How protein tyrosine phosphatases select their substrates. Protein tyrosine phosphatases (PTPs) are enzymes that control the response of cells to divergent environmental stimuli. This project will determine how individual PTPs exert selective effects on cellular communication networks to coordinate organismal development, growth and survival.
Histone deacetylase functions in immune cells. This project aims to define how an enzyme (a histone deacetylase) enables innate immune cells (macrophages) to respond to specific danger signals, such as those activating Toll-like Receptors. To identify processes that provide specificity to signal transduction pathways, this project will characterise protein targets and biological functions of a specific class IIa histone deacetylase in macrophages. This project expects to result in an understandi ....Histone deacetylase functions in immune cells. This project aims to define how an enzyme (a histone deacetylase) enables innate immune cells (macrophages) to respond to specific danger signals, such as those activating Toll-like Receptors. To identify processes that provide specificity to signal transduction pathways, this project will characterise protein targets and biological functions of a specific class IIa histone deacetylase in macrophages. This project expects to result in an understanding of histone deacetylases and protein deacetylation in immune cell responses which can be harnessed to manipulate cell functions for basic science and biotechnology uses.Read moreRead less
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
Deciphering novel cross-talk between innate cytokine receptors. Understanding the basic functions of interferons, how they signal to cells, is central to understanding fundamental immunity. Interferons are crucial molecules of the immune system that are important for normal cell development and they protect the body from viral infection and cancer but can be deleterious in different autoimmune diseases and trauma settings. Preliminary Data shows there is a pathway of interferon signalling that h ....Deciphering novel cross-talk between innate cytokine receptors. Understanding the basic functions of interferons, how they signal to cells, is central to understanding fundamental immunity. Interferons are crucial molecules of the immune system that are important for normal cell development and they protect the body from viral infection and cancer but can be deleterious in different autoimmune diseases and trauma settings. Preliminary Data shows there is a pathway of interferon signalling that has previously been overlooked. This project aims to understand how this pathway works and how it contributes to the normal workings of cells. This fundamental science has future consequences for the design of vaccines and for the design of therapeutics to treat diseases that show defective interferon signalling.Read moreRead less
The role of dysregulated signalling by TORC1 in mitochondrial disease. The mitochondria are tiny subcellular compartments responsible for producing over 90 per cent of the cell's energy. Mitochondrial defects feature both in genetic diseases that directly affect the mitochondria and in most neurodegenerative diseases. These incurable diseases are expected to eclipse cancer as the second major cause of death worldwide by 2040. Using a simple model organism, Dictyostelium, previous research showed ....The role of dysregulated signalling by TORC1 in mitochondrial disease. The mitochondria are tiny subcellular compartments responsible for producing over 90 per cent of the cell's energy. Mitochondrial defects feature both in genetic diseases that directly affect the mitochondria and in most neurodegenerative diseases. These incurable diseases are expected to eclipse cancer as the second major cause of death worldwide by 2040. Using a simple model organism, Dictyostelium, previous research showed that dysregulated intracellular signalling by a cellular energy-sensing alarm protein is responsible for diverse cellular pathologies in mitochondrially diseased cells. This project will determine the role in these pathways of a second cellular stress-sensing protein complex, TORC1. New treatment possibilities may emerge.Read moreRead less
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
Novel mechanisms of early growth response-1 activation through the epidermal growth factor receptor. This project will expand our knowledge of how cytokines and growth factors switch on signalling pathways from the cell surface to the nucleus. Unique antibodies will characterise regulatory routes, state-of-the-art microscopy will define dynamic patterns of receptor co-assembly, and in vivo studies will show receptor crosstalk in animal models.
Cardiac a1-adrenergic receptors in survival of the fittest. This project aims to determine the role of alpha1A-adrenergic receptor inactivation, a receptor/signalling pathway, in mediating cardiac contraction and survival in response to stressors fight-or-flight response triggers.Higher organisms’ ability to respond to environmental changes is central to the survival of the fittest, and is mediated by the release of catecholamines that stimulate adrenergic receptors. The precise receptor and sig ....Cardiac a1-adrenergic receptors in survival of the fittest. This project aims to determine the role of alpha1A-adrenergic receptor inactivation, a receptor/signalling pathway, in mediating cardiac contraction and survival in response to stressors fight-or-flight response triggers.Higher organisms’ ability to respond to environmental changes is central to the survival of the fittest, and is mediated by the release of catecholamines that stimulate adrenergic receptors. The precise receptor and signalling pathways underlying these adaptive responses remain unclear. This project’s research could improve contractility, reduce cardiomyocyte death and define organismal adaptation to extreme environmental changes.Read moreRead less
Statistical analyses for spatial organisation in T cell signalling networks. This project aims to reveal how nanoscale spatial organisation encodes plasticity in the T cell signalling network, and how T cells exploit this plasticity to regulate sensitivity to antigens. In adoptive immunity, T cells respond appropriately to any given antigen, but how they make decisions is unclear. This project will define how nanoscale spatial organisation of signalling molecules shapes signalling strength and p ....Statistical analyses for spatial organisation in T cell signalling networks. This project aims to reveal how nanoscale spatial organisation encodes plasticity in the T cell signalling network, and how T cells exploit this plasticity to regulate sensitivity to antigens. In adoptive immunity, T cells respond appropriately to any given antigen, but how they make decisions is unclear. This project will define how nanoscale spatial organisation of signalling molecules shapes signalling strength and plasticity in the T cell antigen receptor (TCR) network; and infer rules linking spatial organisation and signalling activities in intact T cells. Contextualising the TCR signalling network is expected to reveal the origin and use of network plasticity for T cell decision-making. Such information could be invaluable for the design of vaccines and immune-modulating drugs.Read moreRead less
An active ion transport pathway exploited by coronaviruses. Cells have active transport “pumps” that are regulators of a variety of cellular processes. This project aims to understand how a specific ion pump is exploited by coronaviruses when they infect animal cells. These studies will provide new mechanistic insights into how coronaviruses alter calcium signalling in cells and how a specific ion pump regulates a variety of key processes during coronavirus infection. This work will greatly enha ....An active ion transport pathway exploited by coronaviruses. Cells have active transport “pumps” that are regulators of a variety of cellular processes. This project aims to understand how a specific ion pump is exploited by coronaviruses when they infect animal cells. These studies will provide new mechanistic insights into how coronaviruses alter calcium signalling in cells and how a specific ion pump regulates a variety of key processes during coronavirus infection. This work will greatly enhance our understanding of the intersection between ion pumps and viruses.Read moreRead less