A humanised sensory neuron high-throughput screening platform . Sensory neurons are responsible for converting external stimuli such as touch or temperature into graded electrical signals that allow us to interact with the world around us. However, unlike other cell types, sensory neurons cannot proliferate and thus must be removed from human cadavers, or animals, in order to study their pharmacology and function. This limits our ability to understand neuronal signalling pathways. This project a ....A humanised sensory neuron high-throughput screening platform . Sensory neurons are responsible for converting external stimuli such as touch or temperature into graded electrical signals that allow us to interact with the world around us. However, unlike other cell types, sensory neurons cannot proliferate and thus must be removed from human cadavers, or animals, in order to study their pharmacology and function. This limits our ability to understand neuronal signalling pathways. This project aims to use sensory neurons derived from human stem cells to develop and optimise assays that can be used to study the pharmacology and function of human sensory neurons in vitro. This enhances access to critical model systems and technology platforms and removes the need for isolation of cells from cadavers. Read moreRead less
Regulation of cell proliferation and survival by the ubiquitin system. This project aims to investigate how the fundamental processes of cell division and cell death are controlled at the molecular level by protein degradation enzymes (known as ubiquitin ligases), and how these regulate cellular homeostasis. Using interdisciplinary approaches incorporating proteomics, biochemistry, and molecular cell biology, this project seeks to delineate the components of signalling pathways implicated in the ....Regulation of cell proliferation and survival by the ubiquitin system. This project aims to investigate how the fundamental processes of cell division and cell death are controlled at the molecular level by protein degradation enzymes (known as ubiquitin ligases), and how these regulate cellular homeostasis. Using interdisciplinary approaches incorporating proteomics, biochemistry, and molecular cell biology, this project seeks to delineate the components of signalling pathways implicated in the degradation of proteins implicated in cell division and cell death. Expected outcomes include an increased understanding of how proteins are specifically selected for degradation. Protein degradation pathways operate with remarkable selectivity and this work is expected to illuminate the mechanisms of substrate targeting. The biochemical approaches will provide insight and impact in the areas of cell signaling, organelle biology and cell biology.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
Decoding the spatiotemporal control of DNA replication and repair. DNA replication is the fundamental mechanism of genetic inheritance and essential for all cellular life. This project aims to inform our understanding of how human cells coordinate the DNA replication machinery in time and space to accurately copy the human genome. By applying multiple innovative approaches and employing an interdisciplinary research team, this project is anticipated to generate new knowledge that explains how th ....Decoding the spatiotemporal control of DNA replication and repair. DNA replication is the fundamental mechanism of genetic inheritance and essential for all cellular life. This project aims to inform our understanding of how human cells coordinate the DNA replication machinery in time and space to accurately copy the human genome. By applying multiple innovative approaches and employing an interdisciplinary research team, this project is anticipated to generate new knowledge that explains how the human genome is replicated. This knowledge is expected to generate research publications of high quality and provide economic benefits, such as unlocking new potentially patentable DNA technologies. 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
RhoA signaling: the nanoscale mechanisms of mechanochemical regulation. This project aims to elucidate a new paradigm for regulating cell signals at the nanoscale level. Cell signalling involves the coordination of multi-molecular networks at the plasma membrane, the interface between the cell and its external environment. These are often thought to involve the assembly of multimolecular complexes through the action of protein scaffolds. This project will focus on how the contractile regulator, ....RhoA signaling: the nanoscale mechanisms of mechanochemical regulation. This project aims to elucidate a new paradigm for regulating cell signals at the nanoscale level. Cell signalling involves the coordination of multi-molecular networks at the plasma membrane, the interface between the cell and its external environment. These are often thought to involve the assembly of multimolecular complexes through the action of protein scaffolds. This project will focus on how the contractile regulator, anillin, controls RhoA signalling by kinetic regulation. In particular, how nanoscale clustering of anillin by the dynamic actomyosin cytoskeleton modulates RhoA signalling for contractility and tissue homeostasis. The outcomes of this project are first and foremost fundamental understanding of how cells communicate with one another.Read moreRead less
Discovery Early Career Researcher Award - Grant ID: DE140100558
Funder
Australian Research Council
Funding Amount
$389,220.00
Summary
Caveolae as structural mechanosensors: a link between the intra and extracellular environments? How cells perceive and respond to mechanical cues are fundamental questions in cellular biology. Caveolae are invaginations of the plasma membrane which flatten into the bulk membrane in response to increased membrane tension. This project aims to validate this response at the molecular level in a physiological context. Specifically, the project will investigate how the caveola response coordinates wi ....Caveolae as structural mechanosensors: a link between the intra and extracellular environments? How cells perceive and respond to mechanical cues are fundamental questions in cellular biology. Caveolae are invaginations of the plasma membrane which flatten into the bulk membrane in response to increased membrane tension. This project aims to validate this response at the molecular level in a physiological context. Specifically, the project will investigate how the caveola response coordinates with the extracellular matrix as well as study the fate of caveolar proteins released from caveolae. Besides the establishment of new methodologies, the findings will highlight the role of caveolae in the short and long term adaptive responses to mechanical cues and enhance understanding of how cells integrate the extracellular and intracellular environments.Read moreRead less
Defining mechanisms behind the formation of hierarchical vascular networks. Blood vessels form complex branched networks composed of arteries, capillaries and veins. The development and maintenance of different vessel systems (arteries and veins) is dependent on cell adherence properties within each vessel, yet how these are established and maintained remains unknown. This project aims to analyse the differences in junctional dynamics between sprouting arteries and veins, and to identify arteria ....Defining mechanisms behind the formation of hierarchical vascular networks. Blood vessels form complex branched networks composed of arteries, capillaries and veins. The development and maintenance of different vessel systems (arteries and veins) is dependent on cell adherence properties within each vessel, yet how these are established and maintained remains unknown. This project aims to analyse the differences in junctional dynamics between sprouting arteries and veins, and to identify arterial and venous signalling networks that make and maintain vessel identity. This project will reveal how adhesiveness is regulated in order to make a hierarchical, functional vascular network, with implications for engineering of functional, vascularised organs in the biotech sector.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
Discovery Early Career Researcher Award - Grant ID: DE180100524
Funder
Australian Research Council
Funding Amount
$365,057.00
Summary
Manipulating selected inflammatory responses in macrophages. This project aims to define the structural and functional interactions of a new transmembrane adaptor SCIMP. SCIMP has recently been shown to effect the inflammatory pathway. The project outcomes will include the first structure of this unconventional complex. The project will have significant flow on benefits including new knowledge and new protein methodologies for end-users in research and industry, and ultimately economic impact.