the homeostasis of hundreds of transmembrane receptors required for cell function and survival, regulating processes as diverse as lipid metabolism and cell adhesi ....Structure of the essential Commander protein trafficking complex. This project aims to provide a fundamental understanding of the structure and function of Commander, a large protein complex that controls export and recycling of internalised receptors. Commander is highly conserved throughout evolution and is essential for maintaining the homeostasis of hundreds of transmembrane receptors required for cell function and survival, regulating processes as diverse as lipid metabolism and cell adhesion. Despite advances in the understanding of Commander function, little is known about how Commander is assembled and interacts with other essential proteins. This project will use multidisciplinary cellular and structural biology approaches to reveal the architecture of Commander at an atomic level.Read moreRead less
Lipid droplet membrane tethers at atomic resolution. Eukaryotic cells are distinguished by the presence of membrane-bound compartments called organelles. This project will use structural biology to determine how essential proteins called sorting nexins (SNXs) regulate membrane interactions required for lipid droplet formation. These interactions are essential for life, controlling protein and lipid homeostasis needed for cell survival. The major outcome of this proposal will be a fundamental und ....Lipid droplet membrane tethers at atomic resolution. Eukaryotic cells are distinguished by the presence of membrane-bound compartments called organelles. This project will use structural biology to determine how essential proteins called sorting nexins (SNXs) regulate membrane interactions required for lipid droplet formation. These interactions are essential for life, controlling protein and lipid homeostasis needed for cell survival. The major outcome of this proposal will be a fundamental understanding of how SNXs control this process, and the work will significantly strengthen our international collaboration in this emerging area. The knowledge has potential future translation in the treatment of neurodegenerative disorders where dysregulation of these proteins is known to cause disease.Read moreRead less
The functional architecture of a unique family of lipid droplet proteins. Eukaryotic cells are distinguished by the presence of membrane-bound compartments called organelles. This project will use structural biology to determine how essential proteins called sorting nexins (SNXs) regulate membrane interactions required for lipid droplet formation. These interactions are essential for life, controlling protein and lipid homeostasis needed for cell survival. The major outcome of this proposal will ....The functional architecture of a unique family of lipid droplet proteins. Eukaryotic cells are distinguished by the presence of membrane-bound compartments called organelles. This project will use structural biology to determine how essential proteins called sorting nexins (SNXs) regulate membrane interactions required for lipid droplet formation. These interactions are essential for life, controlling protein and lipid homeostasis needed for cell survival. The major outcome of this proposal will be a fundamental understanding of how SNXs control this process, and the work will significantly strengthen our international collaboration in this emerging area. The knowledge has potential future translation in the treatment of neurodegenerative disorders where dysregulation of these proteins is known to cause disease. Read moreRead less