Imaging the T cell signalling machinery . The conversion of external stimuli to the interior of a cell is a fundamental process that underpins many unique facets of biology, including cellular movement, nerve transmission, response to hormones and immune recognition. However, the basic mechanism by which such signals are transmitted across cellular membranes is poorly understood. This proposal will seek to bridge this gap in our knowledge by imaging a multi-component “decision-making” machine th ....Imaging the T cell signalling machinery . The conversion of external stimuli to the interior of a cell is a fundamental process that underpins many unique facets of biology, including cellular movement, nerve transmission, response to hormones and immune recognition. However, the basic mechanism by which such signals are transmitted across cellular membranes is poorly understood. This proposal will seek to bridge this gap in our knowledge by imaging a multi-component “decision-making” machine that controls whether or not the immune system becomes activated. Accordingly, this proposal will provide far-reaching insights into molecular events that are of central importance to the initiation of immunity, and thus will ultimately benefit society via improvements in health.Read moreRead less
Intramembrane Mechanics of Immunoreceptor Signalling. The cells of the immune system constantly survey the body for markers of injury and infection through molecular sensors that are responsive to the presence of pathogens, tumours and damaged cells. The goal of this project is to understand how the mechanical action of these molecular sensors direct the transmission of information to the cell interior.
Exceptions Prove the Rule: How Antigen Recognition Drives T cell Activation. CD8+ T cells are immune cells that are critical for the adaptive immune response, which is central to immune function in vertebrates. CD8+ T cells mediate their effector functions only after activation, which occurs via T cell receptor (TCR) recognition of foreign antigens. Here, unique reagents and sophisticated technologies will be used to define precisely how the nature of TCR-antigen recognition impacts on T cell ac ....Exceptions Prove the Rule: How Antigen Recognition Drives T cell Activation. CD8+ T cells are immune cells that are critical for the adaptive immune response, which is central to immune function in vertebrates. CD8+ T cells mediate their effector functions only after activation, which occurs via T cell receptor (TCR) recognition of foreign antigens. Here, unique reagents and sophisticated technologies will be used to define precisely how the nature of TCR-antigen recognition impacts on T cell activation and effector function. This work builds on an earlier identification of an entirely novel mode of TCR-antigen recognition, and its success will establish novel paradigms in T cell biology and represent a key advance in knowledge in the life sciences.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.
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
Molecular and cellular mechanisms of action of novel plant guanylyl cyclase enzymes - a new class of overlapping dual-domain molecules. A group of highly unusual catalytic molecules in plants has been identified. The mechanisms of action of these molecules will be studied in this project to learn their role in regulating plant growth in changing climates. The results will reveal how these molecules function and also provide new insights for the development of multi-functional artificial molecule ....Molecular and cellular mechanisms of action of novel plant guanylyl cyclase enzymes - a new class of overlapping dual-domain molecules. A group of highly unusual catalytic molecules in plants has been identified. The mechanisms of action of these molecules will be studied in this project to learn their role in regulating plant growth in changing climates. The results will reveal how these molecules function and also provide new insights for the development of multi-functional artificial molecules.Read moreRead less
Phosphoinositide regulation of lysosome reformation during autophagy. This project aims to investigate a new critical step in the autophagy pathway, autophagic lysosome reformation, a fundamental, evolutionarily conserved mechanism for cellular homeostasis. By combining gene function studies with advanced cellular imaging techniques, this project will investigate the dynamic membrane changes that drive this lysosome recycling pathway and how it is regulated by a hierarchical succession of specif ....Phosphoinositide regulation of lysosome reformation during autophagy. This project aims to investigate a new critical step in the autophagy pathway, autophagic lysosome reformation, a fundamental, evolutionarily conserved mechanism for cellular homeostasis. By combining gene function studies with advanced cellular imaging techniques, this project will investigate the dynamic membrane changes that drive this lysosome recycling pathway and how it is regulated by a hierarchical succession of specific enzymes. The expected outcome will be to re-define the archetypical autophagy pathway and characterise novel mechanisms by which it is controlled. This project will reveal new fundamental biological processes, and act as a framework for developing new imaging modalities and tools for studying autophagy.Read moreRead less
Mechanisms of itch - from endosomal signalling to neural circuits. This project aims to investigate the cellular and circuit mechanisms of itch transmission in the spinal cord by defining the activation and propagation of itch-specific signals. This project expects to generate new knowledge in the area of neuronal signalling and circuitry using novel electrophysiological approaches that target and manipulate specific nerves and cellular components. The project will characterise signalling within ....Mechanisms of itch - from endosomal signalling to neural circuits. This project aims to investigate the cellular and circuit mechanisms of itch transmission in the spinal cord by defining the activation and propagation of itch-specific signals. This project expects to generate new knowledge in the area of neuronal signalling and circuitry using novel electrophysiological approaches that target and manipulate specific nerves and cellular components. The project will characterise signalling within specific spinal subcircuits in order to understand the mechanisms of receptor activation and signalling, and investigate how circuit activity is regulated. This project expects to advance fundamental understanding of itch signalling in the nervous system and provide avenues for future therapeutics.Read moreRead less
Metabolite regulation of mitochondrial fission. This project aims to understand how the function and health of mitochondria – the energy producing structures in cells - are controlled by fat molecules. The project expects to integrate cutting edge techniques and instrumentation to generate new knowledge of how fat molecules interact with, and influence, enzymes that control how cells maintain their mitochondria in response to nutrient state. An anticipated goal is to define a fingerprint for enz ....Metabolite regulation of mitochondrial fission. This project aims to understand how the function and health of mitochondria – the energy producing structures in cells - are controlled by fat molecules. The project expects to integrate cutting edge techniques and instrumentation to generate new knowledge of how fat molecules interact with, and influence, enzymes that control how cells maintain their mitochondria in response to nutrient state. An anticipated goal is to define a fingerprint for enzymes regulated by fat molecules that will be of great interest to researchers across many branches of life sciences. Expected outcomes and benefits will be deeper understanding of fat molecules as nutrient signalling metabolites, and how they influence cell metabolism, growth and development.Read moreRead less
Systems-level characterization of scaffold protein signalling networks. The PEAK family of cell signalling scaffolds regulate cellular responses critical for normal development and physiology. This project will adopt a ‘holistic’ approach to characterizing their mechanism and function, integrating experimental and mathematical approaches and developing predictive computational models. It aims to generate fundamental new knowledge in cell, computational and synthetic biology with broad relevance ....Systems-level characterization of scaffold protein signalling networks. The PEAK family of cell signalling scaffolds regulate cellular responses critical for normal development and physiology. This project will adopt a ‘holistic’ approach to characterizing their mechanism and function, integrating experimental and mathematical approaches and developing predictive computational models. It aims to generate fundamental new knowledge in cell, computational and synthetic biology with broad relevance that will foster establishment of new international linkages. This research will also identify strategies for engineering novel scaffolds that re-program cellular behaviour towards specific, applied outcomes, with potential benefit for the fields of synthetic biology, bioengineering and biotechnology.Read moreRead less