SNARE-mediated perforin and cytokine release in natural killer cells. Cytotoxic cells release toxic granules and cytokine messengers to kill pathogen infected and cancerous cells and to mount immune responses. This project will investigate different SNARE molecules that regulate the secretion of perforin from granules and cytokines from other carriers, assisting in the understanding of complex but essential cellular pathways.
Cholesterol and Hydroxycholesterol Shaping Phagocytosis. Reports now show that membrane cholesterol and 25-hydroxycholesterol (25HC) are required for immune cells to ingest and kill pathogens by phagocytosis. This project will measure phagocytosis in macrophages with genetically or pharmacologically varied cholesterol and 25HC, to compare and quantify the ingestion of different bacteria, fungi and particles. This project will also address the link between cholesterol synthesis, its storage in li ....Cholesterol and Hydroxycholesterol Shaping Phagocytosis. Reports now show that membrane cholesterol and 25-hydroxycholesterol (25HC) are required for immune cells to ingest and kill pathogens by phagocytosis. This project will measure phagocytosis in macrophages with genetically or pharmacologically varied cholesterol and 25HC, to compare and quantify the ingestion of different bacteria, fungi and particles. This project will also address the link between cholesterol synthesis, its storage in lipid bodies and its availability for phagocytosis, based on preliminary data showing such defects in the staggerer mouse model. Notably, cholesterol dysregulation is now a prevalent condition in society and our results will reveal at a fundamental, molecular level how this might compromise immune defenses.Read moreRead less
Function and regulation of the Schlafen gene family: novel regulators of blood cell proliferation and function. The immediate outcomes of the proposed research will be in fundamental knowledge and understanding of important cellular and biological processes in which the Schlafen genes are involved. In particular, Schlafen genes are likely to play a role in inflammatory responses and in blood cell growth. These process clearly have relevance to a range of major human (and animal) diseases includ ....Function and regulation of the Schlafen gene family: novel regulators of blood cell proliferation and function. The immediate outcomes of the proposed research will be in fundamental knowledge and understanding of important cellular and biological processes in which the Schlafen genes are involved. In particular, Schlafen genes are likely to play a role in inflammatory responses and in blood cell growth. These process clearly have relevance to a range of major human (and animal) diseases including infectious disease, auto-immune disease and leukaemia, and thus a long-term outcome may be improved treatments for such disease. 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
New guardians of the mucosa: Molecular characterisation of M cell biology. We aim to completely define the cellular and molecular biology of gut and lung M cells for the first time. We will elucidate how they develop, are regulated and function at a molecular level, and how M cells maintain normal gut and lung tissues and induce immune responses to protect against microbial challenges. In the future, the new insights will be essential pre-requisites for the development of mucosal-based intervent ....New guardians of the mucosa: Molecular characterisation of M cell biology. We aim to completely define the cellular and molecular biology of gut and lung M cells for the first time. We will elucidate how they develop, are regulated and function at a molecular level, and how M cells maintain normal gut and lung tissues and induce immune responses to protect against microbial challenges. In the future, the new insights will be essential pre-requisites for the development of mucosal-based interventions and vaccines that protect the gut and lung from infectious and inflammatory issues. The harnessing of effective immune responses to control such challenges, are of enormous fundamental and long-standing biological interest, and are amongst the most important areas of current scientific research.Read moreRead less
Structure and function of novel macrophage proteins using high throughput crystallography. We will combine the cutting edge technologies of microarray analysis and high throughput crystallography in an innovative approach to study the structure and function of important and uncharacterised macrophage proteins. Our strategy for targeting novel macrophage proteins will maximise the success rate of structure determination, while at the same time focusing our efforts on proteins that are important i ....Structure and function of novel macrophage proteins using high throughput crystallography. We will combine the cutting edge technologies of microarray analysis and high throughput crystallography in an innovative approach to study the structure and function of important and uncharacterised macrophage proteins. Our strategy for targeting novel macrophage proteins will maximise the success rate of structure determination, while at the same time focusing our efforts on proteins that are important in macrophage biology. Structures of the novel proteins will underpin functional analysis at a molecular level and could represent a basis for inhibitor design should the proteins ultimately be shown to be therapeutic targets.Read moreRead less
Moonlighting from sugar to metal. This project intends to use integrated genetics, biochemistry and omics to decipher the roles of the highly conserved OST3 proteins, which have been implicated in the disparate functions of regulating protein glycosylation and transporting magnesium. The project plans to detail the role of OST3 proteins in regulating mammalian glycosylation and reconstruct the vertebrate co-evolutionary trajectory of OST3 protein–substrate interactions. It also aims to identify ....Moonlighting from sugar to metal. This project intends to use integrated genetics, biochemistry and omics to decipher the roles of the highly conserved OST3 proteins, which have been implicated in the disparate functions of regulating protein glycosylation and transporting magnesium. The project plans to detail the role of OST3 proteins in regulating mammalian glycosylation and reconstruct the vertebrate co-evolutionary trajectory of OST3 protein–substrate interactions. It also aims to identify and characterise the regulation, mechanisms and metabolic consequences of OST3 protein-mediated magnesium transport. These outcomes may provide insights into eukaryotic biology, and allow advances in engineered systems for glycoprotein production and modulating cellular metabolism with potential research and therapeutic utility.Read moreRead less
A molecular investigation into the naïve T cell repertoire. This project aims to interrogate the relationship between T cell receptor (TCR) recognition modes and T cell recruitment and activation. CD8+ T cells are important for adaptive immunity. Their recognition, via TCR, of peptides bound to MHC class I antigen-presenting molecules (pMHCI), initiates a signalling cascade which activates T cells effector functions. All structural information on TCR recognition of pMHCI is based on TCRs prevale ....A molecular investigation into the naïve T cell repertoire. This project aims to interrogate the relationship between T cell receptor (TCR) recognition modes and T cell recruitment and activation. CD8+ T cells are important for adaptive immunity. Their recognition, via TCR, of peptides bound to MHC class I antigen-presenting molecules (pMHCI), initiates a signalling cascade which activates T cells effector functions. All structural information on TCR recognition of pMHCI is based on TCRs prevalent in immune responses, and all recognise pMHCI using a conserved orientation. This project aims to use this observation to study the relationship between TCR recognition modes and T cell recruitment and activation.Read moreRead less
Noncanonical epitope recognition by CD8+ T lymphocytes. This proposed research program will provide significant fundamental insight in the areas of immunology and vaccine design. Vaccines for many diseases remain elusive, and this project aims to improve our understanding of the precise regions within pathogens that are the targets for the killer T cells of the immune system. These regions, called epitopes, are likely to be key ingredients in many future vaccines. Although immunologists have gat ....Noncanonical epitope recognition by CD8+ T lymphocytes. This proposed research program will provide significant fundamental insight in the areas of immunology and vaccine design. Vaccines for many diseases remain elusive, and this project aims to improve our understanding of the precise regions within pathogens that are the targets for the killer T cells of the immune system. These regions, called epitopes, are likely to be key ingredients in many future vaccines. Although immunologists have gathered much information about such epitopes, recent studies have shown that some unexpected regions of pathogens are targets for killer T cells. This project will break new ground by utilising unbiased procedures to assess the relative contribution of these noncanonical epitopes to immunity.Read moreRead less
A role for the actin cytoskeleton in suppression of prion pathology in yeast. The discovery that proteins as well as DNA carry genetic information is leading to a re-think of the mechanisms that program cell behaviour. There is a link between proteins that suppress cancer and protein inheritance. This project explores how heritable changes in proteins control cell behaviour and the implications of this for the origin of cancer.