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The molecular basis for efficacy at G protein coupled receptors. This project aims to investigate the molecular steps underlying the relationship between sensing by signal-transmitting proteins on the cell surface called G protein-coupled receptors and cellular response. The project aims to build on studies that have sought to understand the primary, molecular basis for this cellular volume control. This project seeks to use these novel approaches to fill this knowledge gap, providing a deeper u ....The molecular basis for efficacy at G protein coupled receptors. This project aims to investigate the molecular steps underlying the relationship between sensing by signal-transmitting proteins on the cell surface called G protein-coupled receptors and cellular response. The project aims to build on studies that have sought to understand the primary, molecular basis for this cellular volume control. This project seeks to use these novel approaches to fill this knowledge gap, providing a deeper understanding of how physiology and medicines work. The project expects to expand fundamental understanding of signal transmission at this receptor class. This project will deliver benefits including expanded basic knowledge and a contribution to future improvements in drug development.Read moreRead less
Understanding the changes in brain chemistry associated with schizophrenia. Current drugs for schizophrenia only work in 30% of patients. To develop better therapies, we must understand the changes in the brains of people with the disorder. This research will explore a chemical system in the brain that is changed in schizophrenia and begin to investigate whether counteracting these changes are therapeutically beneficial.
The role of P2X7 and P2X4 receptor mediated innate phagocytosis in pathogenesis and treatment of neurodegenerative diseases. This project will identify how inherited variation in two proteins of the brain can accelerate the removal of neurones and predispose to a range of neurodegenerative diseases. Knowledge of the biological basis of this finding will allow a search for new compounds which will slow and protect against this form of neurodegeneration.
Autotransporter assembly: new insights and biotechnological potential. The objective of this project is to improve our understanding of a fundamental biological problem: how autotransporters are assembled into cellular membranes. Autotransporters are a large family of bacterial proteins that play key roles in the pathogenesis of several infectious diseases. Currently, the precise mechanism by which disease-causing molecules are assembled into the outer membranes of bacteria and mitochondria is p ....Autotransporter assembly: new insights and biotechnological potential. The objective of this project is to improve our understanding of a fundamental biological problem: how autotransporters are assembled into cellular membranes. Autotransporters are a large family of bacterial proteins that play key roles in the pathogenesis of several infectious diseases. Currently, the precise mechanism by which disease-causing molecules are assembled into the outer membranes of bacteria and mitochondria is poorly understood. The knowledge that the project develops may inform future strategies aimed at the rational treatment of bacterial and mitochondrial diseases.Read moreRead less
Understanding endogenous allosteric modulators of G protein-coupled receptors. Major life science challenges include how chemicals outside cells signal to proteins inside, how this results in physiological responses, and how dysfunction of these processes leads to pathophysiology. Despite the critical importance of G protein-coupled receptors (GPCRs), much remains to be learned about their regulation by endogenous and synthetic molecules. This project aims to address this gap, by building on rec ....Understanding endogenous allosteric modulators of G protein-coupled receptors. Major life science challenges include how chemicals outside cells signal to proteins inside, how this results in physiological responses, and how dysfunction of these processes leads to pathophysiology. Despite the critical importance of G protein-coupled receptors (GPCRs), much remains to be learned about their regulation by endogenous and synthetic molecules. This project aims to address this gap, by building on recent ground-breaking studies that have been performed, by focusing on alternative binding sites of GPCRs called allosteric sites. The major hypothesis is that these allosteric sites are widespread across GPCRs because the body produces endogenous allosteric ligands that remain largely unidentified, but which can play vital roles in biology.Read moreRead less
Defining the molecular architecture of a lymphocyte-activating receptor complex. A robust immune response requires activation of sentinel T cells. This project will seek to understand the architecture of receptors at the T cell surface that allow these important immune cells to sense the presence of pathogens that react accordingly.
Understanding and controlling neuropeptide GPCR-transducer coupling. G protein-coupled receptors (GPCRs) are physiologically essential, yet the spatiotemporal complexity of receptor function has limited our understanding of their function and success in drug development. Using a multi-disciplinary approach integrating GPCR signalling, trafficking and drug delivery, this research program aims to understand, and control, the molecular mechanisms that enable a single receptor to respond to differen ....Understanding and controlling neuropeptide GPCR-transducer coupling. G protein-coupled receptors (GPCRs) are physiologically essential, yet the spatiotemporal complexity of receptor function has limited our understanding of their function and success in drug development. Using a multi-disciplinary approach integrating GPCR signalling, trafficking and drug delivery, this research program aims to understand, and control, the molecular mechanisms that enable a single receptor to respond to different ligands to promote unique cellular processes. The anticipated outcomes include an enhanced capacity for understanding fundamental biology, and stronger national and international collaborations. It will provide significant benefits including expanded basic knowledge and advancement of drug delivery technology.Read moreRead less
New molecular tools to study the mechanisms of bacterial metal homeostasis. This project aims to provide new insight into how metal ion uptake is regulated. It will precisely measure the cellular concentrations of metal ions, reveal the roles of metal ions in essential cellular processes, and identify the molecular targets of metal toxicity. Metal ions are essential to all forms of life and are used by up to half of all proteins to facilitate cellular chemical processes. The intended outcome of ....New molecular tools to study the mechanisms of bacterial metal homeostasis. This project aims to provide new insight into how metal ion uptake is regulated. It will precisely measure the cellular concentrations of metal ions, reveal the roles of metal ions in essential cellular processes, and identify the molecular targets of metal toxicity. Metal ions are essential to all forms of life and are used by up to half of all proteins to facilitate cellular chemical processes. The intended outcome of the research is to provide new fundamental knowledge of the roles of metal ions in bacterial cells; knowledge that will be key to defining the chemical biology of living systems and will provide information essential to understanding how microbes adapt to changing environments.Read moreRead less
Understanding pore formation by the complement membrane attack complex. The project aims to improve our understanding of the function of the membrane attack complex (MAC). MAC is a large protein complex used by the human immune system to target invading bacteria and parasites by punching holes in the lipid membranes of target cells. The MAC is part of a superfamily of proteins, the MACPF (membrane attack complex/perforin superfamily)/CDC (cholesterol-dependent cytolysins) superfamily, used by an ....Understanding pore formation by the complement membrane attack complex. The project aims to improve our understanding of the function of the membrane attack complex (MAC). MAC is a large protein complex used by the human immune system to target invading bacteria and parasites by punching holes in the lipid membranes of target cells. The MAC is part of a superfamily of proteins, the MACPF (membrane attack complex/perforin superfamily)/CDC (cholesterol-dependent cytolysins) superfamily, used by animals (in venoms and immunity), fungi (in defence) and pathogenic bacteria (in disease). The aim of this project is to image to the highest possible resolution how the MAC form pores in the context of bacterial cells and explore the way it inserts into cells in real time. Intended project outcomes may lay the foundation for applied future research into improved antibiotic delivery and novel pesticide development.Read moreRead less
Purinergic signalling in placentation and vascular adaptation in pregnancy. Our traditional understanding of purinergic signalling in the placenta is significantly outdated and incomplete. The placenta is critical for reproduction in all eutherian mammals, delivering critical nutrition and oxygen to the developing fetus. This project aims to define the role of purinergic signalling as a critical mechanism driving placentation and angiogenesis. This is the first study of its kind and will use sop ....Purinergic signalling in placentation and vascular adaptation in pregnancy. Our traditional understanding of purinergic signalling in the placenta is significantly outdated and incomplete. The placenta is critical for reproduction in all eutherian mammals, delivering critical nutrition and oxygen to the developing fetus. This project aims to define the role of purinergic signalling as a critical mechanism driving placentation and angiogenesis. This is the first study of its kind and will use sophisticated models to improve our fundamental understanding and ability to manipulate mammalian reproduction via the purinoreceptors. This proposal builds on my skills and expertise; improving our knowledge of the processes driving placental and vascular morphogenesis and offers important discoveries for reproductive science.Read moreRead less